RESUMEN
OBJECTIVES: As many disparities in the clinical use of HIV DNA sequencing are observed, a DELPHI-type consensus was initiated in France to homogenize use, techniques and interpretation of results. METHODS: Based on a literature review and clinical experience, a steering committee (SC) of eight virologists and one infectious disease specialist formulated statements. Statements were submitted to an independent and anonymous electronic vote of virologists and HIV clinicians in France, between October 2022 and December 2022. RESULTS: The SC developed 20 statements grouped into six categories: clinical situations for the use of HIV DNA genotyping; techniques for performing HIV DNA genotyping; consideration of apolipoprotein B mRNA editing enzyme (APOBEC) mutations; genotyping results reporting; recycling of antiretrovirals; and availability of HIV DNA genotyping tests and delays. Twenty-one virologists and 47 clinicians participated in two voting rounds and 18/20 (90%) assertions reached a 'strong' consensus. For example, that prior genotyping on HIV DNA is useful for clinical decision-making when considering switching to some long-acting regimens or to reduce the number of antiretroviral agents in virologically suppressed patients for whom RNA data are unavailable/not exploitable/not sufficiently informative. Two statements achieved no consensus: reporting any detected viral minority population for discussion in multidisciplinary meetings (virologists), and possible risk of virological failure when using a second-generation InSTI plus lamivudine or emtricitabine regimen in patients with undetectable viral load within ≥1â year and in the presence of a documented M184V mutation within the last 5â years (clinicians). CONCLUSIONS: This DELPHI-type consensus will facilitate the strengthening and harmonization of good practice when performing HIV DNA sequencing.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , Consenso , ADN/uso terapéutico , Genotipo , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológicoRESUMEN
BACKGROUND: Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy. METHODS: The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24, by the FDA snapshot algorithm. RESULTS: Of 100 participants 91% maintained viral suppression (95% CI: 83.6-95.8) at week 24 and 89% (81.2-94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48 weeks, 7 AEs of grade 3-4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48 weeks, total cholesterol (p = 0.023) and LDL-cholesterol (p = 0.009) decreased, lifestyle and ease subscale significantly improved (p = 0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 (p = 0.007). CONCLUSION: RAL 1200 mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes. TRIAL REGISTRATION: Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13.
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Infecciones por VIH , Seropositividad para VIH , VIH-1 , Adulto , Infecciones por VIH/tratamiento farmacológico , Humanos , Calidad de Vida , Raltegravir Potásico/efectos adversos , Resultado del Tratamiento , Carga ViralRESUMEN
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
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
The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P = 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.
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Antivirales/farmacología , Farmacorresistencia Viral , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/virología , Inhibidores de Proteasas/farmacología , Adulto , Anciano , Antivirales/uso terapéutico , Femenino , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación Missense , Oligopéptidos/farmacología , Oligopéptidos/uso terapéutico , Prolina/análogos & derivados , Prolina/farmacología , Prolina/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Estudios Retrospectivos , Ribavirina/uso terapéutico , Resultado del Tratamiento , Proteínas no Estructurales Virales/genéticaRESUMEN
Hepatitis C virus (HCV) protease inhibitor resistance-associated substitutions are selected during triple-therapy breakthrough. This multicenter quality control study evaluated the expertise of 23 French laboratories in HCV protease inhibitor resistance genotyping. A panel of 12 well-defined blinded samples comprising two wild-type HCV strains, nine transcripts from synthetic NS3 mutant samples or from clinical strains, and one HCV RNA-negative sample was provided to the participating laboratories. The results showed that any laboratory with expertise in sequencing techniques should be able to provide reliable HCV protease inhibitor resistance genotyping. Only a 0.7% error rate was reported for the amino acid sites studied. The accuracy of substitution identification ranged from 75% to 100%, depending on the laboratory. Incorrect results were mainly related to the methodology used. The results could be improved by changing the primers and modifying the process in order to avoid cross-contamination. This study underlines the value of quality control programs for viral resistance genotyping, which is required prior to launching observational collaborative multicenter studies on HCV resistance to direct-acting antiviral agents.
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Antivirales/farmacología , Farmacorresistencia Viral/genética , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/genética , Secuencia de Aminoácidos , Antivirales/química , Secuencia de Bases , Genotipo , Hepacivirus/enzimología , Mutación , Inhibidores de Proteasas/química , Control de Calidad , Análisis de Secuencia de ADNRESUMEN
Beyond virological suppression and immunologic recovery, the objective of long-term antiretroviral therapy is to suppress maximally viremia and to control for persistent immune activation. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens are associated with lower residual viremia. The objective of the study was to evaluate the impact of long term NNRTI-containing treatment on residual viremia and on monocyte activation in a cohort of patients infected with HIV-1. To identify factors associated with residual viremia, adult patients infected with HIV on nevirapine or efavirenz-based therapy with viral load <50 copies/ml for >6 months were included. Residual plasma viremia was quantified using an adapted Cobas/Taqman HIV-1 assay. Viral loads with no detected signal were considered as <1 copy/ml. Monocyte activation was evaluated by quantitation of plasma sCD14 by ELISA assay at the time of residual viremia measurement. Logistic regression was used to determine factors associated with residual viremia <1 copy/ml. In this cohort of 421 patients on long-term NNRTI regimen, three quarters had a residual viremia <1 copy/ml. In multivariate analysis, duration of plasma viral load below 50 copies/ml was the only factor associated with residual viremia <1 copy/ml. Soluble CD14 was in the normal range although treatment with nevirapine was associated with a significant lower level of sCD14 compared to efavirenz. Residual viremia <1 copy/ml was frequent in this cohort of patients with long term virological control and confirmed the results of previous studies. Apart from its antiviral effect, nevirapine as well as efavirenz could decrease monocyte activation.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Receptores de Lipopolisacáridos/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Viremia , Adulto , Alquinos , Benzoxazinas/uso terapéutico , Estudios de Cohortes , Estudios Transversales , Ciclopropanos , Ensayo de Inmunoadsorción Enzimática , Femenino , Infecciones por VIH/inmunología , Humanos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Nevirapina/uso terapéutico , Carga ViralRESUMEN
INTRODUCTION: Hepatitis B is a major cause of death in patients with HIV who usually receive drugs active against hepatitis B virus (HBV). The variability of HBV DNA over time has been little studied. Recombination between different HBV genotypes has been described in many cross-sectional studies, but the frequency of intergenotypic and intragenotypic recombinations in individual patients is unknown. METHODS: 32 HIV-positive and 11 HIV-negative patients who remained HBV viraemic despite antiviral therapy for at least 1 year were studied. Genotyping was based on line probe assays and genotype-specific PCR. The variability of HBV DNA over time was examined with restriction length and single-strand conformational polymorphism (RFLP-SSCP). HBV DNA sequences obtained by cloning a 2800 bp PCR fragment were analysed for phylogenetic parameters (diversity and selection pressure) and recombination was detected with RDP3 software. RESULTS: Large fragments of HBV DNA could be amplified at two different time points in 33 patients. Marked quasi-species modifications occurred in 14 patients. In seven of these patients and in one patient with no change detectable by RFLP-SSCP, the 2800 bp fragment was cloned at two time points at least. In four (57%) of these seven patients, various intergenotypic or intragenotypic recombination events were detected between subvariants present in the initial quasi-species. Recombinant fragments mostly harboured antiviral resistance determinants and reflected a large increase in diversity and in positive selection pressure on the entire HBV quasi-species. CONCLUSIONS: In coinfected patients, HBV DNA recombination events are frequent during antiviral therapy, corresponding to increased positive selection pressure on the HBV quasi-species and to conservation of antiviral resistance mutations. In this population and at the individual level, recombination is a significant source of HBV genetic variability.
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ADN Viral/genética , Infecciones por VIH/genética , VIH/genética , Virus de la Hepatitis B/genética , Hepatitis B/genética , Mutación , Recombinación Genética , Adulto , Estudios Transversales , Femenino , Genotipo , VIH/aislamiento & purificación , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Hepatitis B/complicaciones , Hepatitis B/virología , Virus de la Hepatitis B/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
Many drug-resistance mutations in HIV-1 reverse transcriptase fall within cytotoxic T lymphocytes (CTL) epitopes, but studies of the response to these epitopes in patients with virological failure are lacking. We therefore compared IFN-γ ELISPOT responses to the YV9 epitope (RT181-189) covering the lamivudine resistance mutation, M184V, in HLA-A2(+) antiretroviral treatment (ART)-naive patients (n = 19), to those found in HLA-A2(+) patients with virological failure (n = 15). Ten ART-naive patients had an ELISPOT response to the wild-type epitope that cross-reacted with the mutant epitope. Two patients with virological failure showed a specific response to the 184V mutant epitope. Responses against YV9 were strongly associated (p = 0.005) with the presence of a 177E mutation, and the same tendency was observed in an independent cohort of patients (n = 22). These results indicate that variants in flanking residues may influence CTL responses to conserved subdominant HIV-1 epitopes.
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Farmacorresistencia Viral/genética , Epítopos de Linfocito T/inmunología , Infecciones por VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Fármacos Anti-VIH/inmunología , Células Cultivadas , Ensayo de Immunospot Ligado a Enzimas , Epítopos de Linfocito T/genética , Infecciones por VIH/patología , VIH-1/inmunología , Antígeno HLA-A2/genética , Humanos , Interferón gamma/inmunología , Persona de Mediana Edad , Fenotipo , Linfocitos T Citotóxicos/virologíaRESUMEN
Hepatitis C virus RNA quantification results obtained in 18 laboratories using real-time PCR methods with 10 negative samples and 22 sample dilutions (viral loads of 0.5 to 500 IU/ml) showed a score of correct results of up to 93.5%. However, 55.6% of the laboratories did not follow the recommendations for the interpretation of their results, leading to ambiguous conclusions.
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Técnicas de Apoyo para la Decisión , Hepacivirus/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas , Carga Viral/métodos , Virología/métodos , Virología/normas , Humanos , ARN Viral/sangreRESUMEN
Two quantitative duplex real-time PCR assays were developed for co-amplification of human albumin and cytomegalovirus (CMV) or Epstein Barr virus (EBV) genes after automated extraction on whole blood, and compared two units for expressing viral DNA loads (copies per ml of blood or per 10(6) peripheral blood leukocytes (PBLs)) on 1,138 positive samples. Both PCRs were characterized by high sensitivity, reproducibility, and linear range. Automated extraction by a MagNA Pure LC Instrument was shown to be more efficient when peripheral blood cell count was inferior to 5 x 10(9) PBLs/L. Albumin co-amplification allows the detection of PCR inhibitors and normalization of viral load according to the number of cells calculated in the sample. The two ways of expressing viral load results were highly correlated, but quantitative differences varied in relation to variations of blood cell count. As these two viruses are highly cell associated, viral loads can be underestimated in patients with leucopenia. In the setting of pre-emptive strategies during CMV infection, the units in which results are expressed can influence clinical management, as illustrated in this article.
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Infecciones por Citomegalovirus/terapia , Citomegalovirus/aislamiento & purificación , ADN Viral/sangre , Infecciones por Virus de Epstein-Barr/terapia , Herpesvirus Humano 4/aislamiento & purificación , Reacción en Cadena de la Polimerasa/métodos , Carga Viral , Manejo de Caso , Humanos , Reacción en Cadena de la Polimerasa/normas , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: The aetiology of mycosis fungoides and parapsoriasis (which may be considered as an early stage of mycosis fungoides) remains debated. Previous recent studies have suspected the involvement of viral agents and particularly human herpes viruses (HHV).The aim of the present study was to screen for the presence of HHV-6 and HHV-8 genome in parapsoriasis samples. METHOD: Fifty paraffin-embedded samples from skin biopsies of parapsoriasis were retrospectively collected from archival files in our Dermatology department. Total DNA was extracted from samples using the phenol-chloroform method and the presence of viral genomes was screened using real-time PCR. RESULTS: Forty nine out of the fifty tissue samples of parapsoriasis were interpretable, they were all found negative for HHV-6 and HHV-8. DISCUSSION: This study does not confirm the suspected role of HHV-6 or -8 in parapsoriasis. HHV-8 has been the most studied virus in parapsoriasis and more widely in cutaneous lymphoproliferative diseases and our results are in agreement with most of the studies which found none or few HHV-8 in more advanced stages of cutaneous lymphoproliferative diseases. Concerning HHV-6, our study is the first one investigating the presence of this virus in lesional tissue samples of patients with parapsoriasis. In conclusion, parapsoriasis does not seem to be associated with either HHV-6 or HHV-8.
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Herpesvirus Humano 6/fisiología , Herpesvirus Humano 8/fisiología , Parapsoriasis/fisiopatología , Parapsoriasis/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Micosis Fungoide/fisiopatología , Micosis Fungoide/virología , Estudios Retrospectivos , Piel/patología , Piel/virología , Adulto JovenRESUMEN
The objective was to develop a method of HCV genome sequencing that allowed simultaneous genotyping and NS5A inhibitor resistance profiling. In order to validate the use of a unique RT-PCR for genotypes 1-5, 142 plasma samples from patients infected with HCV were analysed. The NS4B-NS5A partial region was successfully amplified and sequenced in all samples. In parallel, partial NS3 sequences were analyzed obtained for genotyping. Phylogenetic analysis showed concordance of genotypes and subtypes with a bootstrap >95% for each type cluster. NS5A resistance mutations were analyzed using the Geno2pheno [hcv] v0.92 tool and compared to the list of known Resistant Associated Substitutions recently published. In conclusion, this tool allows determination of HCV genotypes, subtypes and identification of NS5A resistance mutations. This single method can be used to detect pre-existing resistance mutations in NS5A before treatment and to check the emergence of resistant viruses while undergoing treatment in major HCV genotypes (G1-5) in the EU and the US.
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Farmacorresistencia Viral/genética , Genotipo , Hepacivirus/genética , Proteínas no Estructurales Virales/genética , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/virología , Humanos , Filogenia , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: The emergence of new strains in RNA viruses is mainly due to mutations or intra and inter-genotype homologous recombination. Non-homologous recombinations may be deleterious and are rarely detected. In previous studies, we identified HCV-1b strains bearing two tandemly repeated V3 regions in the NS5A gene without ORF disruption. This polymorphism may be associated with an unfavorable course of liver disease and possibly involved in liver carcinogenesis. Here we aimed at characterizing the origin of these mutant strains and identifying the evolutionary mechanism on which the V3 duplication relies. METHODS: Direct sequencing of the entire NS5A and E1 genes was performed on 27 mutant strains. Quasispecies analyses in consecutive samples were also performed by cloning and sequencing the NS5A gene for all mutant and wild strains. We analyzed the mutant and wild-type sequence polymorphisms using Bayesian methods to infer the evolutionary history of and the molecular mechanism leading to the duplication-like event. RESULTS: Quasispecies were entirely composed of exclusively mutant or wild-type strains respectively. Mutant quasispecies were found to have been present since contamination and had persisted for at least 10 years. This V3 duplication-like event appears to have resulted from non-homologous recombination between HCV-1b wild-type strains around 100 years ago. The association between increased liver disease severity and these HCV-1b mutants may explain their persistence in chronically infected patients. CONCLUSIONS: These results emphasize the possible consequences of non-homologous recombination in the emergence and severity of new viral diseases.
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Evolución Molecular , Duplicación de Gen , Hepacivirus/genética , Recombinación Genética , Proteínas no Estructurales Virales/genética , Teorema de Bayes , Carcinoma Hepatocelular/virología , Estudios de Cohortes , Sitios Genéticos , Hepatitis C/virología , Interacciones Huésped-Patógeno , Humanos/virología , Neoplasias Hepáticas/virología , Mutación , Filogenia , Polimorfismo Genético , Proteínas del Envoltorio Viral/genéticaRESUMEN
BACKGROUND: Tenofovir DF/FTC/rilpivirine (TDF/FTC/RPV) is a single tablet regimen considered as safe and efficacious in HIV population as long as food requirements, concomitant PPI administration, and compromised antiviral activity have been carefully reviewed. We evaluated TDF/FTC/RPV in a real-life setting with focus on clinical and virological outcomes. METHODS: OCEAN II is a prospective, two-centre observational study. From September 2012 to December 2013, antiretroviral-naive patients with HIV RNA <100,000 copies/mL or wishing to switch for simplification were considered for TDF/FTC/RPV. A systematic review of potential obstacles to TDF/FTC/RPV administration was undertaken during a multidisciplinary meeting, including DNA genotyping to detect archived RPV and/or NRTI-associated resistance mutations if historical RNA resistance testing was lacking. RESULTS: TDF/FTC/RPV was considered for 480 patients, however was not offered to 194 patients (40%), mainly because of risk of insufficient virological efficacy, issues on adherence, patient refusal, meal constraint, or PPI therapy. A total of 286 patients (269 in maintenance; 17 ART-naive) received TDF/FTC/RPV. After a median follow-up of 30 months, virological failure occurred in five patients (1.7%) without the emergence of resistance mutations. Discontinuation of TDF/FTC/RPV occurred in 98 patients, due to adverse events in 43 patients (44%) and non-safety reasons in 55 patients (56%). No grade three-fourth adverse events occurred. CONCLUSION: In this real-life experience, cohort consisting primarily of virologically suppressed patients, TDF/FTC/RPV usually maintained virologic suppression. Discontinuation of therapy because of intolerability was due to mild adverse events. Strict clinical and virological screening probably explained the low rate of virological failure.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/efectos adversos , Combinación de Medicamentos , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/uso terapéutico , ARN Viral/sangre , Respuesta Virológica Sostenida , Comprimidos/efectos adversos , Comprimidos/uso terapéutico , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Real-life effectiveness data of new hepatitis C direct-acting antivirals are now required. The present study aims to assess the rate of sustained viral response (SVR) and virological failure (VF) in patients infected with chronic HCV treated with sofosbuvir (SOF)-based regimens in routine medical practice. METHODS: This observational study included a total of 106 patients infected with HCV genotypes (G)1-4, who initiated SOF-based regimens in 2014. Viral load was followed at baseline, week (W)2, W4, W12 (or W24) and W12 post-treatment. For all VFs, resistance-associated variants (RAVs) were determined at baseline and failure by sequencing of NS5A, NS5B and/or NS3 genes, using the Sanger method. RESULTS: SVR rate was 85% for the whole cohort, 91% for the patients who underwent the full treatment course. The distribution of HCV genotypes was as follows: G1 n=66 (1a=33, 1b=29; 62%), G2 n=8 (8%), G3a n=20 (19%) and G4 n=12 (11%). The main regimens used were SOF+daclatasvir (37%), SOF+ribavirin (33%), SOF+simeprevir (26%) and SOF+ledipasvir (3%). Twenty-five (23%) patients were HIV-coinfected and 1 was HBV-coinfected. Seventy (65%) patients had a prior treatment experience. All VF were relapses (n=9): 3 G1a, 1 G2, 4 G3a and 1 G4, and mutations conferring resistance to NS5A inhibitors were found but none for NS5B polymerase inhibitors. CONCLUSIONS: In a real-life context, the rate of SVR in DAA-treated HCV-infected patients is close to clinical Phase III trial results. RAVs emerged for all patients treated by the anti-NS5A daclatasvir, and persisted several weeks after the end of treatment.
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Antivirales/uso terapéutico , Farmacorresistencia Viral/genética , Hepatitis C Crónica/tratamiento farmacológico , Sofosbuvir/uso terapéutico , Estudios de Cohortes , Quimioterapia Combinada , Hepatitis C Crónica/virología , Humanos , Mutación , Insuficiencia del Tratamiento , Proteínas no Estructurales Virales/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To evaluate the efficacy of salvage regimens containing ritonavir-boosted amprenavir (APV/r) or fosamprenavir (FPV/r) in heavily pretreated protease inhibitor (PI)-experienced HIV-1 patients. METHOD: Evaluation of APV/r- or FPV/r-containing antiretroviral regimens in PI-experienced HIV-1 patients with 2 or more antiretroviral failures. Follow-up continued to 96 weeks with prospective collection of data. RESULTS: 54 episodes (48 on APV/r and 6 on FPV/r) were considered in 45 patients who had received a median of 5 prior antiretroviral regimens (range, 2-13) including a median of 3 PIs (range, 2-4). Median time of treatment at analysis was 72 weeks (range, 12-210). At baseline, plasma viral load (pVL) and CD4 cell count was 67,000 copies/mL and 167 cell/mm(3), respectively. At week 96, the median pVL was < 50 copies/mL and CD4 cell count was 519 cells/mm(3). Proportion of patients with pVL below detection was 62% at week 48 and 61% at week 96. Fifteen patients stopped treatment because of virologic failure; one presented a full resistance profile to APV/r, based on the ANRS 2003 resistance algorithm. Median trough APV plasma concentration 4 weeks after treatment initiation was 1406 ng/mL (range, 452-4321); dose adaptation was required in only 7 patients. CONCLUSION: This study provides long-term follow-up of APV/r and FPV/r in the setting of salvage therapy, showing a high and sustained rate of virologic and immunologic response.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , Organofosfatos/administración & dosificación , Ritonavir/administración & dosificación , Terapia Recuperativa , Sulfonamidas/administración & dosificación , Adulto , Recuento de Linfocito CD4 , Carbamatos , Estudios de Cohortes , Farmacorresistencia Viral Múltiple , Quimioterapia Combinada , Enfuvirtida , Femenino , Estudios de Seguimiento , Furanos , Proteína gp41 de Envoltorio del VIH/administración & dosificación , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/sangre , Humanos , Masculino , Persona de Mediana Edad , Organofosfatos/sangre , Fragmentos de Péptidos/administración & dosificación , Sulfonamidas/sangre , Insuficiencia del Tratamiento , Carga ViralAsunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , Integrasa de VIH/genética , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Mutación , Adenina/análogos & derivados , Adenina/uso terapéutico , Anciano , Alanina , Amidas , Línea Celular , Quimioterapia Combinada , Emtricitabina/uso terapéutico , Células HEK293 , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Células HeLa , Compuestos Heterocíclicos con 3 Anillos , Humanos , Masculino , Piperazinas , Piridonas , Tenofovir/análogos & derivados , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)/ritonavir sparing regimens may be useful to some HIV-infected patients. Nevirapine (NVP) and raltegravir (RAL) are both potent antiretrovirals with good long-term safety profiles. METHODS: We retrospectively identified from our electronic database all patients with HIV RNA<50 copies/ml for >6 months on an NVP-containing regimen and no prior exposure to integrase strand transfer inhibitors who were switched to RAL plus NVP. Data was collected for 36 months or until discontinuation of RAL plus NVP for any reason. RESULTS: A total of 39 patients (30 male) were included in this analysis. Median duration of prior antiretroviral therapy was 14 years (IQR 10-17) and median duration with plasma HIV-1 RNA<50 copies/ml prior to switch was 50 months (IQR 22-96). Switched regimens included mainly a boosted PI (n=24) or tenofovir disoproxil fumarate/emtricitabine (n=12). After switching, the percentages of patients with HIV-1 RNA<50 copies/ml were 87.2% (95% CI 76.7, 97.7) and 82.1% (95% CI 70.0, 94.1) at 6 and 12 months, respectively, in the intent-to-treat-exposed analysis, 97.1% (95% CI 91.6, 100) and 94.1% (95% CI 86.2, 100), respectively, in the per-protocol analysis. All patients with follow-up to month 24 (n=22) or month 36 (n=14) had HIV-1 RNA<50 copies/ml. One virological failure was observed (related to archived non-nucleoside reverse transcriptase inhibitor resistance mutation). During follow-up, no patient experienced Grade 3 or 4 adverse events. Median values of serum creatinine and lipids significantly improved after switch. CONCLUSIONS: In patients with prolonged HIV-1 RNA<50 copies/ml, switching to NVP-RAL combination maintained virological suppression throughout 36 months. This combination deserves further evaluation in patients unable to tolerate NRTI or PI/ritonavir agents.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1 , Nevirapina/uso terapéutico , Pirrolidinonas/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Combinación de Medicamentos , Sustitución de Medicamentos , Femenino , Estudios de Seguimiento , Infecciones por VIH/inmunología , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteasas , Raltegravir Potásico , Estudios Retrospectivos , Inhibidores de la Transcriptasa Inversa , Factores de Riesgo , Resultado del Tratamiento , Carga ViralRESUMEN
INTRODUCTION: With the implementation of combined antiretroviral therapy (cART) and prevention of mother-to-child transmission (MTCT) we observed dramatic decreases in rates of perinatal MTCT of HIV, 0.3% in France in women with plasma viral load (pVL) <50 c/mL at delivery. We describe a case of MTCT which occurred despite virologic suppression of the mother at delivery, the first case in our centre since 2002. DESCRIPTION OF THE CASE: A 26-year-old black woman, Guinea-native, living in France since 2007, was diagnosed with HIV-1 CRF02 in 2008 and lost to follow-up since November 2012 after second delivery (2 female born in March 2009 and October 2012, uninfected). Third pregnancy began in July 2013 and baseline characteristics in September were as follows: week 13 of gestational age (GA), CDC stage A, CD4 317/mm(3), pVL 4.89 log c/mL. cART with abacavir/lamivudine and atazanavir/ritonavir 300/100 mg daily (qd) was introduced. VL decreased to 2.4 log c/mL in 4 weeks and CD4 increased to 456/mm(3). In December, at week 22 of GA, viral rebound at 4.14 log c/mL due to sub-optimal maternal adherence was observed. After counselling, pVL decreased to 1.69 log c/mL in March 2014, at week 35 of GA and 1.3 log c/mL at delivery. As pVL was <400 c/mL at week 36 of GA, vaginal delivery with IV zidovudine was decided. However, because of poor/uncertain maternal adherence to cART, the neonate was treated with a combination of 2 drugs (lamivudine-nevirapine) with the 4-week zidovudine regimen, until the result of delivery pVL. This combination was stopped at day 2 when maternal delivery pVL (22 c/mL) was received and standard oral zidovudine prophylaxis was continued. Infant was tested for HIV infection at baseline (day 3) and found to be HIV-infected (HIV-RNA 60 c/mL) attesting in-utero HIV transmission. On day 15, zidovudine prophylaxis was discontinued and treatment for HIV infection initiated with standard cART according to the French Paediatric Antiretroviral Guidelines. CONCLUSIONS: The risk of HIV acquisition is low in infants born to women who receive standard cART during pregnancy and labour and achieve undetectable VL at delivery. However, transmission remains a hazard, with possibility of in-utero infection during episodes of non-adherence, and the risk of a possible MTCT has to be mentioned to all pregnant women.