RESUMEN
OBJECTIVES: The penetration of antiretroviral drugs into deep compartments, such as the CNS, is a crucial component of strategies towards an HIV cure. This study aimed to determine CSF concentrations of bictegravir, emtricitabine and tenofovir in patients with HIV-related CNS impairment (HCI) enrolled in a real-life observational study. METHODS: Patients with HCI treated by optimized ART, including bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) for at least 1 month were enrolled. Plasma and CSF concentrations were measured by quality control-validated assays (LC-MS/MS). The inhibitory quotient (IQARV) was calculated as the ratio of unbound (bictegravir) or total (emtricitabine and tenofovir) concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir). All numerical variables are expressed as median (range). RESULTS: Twenty-four patients (nine women) were enrolled. The age was 45 (26-68) years. Unbound bictegravir and total emtricitabine and tenofovir CSF concentrations were 4.4 (1.6-9.6), 84.4 (28.6-337.4) and 1.6 (0.7-4.3) ng/mL, respectively. The unbound bictegravir CSF fraction was 34% (15%-82%) versus 0.33% (0.11%-0.92%) in plasma. Three patients had an IQARV above unity for the three antiretrovirals. Factors positively associated with the CSF concentration (unbound for bictegravir) were age and total plasma concentration for the three antiretrovirals. Patients aged over 51 years had higher CSF concentrations (unbound for bictegravir). CONCLUSIONS: We observed low CSF exposure to bictegravir, emtricitabine and tenofovir. These results suggest that BIC/FTC/TAF should be used with caution as first-line treatment for people living with HIV with HCI under 51 years of age.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adenina/uso terapéutico , Anciano , Alanina/uso terapéutico , Amidas , Fármacos Anti-VIH/uso terapéutico , Cromatografía Liquida , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Persona de Mediana Edad , Oxazinas/uso terapéutico , Piperazinas , Piridonas/uso terapéutico , Espectrometría de Masas en Tándem , Tenofovir/uso terapéuticoRESUMEN
BACKGROUND: Successful 2-drug regimens (2DRs) for HIV were made possible by the availability of drugs combining potency and tolerability with a high genetic barrier to resistance. How these deal with resistance development/re-emergence, compared with 3DRs, is thus of paramount importance. MATERIALS AND METHODS: A national survey including patients who were either naive or experienced with any 2DR or 3DR but failing integrase strand transfer inhibitor (INSTI)-containing regimens [two consecutive plasma viral load (VL) values >50 copies/mL] was conducted between 2014 and 2019. Genotypic resistance tests were interpreted with the v28 ANRS algorithm. RESULTS: Overall, 1104 patients failing any INSTI-containing regimen (2DRs, nâ=â207; 3DRs, nâ=â897) were analysed. Five hundred and seventy-seven (52.3%) patients were infected with a B subtype and 527 (47.3%) with non-B subtypes. Overall, 644 (58%) patients showed no known integrase resistance mutations at failure. In multivariate analysis, factors associated with the emergence of at least one integrase mutation were: high VL at failure (ORâ=â1.24 per 1 log10 copies/mL increase); non-B versus B subtype (ORâ=â1.75); low genotypic sensitivity score (GSS) (ORâ=â0.10 for GSSâ=â2 versus GSSâ=â0-0.5); and dolutegravir versus raltegravir (ORâ=â0.46). Although 3DRs versus 2DRs reached statistical significance in univariate analysis (ORâ=â0.59, Pâ=â0.007), the variable is not retained in the final model. CONCLUSIONS: This study is one of the largest studies characterizing integrase resistance in patients failing any INSTI-containing 2DR or 3DR in routine clinical care and reveals factors associated with emergence of integrase resistance that should be taken into consideration in clinical management. No difference was evidenced between patients receiving a 2DR or a 3DR.
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Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Integrasa de VIH/genética , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/uso terapéutico , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Mutación , Piridonas , Raltegravir Potásico/uso terapéuticoRESUMEN
OBJECTIVES: Patients with primary HIV-1 infection (PHI) are a particular population, giving important insight about ongoing evolution of transmitted drug resistance-associated mutation (TDRAM) prevalence, HIV diversity and clustering patterns. We describe these evolutions of PHI patients diagnosed in France from 2014 to 2016. METHODS: A total of 1121 PHI patients were included. TDRAMs were characterized using the 2009 Stanford list and the French ANRS algorithm. Viral subtypes and recent transmission clusters (RTCs) were also determined. RESULTS: Patients were mainly MSM (70%) living in the Paris area (42%). TDRAMs were identified among 10.8% of patients and rose to 18.6% when including etravirine and rilpivirine TDRAMs. Prevalences of PI-, NRTI-, first-generation NNRTI-, second-generation NNRTI- and integrase inhibitor-associated TDRAMs were 2.9%, 5.0%, 4.0%, 9.4% and 5.4%, respectively. In a multivariable analysis, age >40 years and non-R5 tropic viruses were associated with a >2-fold increased risk of TDRAMs. Regarding HIV diversity, subtype B and CRF02_AG (where CRF stands for circulating recombinant form) were the two main lineages (56% and 20%, respectively). CRF02_AG was associated with higher viral load than subtype B (5.83 versus 5.40 log10 copies/mL, P=0.004). We identified 138 RTCs ranging from 2 to 14 patients and including overall 41% from the global population. Patients in RTCs were younger, more frequently born in France and more frequently MSM. CONCLUSIONS: Since 2007, the proportion of TDRAMs has been stable among French PHI patients. Non-B lineages are increasing and may be associated with more virulent CRF02_AG strains. The presence of large RTCs highlights the need for real-time cluster identification to trigger specific prevention action to achieve better control of the epidemic.
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Farmacorresistencia Viral/genética , Monitoreo Epidemiológico , Variación Genética , Infecciones por VIH/epidemiología , VIH-1/genética , Adulto , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Evolución Molecular , Femenino , Francia/epidemiología , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Filogenia , Análisis de Secuencia de ADN , Minorías Sexuales y de Género , Carga Viral , VirulenciaRESUMEN
OBJECTIVES: To describe integrase strand transfer inhibitor (INSTI) resistance profiles and factors associated with resistance in antiretroviral-naive and -experienced patients failing an INSTI-based regimen in clinical practice. METHODS: Data were collected from patients failing an INSTI-containing regimen in a multicentre French study between 2014 and 2017. Failure was defined as two consecutive plasma viral loads (VL) >50 copies/mL. Reverse transcriptase, protease and integrase coding regions were sequenced at baseline and failure. INSTI resistance-associated mutations (RAMs) included in the Agence Nationale de Recherches sur le SIDA genotypic algorithm were investigated. RESULTS: Among the 674 patients, 359 were failing on raltegravir, 154 on elvitegravir and 161 on dolutegravir therapy. Overall, 90% were experienced patients and 389 (58%) patients showed no INSTI RAMs at failure. The strongest factors associated with emergence of at least one INSTI mutation were high VL at failure (OR = 1.2 per 1 log10 copies/mL increase) and low genotypic sensitivity score (GSS) (OR = 0.08 for GSS ≥3 versus GSS = 0-0.5). Patients failing dolutegravir also had significantly fewer INSTI RAMs at failure than patients failing raltegravir (OR = 0.57, P = 0.02) or elvitegravir (OR = 0.45, P = 0.005). Among the 68 patients failing a first-line regimen, 11/41 (27%) patients on raltegravir, 7/18 (39%) on elvitegravir and 0/9 on dolutegravir had viruses with emergent INSTI RAMs at failure. CONCLUSIONS: These results confirmed the robustness of dolutegravir regarding resistance selection in integrase in the case of virological failure in routine clinical care.
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Farmacorresistencia Viral Múltiple/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , VIH-1/efectos de los fármacos , Carga Viral/efectos de los fármacos , Adulto , Femenino , Genotipo , Seropositividad para VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Factores de Riesgo , Análisis de Secuencia de ADN , Insuficiencia del TratamientoRESUMEN
OBJECTIVES: We estimated the prevalence of transmitted-drug-resistance-associated mutations (TDRAMs) in antiretroviral-naive chronically HIV-1-infected patients. PATIENTS AND METHODS: TDRAMs were sought in samples from 660 diagnosed HIV-1-infected individuals in 2015/2016 in 33 HIV clinical centres. Weighted analyses, considering the number of patients followed in each centre, were used to derive representative estimates of the percentage of individuals with TDRAMs. Results were compared with those of the 2010/2011 survey (nâ=â661) using the same methodology. RESULTS: At inclusion, median CD4 cell counts and plasma HIV-1 RNA were 394 and 350/mm3 (Pâ=â0.056) and 4.6 and 4.6 log10 copies/mL (Pâ=â0.360) in the 2010/2011 survey and the 2015/2016 survey, respectively. The frequency of non-B subtypes increased from 42.9% in 2010/2011 to 54.8% in 2015/2016 (P < 0.001), including 23.4% and 30.6% of CRF02_AG (Pâ=â0.004). The prevalence of virus with protease or reverse-transcriptase TDRAMs was 9.0% (95% CIâ=â6.8-11.2) in 2010/2011 and 10.8% (95% CIâ=â8.4-13.2) in 2015/2016 (Pâ=â0.269). No significant increase was observed in integrase inhibitor TDRAMs (6.7% versus 9.2%, Pâ=â0.146). Multivariable analysis showed that men infected with the B subtype were the group with the highest risk of being infected with a resistant virus compared with others (adjusted ORâ=â2.2, 95% CIâ=â1.3-3.9). CONCLUSIONS: In France in 2015/2016, the overall prevalence of TDRAMs was 10.8% and stable compared with 9.0% in the 2010/2011 survey. Non-B subtypes dramatically increased after 2010. Men infected with B subtype were the group with the highest risk of being infected with a resistant virus, highlighting the need to re-emphasize safe sex messages.
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Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/transmisión , VIH-1/genética , Mutación , Adulto , Recuento de Linfocito CD4 , Enfermedad Crónica/epidemiología , Femenino , Francia/epidemiología , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Seropositividad para VIH/epidemiología , VIH-1/clasificación , VIH-1/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , ARN Viral/sangreRESUMEN
BackgroundEnding the HIV pandemic must involve new tools to rapidly identify and control local outbreaks and prevent the emergence of recombinant strains with epidemiological advantages.AimThis observational study aimed to investigate in France a cluster of HIV-1 cases related to a new circulating recombinant form (CRF). The confirmation this CRF's novelty as well as measures to control its spread are presented.MethodsPhylogenetic analyses of HIV sequences routinely generated for drug resistance genotyping before 2018 in French laboratories were employed to detect the transmission chain. The CRF involved was characterised by almost full-length viral sequencing for six cases. Cases' clinical data were reviewed. Where possible, epidemiological information was collected with a questionnaire.ResultsThe transmission cluster comprised 49 cases, mostly diagnosed in 2016-2017 (n = 37). All were infected with a new CRF, CRF94_cpx. The molecular proximity of this CRF to X4 strains and the high median viraemia, exceeding 5.0 log10 copies/mL, at diagnosis, even in chronic infection, raise concerns of enhanced virulence. Overall, 41 cases were diagnosed in the Ile-de-France region and 45 were men who have sex with men. Among 24 cases with available information, 20 reported finding partners through a geosocial networking app. Prevention activities in the area and population affected were undertaken.ConclusionWe advocate the systematic use of routinely generated HIV molecular data by a dedicated reactive network, to improve and accelerate targeted prevention interventions. Geosocial networking apps can play a role in the spread of outbreaks, but could also deliver local targeted preventive alerts.
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Infecciones por VIH/transmisión , VIH-1/clasificación , VIH-1/genética , Filogenia , Recombinación Genética , Adulto , Análisis por Conglomerados , ADN Viral/genética , Brotes de Enfermedades/prevención & control , Farmacorresistencia Viral/genética , Francia/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , VIH-1/patogenicidad , Humanos , Masculino , Redes Sociales en Línea , Filogeografía , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Minorías Sexuales y de Género/estadística & datos numéricos , Carga Viral , Viremia/virología , Virulencia , Secuenciación Completa del GenomaRESUMEN
Background: Minority resistant variants of human immunodeficiency virus type 1 (HIV-1) could influence the virological response to treatment based on nonnucleoside reverse transcriptase inhibitors (NNRTIs). Data on minority rilpivirine-resistant variants are scarce. This study used next-generation sequencing (NGS) to identify patients harboring minority resistant variants to nucleos(t)ide reverse transcriptase inhibitors and NNRTIs and to assess their influence on the virological response (VR). Methods: All the subjects, 541 HIV-1-infected patients started a first-line regimen containing rilpivirine. VR was defined as a HIV-1 RNA load <50 copies/mL at month 6 with continued suppression at month 12. NGS was performed at baseline (retrospectively) on the 454 GS-FLX platform (Roche). Results: NGS revealed resistance-associated mutations accounting for 1% to <5% of variants in 17.2% of samples, for 5%-20% in 5.7% of samples, and for >20% in 29% of samples. We identified 43 (8.8%) and 36 (7.4%) patients who harbored rilpivirine-resistant variants with a 1% sensitivity threshold according to the French National Agency for Research on AIDS and Viral Hepatitis and Stanford algorithms, respectively. The VR was 96.9% at month 12. Detection of minority rilpivirine resistant variants was not associated with virological failure (VF). Multivariate analysis indicated that VF at month 12 was associated with a CD4 count <250 cells/µL at baseline, a slower decrease in viral load at month 3, and rilpivirine resistance at baseline using the Stanford algorithm with a 20% threshold. Conclusions: Minority resistant variants had no impact on the VR of treatment-naive patients to a rilpivirine-based regimen.
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Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , Rilpivirina/uso terapéutico , Adulto , Farmacorresistencia Viral , Femenino , Variación Genética , Humanos , Masculino , Mutación , Rilpivirina/administración & dosificación , Carga ViralRESUMEN
Objectives: To assess the phenotypic susceptibility of the E157Q polymorphism in HIV-1 integrase (IN) and the virological outcome of patients infected with E157Q-mutated virus initiating an IN inhibitor (INI)-based regimen. Methods: This was a multicentre study assessing IN sequences from INI-naive patients among 17 French HIV clinical centres. E157Q site-directed mutants in pNL4.3 and pCRF02_AG contexts were assessed in a recombinant phenotypic assay. Results: Prevalence of the E157Q polymorphism was 2.7% among 8528 IN sequences from INI-naive patients and its distribution was 1.7%, 5.6% and 2.2% in B, CRF02_AG and various non-B subtypes, respectively. Thirty-nine INI-naive patients with E157Q-mutated virus initiated an INI-based regimen. Among them, 15 had a viral load (VL) <50 copies/mL at initiation and virological suppression was maintained during the first year of follow-up in all but two exhibiting a viral blip. Twenty-four patients had a VL >â50 copies/mL at the time of INI-based regimen initiation. Among them eight were receiving a first-line regimen and the only two patients who did not reach VL <â50 copies/mL at week 24 were receiving elvitegravir. The 16 remaining patients were ART experienced in virological failure with drug-resistant viruses displaying several virological outcomes independently of the genotypic susceptibility score. Phenotypic analyses showed a fold change in EC50 of 0.6, 0.9 and 1.9 for raltegravir, dolutegravir and elvitegravir, respectively, in a subtype B context, and 1.1, 1.9 and 2.4 for raltegravir, dolutegravir and elvitegravir, respectively, in a CRF02_AG context. Conclusions: Assessment of virological response in 39 patients initiating an INI-based regimen with E157Q-mutated virus, in combination with phenotypic analysis, suggests that particular attention should be paid to antiretroviral-naive patients and dolutegravir should be preferentially used in these patients.
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Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Inhibidores de Integrasa VIH/administración & dosificación , Integrasa de VIH/genética , VIH-1/genética , Mutación Missense , Carga Viral , Francia , Frecuencia de los Genes , Genotipo , VIH-1/aislamiento & purificación , Humanos , Prevalencia , Resultado del TratamientoRESUMEN
Background: HIV therapy reduces the CSF HIV RNA viral load (VL) and prevents disorders related to HIV encephalitis. However, these brain disorders may persist in some cases. A large population of antiretroviral-treated patients who had a VL > 1.7 log 10 copies/mL in CSF with detectable or undetectable VL in plasma associated with cognitive impairment was studied, in order to characterize discriminatory factors of these two patient populations. Methods: Blood and CSF samples were collected at the time of neurological disorders for 227 patients in 22 centres in France and 1 centre in Switzerland. Genotypic HIV resistance tests were performed on CSF. The genotypic susceptibility score was calculated according to the last Agence Nationale de Recherche sur le Sida et les hépatites virales Action Coordonnée 11 (ANRS AC11) genotype interpretation algorithm. Results: Among the 227 studied patients with VL > 1.7 log 10 copies/mL in CSF, 195 had VL detectable in plasma [median (IQR) HIV RNA was 3.7 (2.7-4.7) log 10 copies/mL] and 32 had discordant VL in plasma (VL < 1.7 log 10 copies/mL). The CSF VL was lower (median 2.8 versus 4.0 log 10 copies/mL; P < 0.001) and the CD4 cell count was higher (median 476 versus 214 cells/mm 3 ; P < 0.001) in the group of patients with VL < 1.7 log 10 copies/mL in plasma compared with patients with plasma VL > 1.7 log 10 copies/mL. Resistance to antiretrovirals was observed in CSF for the two groups of patients. Conclusions: Fourteen percent of this population of patients with cognitive impairment and detectable VL in CSF had well controlled VL in plasma. Thus, it is important to explore CSF HIV (VL and genotype) even if the HIV VL is controlled in plasma because HIV resistance may be observed.
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Antirretrovirales/uso terapéutico , Líquido Cefalorraquídeo/virología , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Plasma/virología , Carga Viral , Adulto , Femenino , Francia , Genotipo , Técnicas de Genotipaje , Infecciones por VIH/virología , VIH-1/genética , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , SuizaRESUMEN
The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) is a key target for antiviral intervention. The goal of this study was to identify the binding site and unravel the molecular mechanism by which natural flavonoids efficiently inhibit HCV RdRp. Screening identified the flavonol quercetagetin as the most potent inhibitor of HCV RdRp activity. Quercetagetin was found to inhibit RdRp through inhibition of RNA binding to the viral polymerase, a yet unknown antiviral mechanism. X-ray crystallographic structure analysis of the RdRp-quercetagetin complex identified quercetagetin's binding site at the entrance of the RNA template tunnel, confirming its original mode of action. This antiviral mechanism was associated with a high barrier to resistance in both site-directed mutagenesis and long-term selection experiments. In conclusion, we identified a new mechanism for non-nucleoside inhibition of HCV RdRp through inhibition of RNA binding to the enzyme, a mechanism associated with broad genotypic activity and a high barrier to resistance. Our results open the way to new antiviral approaches for HCV and other viruses that use an RdRp based on RNA binding inhibition, that could prove to be useful in human, animal or plant viral infections.
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Antivirales/farmacología , Cromonas/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Antivirales/toxicidad , Línea Celular , Cromonas/química , Cromonas/toxicidad , Farmacorresistencia Viral , Flavonas , Flavonoides/química , Flavonoides/farmacología , Hepacivirus/genética , Hepacivirus/fisiología , Humanos , ARN/metabolismo , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
OBJECTIVES: The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. METHODS: Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. RESULTS: On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P=0.0455) and T215Y (P=0.0455). CONCLUSIONS: In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performed.
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Farmacorresistencia Viral , Infecciones por VIH/virología , VIH-1 , Adulto , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Femenino , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mutación , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/etiología , Carga ViralAsunto(s)
Biotina/uso terapéutico , Hepatitis B/diagnóstico , Hepatitis C/diagnóstico , Inmunoensayo/métodos , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Anticuerpos Antivirales/análisis , Anticuerpos Antivirales/sangre , Artefactos , Proteínas Bacterianas , Biotina/análogos & derivados , Reacciones Falso Negativas , Reacciones Falso Positivas , Hepacivirus , Virus de la Hepatitis B , Humanos , Esclerosis Múltiple Crónica Progresiva/virologíaRESUMEN
OBJECTIVES: As recommended by the French ANRS programme for the surveillance of HIV-1 resistance, we estimated the prevalence of transmitted drug resistance-associated mutations (RAMs) in antiretroviral-naive, chronically HIV-1-infected patients. METHODS: RAMs were sought in samples from 661 newly diagnosed HIV-1-infected patients in 2010/11 at 36 HIV clinical care centres. Weighted analyses were used to derive representative estimates of the percentage of patients with RAMs. RESULTS: At patient inclusion, the prevalence of virus with protease (PR) or reverse transcriptase (RT) RAMs was 9.0% (95% CI 6.8%-11.2%). No integrase RAMs were observed. The prevalences of protease inhibitor, nucleoside RT inhibitor and non-nucleoside RT inhibitor RAMs were 1.8%, 6.2% and 2.4%, respectively. Resistance to one, two and three classes of antiretroviral agent was observed in 7.9%, 0.9% and 0.2% of patients, respectively. The frequency of RAMs was higher in patients infected with B compared with non-B subtype virus (11.9% versus 5.1%, P = 0.003). Baseline characteristics (gender, age, country of transmission, CD4 cell count and viral load) were not associated with the prevalence of transmitted RAMs. However, men having sex with men (MSM) were more frequently infected with resistant virus than were other transmission groups (12.5% versus 5.8%, P = 0.003). Compared with the 2006/07 survey, the overall prevalence of resistance remained stable. However, a significant decrease in the frequency of virus with PR RAMs was observed in 2010/11 compared with the 2006/07 survey (1.8% versus 5.0%, P = 0.003). CONCLUSIONS: In France in 2010/11, the global prevalence of transmitted drug-resistant variants was 9.0%, and the prevalence was stable compared with the 2006/07 survey. MSM and B subtype-infected patients are the groups with a higher prevalence of drug resistance.
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Transmisión de Enfermedad Infecciosa , Farmacorresistencia Viral , Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , VIH-1/efectos de los fármacos , Adolescente , Adulto , Anciano , Femenino , Francia/epidemiología , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Mutación , Prevalencia , ARN Viral/genética , Vigilancia de Guardia , Adulto JovenRESUMEN
BACKGROUND: Chronic hepatitis B (CHB) is a clinical concern in human immunodeficiency virus (HIV)-infected individuals due to substantial prevalence, difficulties to treat, and severe liver disease outcome. A large nationwide cross-sectional multicentre analysis of HIV-HBV co-infected patients was designed to describe and identify parameters associated with virological and clinical outcome of CHB in HIV-infected individuals with detectable HBV viremia. METHODS: A multicenter collaborative cross-sectional study was launched in 19 French University hospitals distributed through the country. From January to December 2007, HBV load, genotype, clinical and epidemiological characteristics of 223 HBV-HIV co-infected patients with an HBV replication over 1000 IU/mL were investigated. RESULTS: Patients were mostly male (82%, mean age 42 years). Genotype distribution (A 52%; E 23.3%; D 16.1%) was linked to risk factors, geographic origin, and co-infection with other hepatitis viruses. This genotypic pattern highlights divergent contamination event timelines by HIV and HBV viruses. Most patients (74.7%) under antiretroviral treatment were receiving a drug with anti-HBV activity, including 47% receiving TDF. Genotypic lamivudine-resistance detected in 26% of the patients was linked to duration of lamivudine exposure, age, CD4 count and HIV load. Resistance to adefovir (rtA181T/V) was detected in 2.7% of patients. Advanced liver lesions were observed in 54% of cases and were associated with an older age and lower CD4 counts but not with viral load or genotype. Immune escape HBsAg variants were seldom detected. CONCLUSIONS: Despite the detection of advanced liver lesions in most patients, few were not receiving anti-HBV drugs and for those treated with the most potent anti-HBV drugs, persistent replication suggested non-optimal adherence. Heterogeneity in HBV strains reflects epidemiological differences that may impact liver disease progression. These findings are strong arguments to further optimize clinical management and to promote vaccination in HIV-infected patients.
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Coinfección/virología , Infecciones por VIH/virología , VIH-1/fisiología , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/virología , Adulto , Anticuerpos Antivirales/inmunología , Coinfección/epidemiología , Coinfección/inmunología , Estudios Transversales , Femenino , Francia/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , VIH-1/genética , VIH-1/aislamiento & purificación , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Carga ViralRESUMEN
BACKGROUND & AIMS: Silymarin is a mixture of flavonolignans extracted from the milk thistle. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Intravenous infusion of silibinin induces dose-dependent reduction of hepatitis C virus (HCV) RNA levels. The aim of this study was to test the principal isomers contained in silymarin preparations for their ability to inhibit HCV enzymatic functions and replication in different models. METHODS: The inhibitory activity of silymarin components was tested in HCV RNA-dependent RNA polymerase and NS3/4A protease enzyme assays. Their ability to inhibit replication of an HCV genotype 1b replicon model and the JFH1 infectious HCV model in cell culture was also studied. RESULTS: Silibinin A, silibinin B, their water-soluble dihydrogen succinate forms and Legalon SIL, a commercially available intravenous preparation of silibinin, inhibited HCV RNA-dependent RNA polymerase function, with inhibitory concentrations 50% of the order of 75-100 microM. Silibinin A and silibinin B also inhibited HCV genotype 1b replicon replication and HCV genotype 2a strain JFH1 replication in cell culture. None of these compounds inhibited HCV protease function. CONCLUSIONS: Silibinin A and silibinin B, as well as Legalon SIL, inhibit HCV replicon and JFH1 replication in cell culture. This effect is at least partly explained by the ability of these compounds to inhibit HCV RNA-dependent RNA polymerase activity. Our results provide a basis for the optimization and subsequent development of members of the Flavonoid family as specific HCV antivirals.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral , Genotipo , Hepacivirus/enzimología , Hepacivirus/genética , Hepacivirus/crecimiento & desarrollo , Humanos , Mutación , ARN Polimerasa Dependiente del ARN/genética , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Silibina , Silimarina/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
The IL-7R alpha-chain and the common gamma-chain (gamma(c)) are both components of IL-7R. Human plasma harbors soluble forms of IL-7R (sIL-7Ralpha and sgamma(c)) that are detected and assayed by Western blotting, showing that the levels of sIL-7Ralpha are higher than the levels of sgamma(c) (47.5 ng/ml and 1.5 ng/ml, respectively). Gel electrophoresis and tandem mass spectrometry used to analyze deglycosylated, affinity-purified protein showed that sIL-7Ralpha is generated through differentially spliced mRNA, not by membrane receptor shedding. Plasma sIL-7Ralpha and sgamma(c) are present as heterocomplexes and sgamma(c) was found to be mainly associated with sIL-7Ralpha. The affinities of two IL-7 binding sites (K(d) = 35 +/- 8 pM and K(d) = 3 +/- 1 nM) were similar to that of the membrane receptor, suggesting that the sIL-7Ralpha/sgamma(c) complex retains high affinity for IL-7. sIL-7Ralpha mRNA is constitutively present among peripheral T lymphocytes and is down-modulated in vitro by IL-7. Chronically HIV-1-infected patients (n = 20) showed no significant (p > 0.714) variation in sgamma(c) levels and a significant (p < 0.0014) 2-fold decrease in plasma sIL-7Ralpha levels compared with those in control healthy individuals. Plasma IL-7 and sIL-7Ralpha levels did not show any obvious relationship.
Asunto(s)
Infecciones por VIH/sangre , Infecciones por VIH/inmunología , VIH-1/inmunología , Subunidad gamma Común de Receptores de Interleucina/sangre , Subunidad gamma Común de Receptores de Interleucina/inmunología , Subunidad alfa del Receptor de Interleucina-7/sangre , Subunidad alfa del Receptor de Interleucina-7/inmunología , Adulto , Empalme Alternativo/genética , Secuencia de Aminoácidos , Secuencia de Bases , Células Cultivadas , Humanos , Subunidad gamma Común de Receptores de Interleucina/genética , Interleucina-7/inmunología , Interleucina-7/metabolismo , Subunidad alfa del Receptor de Interleucina-7/química , Subunidad alfa del Receptor de Interleucina-7/genética , Espectrometría de Masas , Persona de Mediana Edad , Datos de Secuencia Molecular , Unión Proteica , Biosíntesis de Proteínas/genética , ARN Mensajero/genética , SolubilidadRESUMEN
Genotypic algorithms for prediction of HIV-1 coreceptor usage need to be evaluated in a clinical setting. We aimed at studying (i) the correlation of genotypic prediction of coreceptor use in comparison with a phenotypic assay and (ii) the relationship between genotypic prediction of coreceptor use at baseline and the virological response (VR) to a therapy including maraviroc (MVC). Antiretroviral-experienced patients were included in the MVC Expanded Access Program if they had an R5 screening result with Trofile (Monogram Biosciences). V3 loop sequences were determined at screening, and coreceptor use was predicted using 13 genotypic algorithms or combinations of algorithms. Genotypic predictions were compared to Trofile; dual or mixed (D/M) variants were considered as X4 variants. Both genotypic and phenotypic results were obtained for 189 patients at screening, with 54 isolates scored as X4 or D/M and 135 scored as R5 with Trofile. The highest sensitivity (59.3%) for detection of X4 was obtained with the Geno2pheno algorithm, with a false-positive rate set up at 10% (Geno2pheno10). In the 112 patients receiving MVC, a plasma viral RNA load of <50 copies/ml was obtained in 68% of cases at month 6. In multivariate analysis, the prediction of the X4 genotype at baseline with the Geno2pheno10 algorithm including baseline viral load and CD4 nadir was independently associated with a worse VR at months 1 and 3. The baseline weighted genotypic sensitivity score was associated with VR at month 6. There were strong arguments in favor of using genotypic coreceptor use assays for determining which patients would respond to CCR5 antagonist.
Asunto(s)
Ciclohexanos/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/metabolismo , Receptores del VIH/genética , Triazoles/uso terapéutico , Tropismo , Adulto , Antagonistas de los Receptores CCR5 , Ciclohexanos/farmacología , Femenino , Genotipo , Proteína gp120 de Envoltorio del VIH , Inhibidores de Fusión de VIH/farmacología , Infecciones por VIH/virología , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/fisiología , Humanos , Masculino , Maraviroc , Persona de Mediana Edad , Datos de Secuencia Molecular , Fenotipo , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores del VIH/metabolismo , Sensibilidad y Especificidad , Análisis de Secuencia de ADN , Resultado del Tratamiento , Triazoles/farmacologíaRESUMEN
OBJECTIVES: To estimate the prevalence of transmitted drug resistance mutations and non-B subtype circulation in antiretroviral-naive chronically HIV-1-infected patients in France. METHODS: Resistance mutations were sought in samples from 530 newly diagnosed HIV-1-infected patients from October 2006 to March 2007. Protease and reverse transcriptase mutations were identified from the 2007 Stanford Resistance Surveillance list. RESULTS: Reverse transcriptase and protease resistance mutations were determined in 466 patients with duration of seropositivity <5 years. 42% of patients were infected with non-B subtype strains (CRF02 18.3%). The overall prevalence of viruses with protease or reverse transcriptase mutations was 10.6% (95% confidence interval 6.7-16.3). The prevalence of protease inhibitor, nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor resistance-associated mutations was 4.7%, 5.8% and 2.8%, respectively. Frequency of resistance was not different in patients infected with B (9.5%) and non-B (CRF02 7.8% and other 11.2%) subtypes. Baseline characteristics such as gender, age, transmission group, country of transmission, disease stage, CD4 counts and viral load were not associated with the prevalence of transmitted drug resistance. CONCLUSIONS: In France in 2006/2007, the prevalence of transmitted drug-resistant variants was 10.6%. Prevalence of transmitted drug resistance was comparable in B and non-B subtypes. Prevalence of non-B subtypes is still rising.
Asunto(s)
Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral/genética , Infecciones por VIH/transmisión , VIH-1/efectos de los fármacos , Mutación , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/uso terapéutico , Enfermedad Crónica , Femenino , Francia/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , Seropositividad para VIH/tratamiento farmacológico , Seropositividad para VIH/epidemiología , Seropositividad para VIH/transmisión , Seropositividad para VIH/virología , VIH-1/clasificación , VIH-1/enzimología , VIH-1/genética , Humanos , Masculino , Prevalencia , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
UNLABELLED: In patients with hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil administration selects variants bearing reverse transcriptase rtN236T and/or rtA181V/T substitutions in 29% of cases after 5 years. The aim of this study was to characterize the dynamics of adefovir-resistant variant populations during adefovir monotherapy in order to better understand the molecular mechanisms underlying hepatitis B virus resistance to this class of nucleotide analogues. Patients included in a 240-week clinical trial of adefovir monotherapy who developed adefovir resistance-associated substitutions were studied. The dynamics of hepatitis B virus populations were analyzed over time, after generating nearly 4,000 full-length reverse transcriptase sequences, and compared with the replication kinetics of the virus during therapy. Whatever the viral kinetics pattern, adefovir resistance was characterized by exclusive detection of a dominant wild-type, adefovir-sensitive variant population at baseline and late and gradual selection by adefovir of several coexisting resistant viral populations, defined by the presence of amino acid substitutions at position rt236, position rt181, or both. The gain in fitness of one or the other of these resistant populations during adefovir administration was never associated with the selection of additional amino acid substitutions in the reverse transcriptase. CONCLUSION: Our results suggest that adefovir administration selects poorly fit preexisting or emerging viral populations with low-level adefovir resistance, which subsequently compete to fill the replication space. Viral kinetics depends on the initial virological response to adefovir. Lamivudine add-on restores some antiviral efficacy, but adefovir-resistant variants remain predominant. Whether these adefovir resistance-associated substitutions may confer cross-resistance to tenofovir in vivo will need to be determined.
Asunto(s)
Adenina/análogos & derivados , Antivirales/uso terapéutico , Farmacorresistencia Viral , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Adenina/farmacología , Adenina/uso terapéutico , Adulto , Antivirales/farmacología , ADN Viral/química , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Organofosfonatos/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Viral load (VL) determination is an essential parameter of the management of patients infected with HIV, HBV or HCV. Many available molecular systems run on a "batch" mode while "random access" systems provide more flexibility. OBJECTIVES: We compared the performance of HIV-1, HCV and HBV quantification assays on the recently developed Abbott Alinity m system to the m2000 RealTime assays. STUDY DESIGN: Plasma specimens sent for viral load determination were prospectively tested on m2000 and Alinity m systems, according to manufacturers' instructions. Additional low and high tittered samples were used to assess reproducibility. RESULTS: Assays concordance was evaluated from 180 samples for HIV-1, 122 for HBV, and 92 for HCV. A good correlation and a linear relation over the quantification range was observed for the three markers (r > 0.974). The Alinity m assays yielded higher results with a mean quantification bias of 0.22 log cp/ml for 75 HIV-1, 0.3 log IU/ml for 79 HBV, and 0.2 log for 35 HCV samples, though results were equivalent within an allowable difference of 0.3-0.4 log. Qualitative discordance was observed for 43/180 HIV results, 10/122 HBV and 7/92 HCV and involved undetectable or low-level VL. CONCLUSION: The Alinity m assays have performance equivalent to m2000. Upon implementation, physicians should be aware of the relative overquantification compared to previous Abbott assays, particularly around clinical decision thresholds. With reduced turnarounds and hands-on times compared to the m2000 system, the Alinity m platform may improve significantly the laboratory workflow efficiency for the benefit of physicians and patients.