RESUMEN
OBJECTIVES: Charaterization of the plasma concentrations of antiretrovirals in a 4-days-a-week maintenance treatment strategy in the ANRS-170-QUATUOR study. METHODS: Patients were randomized in two groups receiving triple therapy taken 4-days-ON and 3-days-OFF (4/7) or continuous therapy (7/7). Plasma antiretroviral concentrations were monitored during the 'ON-treatment period' (Day 3 or 4 of the 4-day treatment block) and the 'OFF-treatment period' (Day 3 of the 3-day drug cessation) for the 4/7 group, or before the daily drug intake for the 7/7 group, until week-48 (W48). After W48, all patients switched to the 4/7 strategy and were followed until W96. RESULTS: W0 measured concentrations were comparable in both groups, except for raltegravir, concentrations of which were higher in the 4/7 group, and were all above the values usually recommended to be effective in therapeutic drug monitoring. Comparison of ON-period median concentrations between the two groups showed a statistical difference for rilpivirine [88 ng/mL (interquartile range (IQR)â=â64-112) for 4/7 arm versus 130 ng/mL (82-160) for 7/7 arm, Pâ<â0.001] and tenofovir [tenofovir disoproxil fumarate: 93 ng/mL (73-135) for 4/7 arm versus 117 ng/mL (83-160) for 7/7 arm, Pâ<â0.001; tenofovir alafenamide: 11 ng/mL (7-15) for 4/7 arm versus 14 ng/mL (11-18) for 7/7 arm, Pâ=â0.001]. Median OFF concentrations were significantly lower (Pâ<â0.001) at the 48 week analysis for all medications except for raltegravir (Pâ=â0.493) and atazanavir (Pâ=â0.105), for which the numbers of patients were very small. CONCLUSIONS: The 4/7-day treatment option led to antiretroviral blood levels close to continuous treatment after the four consecutive days of medication, and to low levels at the end of the non-treatment period.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/sangre , Masculino , Femenino , Adulto , Persona de Mediana Edad , VIH-1/efectos de los fármacos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Monitoreo de Drogas/métodos , Terapia Antirretroviral Altamente Activa , Quimioterapia de Mantención/métodos , Resultado del Tratamiento , Carga Viral , Tenofovir/sangre , Tenofovir/uso terapéutico , Tenofovir/farmacocinética , Tenofovir/administración & dosificaciónRESUMEN
BACKGROUND: Initiating same-day ART for newly HIV-diagnosed individuals reduces secondary HIV transmissions and the risk of them being lost to follow-up between diagnosis and initiation of ART. METHODS: The FAST study was a national, prospective, single-arm study assessing the efficacy, safety and feasibility of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in a same-day initiation model. ART had to be started on the first medical appointment, before any laboratory results were available. Participants completed a self-administered questionnaire at each visit including a HIV anxiety 5-point Likert scale. The primary outcome was the proportion of participants in the ITT population with plasma HIV RNA (pVL)â<â50 copies/mL at Week (W) 24 using the FDA Snapshot algorithm. RESULTS: Overall, 112 participants were included in the ITT population. During follow-up, seven participants discontinued the study drug but remained on the study, and seven others discontinued follow-up. According to FDA Snapshot analysis, at W24 and W48, 90/112, (80.4%; 95% CI: 71.8-87.3) and 95/112 (84.8%; 95% CI: 76.8-90.9) of participants achieved pVLâ<â50 copies/mL, respectively. The protocol-defined virological failure (PDVF, 2 consecutive pVLâ≥â50 copies/mL as of W24) was observed in 11/112 (9.8%) at W24 and 14/112 (12.5%) at W48. No emergent resistance-associated mutation was detected in those with PDVF at W24 and W48. BIC/FTC/TAF was well tolerated through to W48, with a low incidence of grade 3-4 adverse events (15/100 person-years). Patient opinion of same-day treatment initiation and continuing BIC/FTC/TAF was very favourable. CONCLUSIONS: These results suggest that BIC/FTC/TAF is safe, effective and well accepted for same-day initiation.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Infecciones por VIH/tratamiento farmacológico , Emtricitabina/uso terapéutico , Estudios Prospectivos , Adenina , Alanina/uso terapéutico , Piridonas/uso terapéutico , Combinación de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Fármacos Anti-VIH/uso terapéuticoRESUMEN
BACKGROUND: Hypermutated viruses induced by APOBEC3 (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3) proteins comprise some of the defective viruses in the HIV reservoir. Here, we assessed the proportion of APOBEC3-induced defective proviruses in HIV-positive patients before and after receiving dolutegravirâ+âlamivudine dual therapy. METHODS: PBMCs of virologically suppressed patients enrolled in the ANRS 167 LAMIDOL trial, evaluating a switch from triple therapy to dolutegravirâ+âlamivudine, were collected 8â weeks before (W-8) and 48â weeks after (W48) dual-therapy initiation. The Vif and RT regions were subject to next-generation sequencing. Bioinformatic algorithms were developed to identify APOBEC3-defective sequences and APOBEC3-related drug resistance mutations (APOMuts). All hypermutated sequences and those containing at least one stop codon were considered as defective. RESULTS: One hundred and four patients were enrolled (median virological suppression duration: 4.2â years; IQR: 2.0-9.1). Proviral defective reads at W-8 and W48 were detected in Vif in 22% and 29% of patients, respectively, and in RT in 38% and 42% of patients, respectively. At least one APOMut was present in proviruses of 27% and 38% of patients at W-8 and W48, respectively. The ratio of APOMuts/number of potential APOMut sites was significantly higher at W48 (16.5%) than at W-8 (9.8%, Pâ=â0.007). The presence of APOBEC3-defective viruses at W-8 was not associated with HIV total DNA level, nor with the third drug class received prior to switching to dolutegravirâ+âlamivudine, nor with the duration of virological suppression. CONCLUSIONS: Whereas no significant change in the proportion of patients with APOBEC3-defective proviruses was evidenced after 1â year of dolutegravirâ+âlamivudine maintenance, enrichment in APOMuts was observed. Further longer-term studies are needed to assess the other forms of defective viruses with dual-therapy.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Fármacos Anti-VIH/uso terapéutico , Desaminasas APOBEC/genética , ADN/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Piridonas/uso terapéutico , Carga ViralRESUMEN
BACKGROUND: In a 4 days/week (4/7 days) maintenance strategy (ANRS-170 QUATUOR trial), the virological impact of an intermittent strategy was assessed by ultrasensitive virological analyses of reservoirs and resistance. METHODS: HIV-1 total DNA, ultra-sensitive plasma viral load (USpVL) and semen VL were measured in the first 121 participants. Sanger and ultra-deep sequencing (UDS) were performed on the HIV-1 genome (Illumina technology) according to the ANRS consensus. A generalized estimation equation with a Poisson distribution was used to compare changes in the proportion of residual viraemia, detectable semen HIV RNA and HIV DNA within and between the two groups over time. RESULTS: The proportion of participants with residual viraemia at Day 0 (D0) and Week 48 (W48) was 16.7% and 25.0% in the 4/7 days group and 22.4% and 29.7% in the 7/7 days group, respectively (+8.3% versus +7.3%, P = 0.971). The proportion of detectable DNA (>40 copies/106 cells) at D0 and W48 was 53.7% and 57.4% in the 4/7 days group and 56.1% and 51.8% in the 7/7 days group, respectively (+3.7% versus -4.3%, P = 0.358). Semen HIV RNA was detectable (≥100 copies/mL) in 2.2% of participants at D0 and 4.5% at W48 in the 4/7 days group versus 6.1% and 9.1% in the 7/7 days group, respectively (+2.3% versus +3.0%, P = 0.743). Emerging resistance at failure was more frequent in the 4/7 days group detected by Sanger sequencing: 3/6 participants versus 1/4 in the 7/7 days group, and similar with the UDS assay: 5/6 versus 4/4, respectively. CONCLUSIONS: These findings support the potency of a 4/7 days maintenance strategy on virological suppression at the reservoirs and emergent resistance level, including minority variants.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Viremia/tratamiento farmacológico , Antirretrovirales/uso terapéutico , ARN/farmacología , ARN/uso terapéutico , Carga Viral , Resistencia a Medicamentos , Farmacorresistencia Viral/genéticaRESUMEN
We compared the proportion of participants achieving first undetectable HIV-1 RNA (VL) in seminal plasma (SP) and blood plasma (BP) in 19 men starting dolutegravir-based regimen at primary HIV infection. At baseline, median VL was 6.5 (interquartile range [IQR], 5.6-7.9) and 4.5 (IQR, 3.5-5.0) log10 copies/mL in BP and SP, respectively. Between baseline and week 48, significantly higher proportion of participants achieved first VL below limit of quantification in SP (93.0%) than in BP (84.2%; P = .008). Time to first undetectable VL was 8 weeks in SP (95% confidence interval [CI], 5.6-10.4) and 24 weeks in BP (95% CI, 14.1-33.9).
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/uso terapéutico , Piperazinas/uso terapéutico , Piridonas/uso terapéutico , Semen/virología , Adulto , Infecciones por VIH/genética , Humanos , Cinética , Masculino , Persona de Mediana Edad , ARN Viral/genética , Carga ViralRESUMEN
BACKGROUND: Multivariable baseline factor analysis across cabotegravirâ+ârilpivirine clinical trials showed that HIV-1 subtypes A6/A1 and the presence of rilpivirine resistance-associated mutations (RAMs) were associated with an increased risk of virological failure of this dual therapy. The aim of this study was to describe the prevalence of genotypic baseline risk factors for cabotegravirâ+ârilpivirine failure among ARV-naive patients. PATIENTS AND METHODS: From 2010 to 2020, 4212 sequences from ARV-naive patients were collected from three large Parisian academic hospital genotypic databases. Cabotegravir and rilpivirine RAMs were defined according to the ANRS algorithm. RESULTS: Among 4212 ARV-naive patients, 38.6% were infected with subtype B, 32.4% with CRF02_AG (32.4%) and 5.1% with subtype A (85.5% being A6/A1 subtype). Overall, the presence of at least one cabotegravir or rilpivirine RAM was 16.2% and 14.3%, respectively. Considering genotypic resistance interpretation, using the ANRS algorithm, 0.74% (nâ=â31), 6.2% (nâ=â261) and 0.09% (nâ=â4) of sequences were resistant to cabotegravir, rilpivirine or both, respectively. The overall prevalence of L74I in integrase and E138A in RT was 13.0% and 3.2%, respectively, and stable over the decade. Thus, adding 183 subtype A6/A1 sequences to 244 sequences interpreted as resistant to rilpivirine led to 427 (10.1%) sequences combining both baseline virological risk factors for cabotegravirâ+ârilpivirine dual-therapy failure. CONCLUSIONS: Among large sequence databases, when adding prevalence of rilpivirine-resistant viruses and HIV-1 subtype A6/A1 sequences, 10.1% of patients would not be eligible for cabotegravirâ+ârilpivirine dual therapy. These data re-emphasize the need for a pre-therapeutic genotypic resistance test to detect polymorphisms and transmitted drug resistance and to define HIV-1 subtype.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH-1/genética , Humanos , Prevalencia , Piridonas , Rilpivirina/uso terapéutico , Factores de RiesgoRESUMEN
INTRODUCTION: Few data are available on plasma concentrations of antiretroviral therapy (ARV) during intermittent treatment. OBJECTIVE: To compare plasma concentrations in OFF vs ON treatment periods at several time points during treatment. METHODS: During a successful 48-week multicenter study (ANRS 162-4D trial) of 4 days with treatment (ON) followed by 3 days without treatment (OFF) in adults treated by two nucleoside analogues and a third agent belonging to a boosted protease-inhibitor (PI, darunavir [DRV], atazanavir [ATV], lopinavir [LPV]) or a non-nucleoside-reverse-transcriptase inhibitor (NNRTI, efavirenz [EFV], etravirine [ETR], rilpivirine [RPV]) conducted in 100 patients (96% success), we determined the plasma concentrations of ARV. Blood samples were collected for analysis at inclusion (W0, 7/7 strategy for all patients), W16 and W40 (ON) and at W4, W8, W12, W24, W32 and W48 (OFF). RESULTS: A total of 866 samples was analysed. Plasma concentrations were not statistically lower after 4 days (ON) vs 7/7 days of treatment except for RPV (-30 ng/mL at 4/7, P = 0.003). Significant lower plasma concentrations were observed for OFF vs ON except for ETR (n = 5, P = 0.062). Overall, 87.1% of ON concentrations (ATV 92.1%, DRV 51.1%, LPV 62.5%, EFV 94.4%, ETR 100% and RPV 94.9%) and 21.8% of OFF concentrations (ATV 1.4%, DRV 0.0%, LPV 0.0%, EFV 16.0%, ETR 92.6% and RPV 39.0%) were above the theoretical limit of efficacy of the molecule. In the OFF period, 85.8% of PI concentrations were under the limit of quantification, while 98.0% of NNRTI concentrations were quantifiable. CONCLUSION: Despite low/undetectable PI/NNRTI plasma concentrations in the OFF period, patients maintained an undetectable viral load. The mechanistic explanation should be investigated.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Inhibidores de la Transcriptasa Inversa , Rilpivirina/uso terapéutico , Carga ViralRESUMEN
OBJECTIVES: To describe plasma residual HIV viraemia, cellular HIV reservoir size, blood plasma drug concentrations and their male genital tract penetration during the maintenance dual therapy dolutegravir + lamivudine. PATIENTS AND METHODS: ANRS167 LAMIDOL enrolled 104 virologically suppressed patients to switch to dolutegravir + lamivudine. In this pharmacovirological substudy, ultrasensitive plasma viral load (USpVL) and plasma drug concentrations were measured at Day 0 (D0), Week 24 (W24) and W48 of dolutegravir + lamivudine, and HIV-DNA was measured at W-8 and W48. Semen samples were collected at D0 and W24 from 18 participants. Total and unbound blood and seminal plasma drug concentrations were measured using UPLC-MS/MS. RESULTS: Median HIV-DNA was 2.5 log10 copies/106 PBMC (IQR = 2.2-3.0, n = 100) at W-8 and 2.4 log10 copies/106 PBMC (IQR = 2.1-2.9, n = 100) at W48 (P = 0.17). The proportion of patients with undetected USpVL was 38% (n = 98), 43% (n = 98) and 49% (n = 97) at D0, W24 and W48, respectively (P = 0.08). Total and unbound plasma dolutegravir concentrations were stable between timepoints (P = 0.13) and all total plasma dolutegravir concentrations except one were adequate. Median free fraction of dolutegravir in plasma was 0.21%. Median blood plasma and seminal plasma concentrations of total dolutegravir at 24 h were 1812 ng/mL and 206 ng/mL, respectively. Median seminal plasma/blood plasma total concentration ratios were 11.6% and 2478% for dolutegravir and lamivudine, respectively. HIV-RNA (365 to 475 copies/mL) was detected in seminal plasma of one patient at D0 (5.9%) and of two patients at W24 (11.8%). CONCLUSIONS: These findings add further important information regarding the effectiveness of dolutegravir + lamivudine maintenance dual therapy in terms of plasma residual viraemia, cellular reservoir size and drug penetration in the male genital tract.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/uso terapéutico , Cromatografía Liquida , Genitales Masculinos , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Lamivudine/uso terapéutico , Leucocitos Mononucleares , Masculino , Oxazinas , Piperazinas/uso terapéutico , Piridonas , Espectrometría de Masas en Tándem , Carga ViralRESUMEN
OBJECTIVES: To assess, at ART initiation, the impact of baseline substitutions in protease, Gag and gp41 regions on the virological response to a first-line PI-based regimen. PATIENTS AND METHODS: One hundred and fifty-four HIV-infected ART-naive patients initiating a PI-based regimen including darunavir (nâ=â129) or atazanavir (nâ=â25) were assessed, including 36 experiencing virological failure (VF). Whole pol, gag and gp41 genes were sequenced at ART baseline by ultra-deep sequencing (UDS) using Illumina® technology. Supervised data-mining analyses were performed to identify mutations associated with virological response. Structural analyses were performed to assess the impact of mutations on protease conformation. RESULTS: UDS was successful in 127, 138 and 134 samples for protease, Gag and gp41, respectively (31% subtype B and 38% CRF02_AG). Overall, T4A and S37T mutations in protease were identified as being associated with VF (Pâ=â0.02 and Pâ=â0.005, respectively). Among CRF02_AG sequences, I72M and E21D mutations were associated with VF (Pâ=â0.03 for both). They all induced some conformational changes of some protease side-chain residues located near mutated residues. In Gag, mutations associated with VF were G62D, N315H and Y441S (Pâ=â0.005, Pâ=â0.007 and Pâ=â0.0003, respectively). All were localized outside Gag cleavage sites (G62D, matrix; N315H, capsid; and Y441S, p1). In gp41, the I270T mutation, localized in the cytoplasmic tail, was associated with VF (Pâ=â0.003), and the I4L mutation, in the fusion peptide, was associated with virological success (Pâ=â0.004). CONCLUSIONS: In this study, new baseline substitutions in Gag, protease and g41, potentially impacting PI-based regimen outcome, were evidenced. Phenotypic analyses are required to confirm their role in the PI-resistance mechanism.
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Farmacorresistencia Viral , Proteína gp41 de Envoltorio del VIH/genética , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/genética , VIH-1/efectos de los fármacos , Mutación , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Secuencia de Aminoácidos , Recuento de Linfocito CD4 , Femenino , Proteína gp41 de Envoltorio del VIH/química , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/uso terapéutico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Modelos Moleculares , Conformación Proteica , Carga Viral , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/químicaRESUMEN
OBJECTIVES: To evaluate the dolutegravir+lamivudine combination in virologically suppressed patients living with HIV. METHODS: The ANRS 167 LAMIDOL trial was an open-label, single arm, multicentre trial assessing once-daily dolutegravir (50 mg)+lamivudine (300 mg) in virologically suppressed HIV-1 patients on first-line triple-drug regimens. The main criteria for inclusion in the trial were plasma viral load (pVL) ≤50 copies/mL for ≥2 years, CD4 nadir >200 cells/mm3 and WT HIV prior to treatment initiation. From week -8 (W-8) to day 0 (D0) (Phase 1), the current third agent was switched to dolutegravir. From D0 to W48 (Phase 2), patients received once-daily dolutegravir+lamivudine, except if intolerant or if pVL >50 copies/mL during Phase 1. Virological failure was defined as pVL >50 copies/mL in two consecutive samples. The study was designed to show that the strategy had an efficacy of ≥80%, assuming a 90% success rate with a type I error of 5% and a power of 90%. RESULTS: In total, 104 of 110 patients enrolled in Phase 1 were included in Phase 2. These 104 patients were 86% male, 72% MSM and 87% CDC stage A. Their characteristics were (median): age 45 years, CD4 nadir 339 cells/mm3, baseline CD4 743 cells/mm3 and duration of viral suppression 4.5 years. The overall success rate at W48 was 97% (95% CI: 94%-100%), meeting the design expectation/assumption. Three therapeutic failures occurred: one virological failure at W4, one lost to follow-up at W32 and one interruption of therapeutic strategy at W40 after a blip (pVL 59 copies/mL but control pVL <50 copies/mL). Three viral blips occurred in two additional patients. Neither M184V nor integrase resistance mutations were detected after failure or blips. CONCLUSIONS: Dolutegravir+lamivudine is a promising maintenance therapy in HIV-1-infected patients with controlled virological suppression.
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Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Lamivudine/uso terapéutico , Carga Viral , Adulto , Anciano , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Monitoreo de Drogas , Resistencia a Antineoplásicos , Femenino , Infecciones por VIH/inmunología , VIH-1/inmunología , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Lamivudine/administración & dosificación , Lamivudine/efectos adversos , Lamivudine/farmacocinética , Masculino , Persona de Mediana Edad , Oxazinas , Piperazinas , Piridonas , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To further characterize HIV-1 viruses of patients experiencing unexplained virological failure (VF) on PI-containing regimens, ultradeep sequencing was performed on protease, gag and gp41 genes in patients failing a first-line treatment. METHODS: All naive patients initiating an antiretroviral treatment based on boosted darunavir, atazanavir or lopinavir and experiencing VF without any transmitted drug resistance mutation detected by Sanger sequencing on protease and reverse transcriptase genes were selected. Ultradeep sequencing (IlluminaTM Nextera®) was performed on protease, gag and gp41 genes in plasma before initiation of treatment and at VF to identify emergent mutations. RESULTS: Among the 32 patients included in the study, emergent and previously undescribed mutations in the viral protease gene were identified in five patients at VF: 64M (1 CRF02_AG), 64M/70R with mutation 15V (2 CRF02_AG), 79A (1 CRF06_cpx) and 79A with mutation 15V (1 CRF02_AG). Two patients showed the emergence of R286K in the gag region, outside of cleavage sites (2 CRF02_AG). In the gp41 region, the V321I mutation emerged inside the cytoplasmic tail (1 subtype A and 1 subtype B). All these patients were treated with a darunavir/ritonavir-based regimen. CONCLUSIONS: In some cases of VF to PIs, we observed the emergence of protease, Gag or Gp41 mutations that had not previously been associated with VF or PI resistance. These mutations should be further studied, in particular the 15V/64M/70R pattern in the protease gene identified among CRF02_AG viruses.
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Farmacorresistencia Viral , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Adulto , Femenino , Proteína gp41 de Envoltorio del VIH/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/uso terapéutico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Carga Viral , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
OBJECTIVES: To evaluate, in a clinical cohort of HIV-1-infected patients, the prevalence of PI minority resistant variants (MRV) at ART baseline and their impact on the virological response to a first-line PI-based regimen. PATIENTS AND METHODS: In an observational single-centre cohort, we assessed all ART-naive patients initiating a first-line regimen including two NRTI and one boosted PI, darunavir/ritonavir or atazanavir/ritonavir, between January 2012 and March 2015. Ultra-deep sequencing of the pol gene was performed using Illumina® technology. Protease mutations were identified using the WHO transmitted drug resistance list and major PI resistance mutations (IAS-USA drug resistance mutations list). RESULTS: Ninety-four and 16 patients initiating a darunavir/ritonavir-based regimen and an atazanavir/ritonavir-based regimen, respectively, were assessed. Twenty-eight percent of the patients were HIV-1 subtype B, 39% CRF02_AG and 33% other non-B subtypes. Thirteen patients (13.8%) in the darunavir group and three patients (18.8%) in the atazanavir group experienced a virological failure (VF). Overall, 13 (11.8%) subjects had PI MRV at baseline in the median proportion of 1.3% (IQR = 1.1-1.7). The most prevalent PI MRV were G73C (n = 5) and M46I (n = 3). The proportion of patients harbouring baseline PI MRV was similar between those with virological success (10.6%) and those experiencing VF (18.8%) (P = 0.40). No difference was observed in the rate of PI MRV by viral subtype (P = 0.51) or by PI drug (P = 0.40). CONCLUSIONS: This study showed a prevalence of 11.8% of PI MRV among 110 ART-naive subjects, without significant impact on the virological response to a first-line PI-based regimen containing darunavir or atazanavir.
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Fármacos Anti-VIH/uso terapéutico , Sulfato de Atazanavir/uso terapéutico , Darunavir/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Proteasa del VIH/genética , VIH-1/efectos de los fármacos , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética , Adulto , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Femenino , VIH-1/genética , Humanos , Masculino , Ritonavir/uso terapéutico , Carga Viral/efectos de los fármacosRESUMEN
Objectives: To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to a dolutegravir-based regimen, regardless of the genotypic susceptibility score (GSS). Patients and methods: This was an observational single-centre study assessing ART-treated patients with plasma viral load (pVL) <50 copies/mL who were switched to a dolutegravir-based regimen with 1 year of follow-up. PCR negative was defined as an undetected PCR signal. Trough plasma concentration (C24) was determined using UPLC-MS/MS. Results: Two hundred and thirty-nine patients initiated a dolutegravir-based regimen: 12%, 29% and 59% had a total GSS of 1 or 1.5 (group 1), 2 or 2.5 (group 2) and 3 (group 3), respectively. At switch initiation, the median time since first ART and the median duration with pVL <50 copies/mL were 13 years (IQR = 6-19) and 3 years (IQR = 1-6), respectively. Median times since last genotype were 9, 10 and 5 years for groups 1, 2 and 3, respectively. Twenty patients (8.4%) discontinued the dolutegravir-based regimen due to adverse events. During the study, 96.4% (n = 661/686) of all pVL were <50 copies/mL. Four patients (1.7%) experienced virological failure (two pVL >50 copies/mL) without emergence of resistance; these patients' GSSs were 2, 2.5, 3 and 3. The median dolutegravir C24 was 1545 ng/mL (IQR = 1150-2097). Of the patients with pVL <20 copies/mL, 72% were PCR negative during the follow-up, with no difference between the three groups of patients. Conclusions: This observational cohort study showed a high level of virological suppression maintenance in the first year following the switch to a dolutegravir-based regimen, even in patients with GSS ≤2.
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Fármacos Anti-VIH/uso terapéutico , Genotipo , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Carga Viral/efectos de los fármacos , Fármacos Anti-VIH/sangre , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Estudios de Cohortes , Farmacorresistencia Viral/genética , Sustitución de Medicamentos , Femenino , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos/sangre , Humanos , Masculino , Persona de Mediana Edad , Oxazinas , Piperazinas , Piridonas , ARN Viral/sangreRESUMEN
Background: Sparing of antiretroviral drug classes could reduce the toxicity and cost of maintenance treatment for HIV infection. Objectives: To evaluate the non-inferiority of efficacy and the safety of lopinavir/ritonavir (r) monotherapy versus a single-tablet regimen of efavirenz, emtricitabine and tenofovir (EFV/FTC/TDF) over 2 years. Methods: Adults on stable ART with plasma HIV-1 RNA viral load <50 copies/mL for the past 12 months and no documented treatment failure were randomized to receive either lopinavir/r or EFV/FTC/TDF for 2 years. The primary endpoint was the proportion of patients without treatment failure at week 96 (viral load <50 copies/mL at week 96, confirmed at week 98), without study treatment discontinuation, a new AIDS-defining illness, or death. Results: In the ITT analysis, the primary endpoint was reached by, respectively, 64% and 71% of patients in the lopinavir/r (n = 98) and EFV/FTC/TDF arms (n = 97), yielding a difference of -6.8% (lower limit of the 95% two-sided CI: -19.9%). Sanger and UltraDeep sequencing showed the occurrence of PI mutations in the lopinavir/r arm (n = 4) and of NNRTI and/or NRTI mutations in the EFV/FTC/TDF arm (n = 2). No unexpected serious clinical events occurred. Conclusions: Lopinavir/r monotherapy cannot be considered non-inferior to EFV/FTC/TDF. PI resistance rarely emerged in the lopinavir/r arm and did not undermine future PI options. Two years of lopinavir/r monotherapy had no deleterious clinical impact when compared with EFV/FTC/TDF.
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Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Lopinavir/uso terapéutico , Ritonavir/uso terapéutico , Carga Viral/efectos de los fármacos , Adulto , Femenino , Francia , VIH-1/efectos de los fármacos , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
Background: Intermittent treatment could improve the convenience, tolerability and cost of ART, as well as patients' quality of life. We conducted a 48 week multicentre study of a 4-days-a-week antiretroviral regimen in adults with controlled HIV-1-RNA plasma viral load (VL). Methods: Eligible patients were adults with VL <â50 copies/mL for at least 1 year on triple therapy with a ritonavir-boosted PI (PI/r) or an NNRTI. The study protocol consisted of the same regimen taken on four consecutive days per week followed by a 3 day drug interruption. The primary outcome was the proportion of participants remaining in the strategy with VL <â50 copies/mL up to week 48. The study was designed to show an observed success rate of >â90%, with a power of 87% and a 5% type 1 error. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29). Results: One hundred patients (82 men), median age 47 years (IQR 40-53), were included. They had been receiving ART for a median of 5.1 (IQR 2.9-9.3) years and had a median CD4 cell count of 665 (IQR 543-829) cells/mm3. The ongoing regimen included PI/r in 29 cases and NNRTI in 71 cases. At 48 weeks, 96% of participants (95% CI 90%-98%) had no failure while remaining on the 4-days-a-week regimen. Virological failure occurred in three participants, who all resumed daily treatment and became resuppressed. One participant stopped the strategy. No severe treatment-related events occurred. Conclusions: Antiretroviral maintenance therapy 4 days a week was effective for 48 weeks in 96% of patients, leading to potential reduction of long-term toxicities, high adherence to the antiretroviral regimen and drug cost saving.
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Antirretrovirales/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adulto , Antirretrovirales/uso terapéutico , Recuento de Linfocito CD4 , Esquema de Medicación , Quimioterapia Combinada , Femenino , Infecciones por VIH/virología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Calidad de Vida , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Resultado del Tratamiento , Carga Viral/efectos de los fármacosRESUMEN
For many patients living with HIV-1, the efficacy of combined ART (cART) has made the infection turn to a chronic disease. Because cART is associated with a risk of long-term toxicity, switching patients with virological success to another therapy remains a major issue. Studies undertaken and published over recent years have shown that switching patients exhibiting virological suppression to less-drug regimens (LDR) is a possible option of maintenance strategy. The use of ritonavir-boosted PIs (PI/r) as the backbone of LDR-based maintenance therapy is consistent with their virological potency and a high genetic barrier of resistance. Atazanavir is the most documented PI/r regarding maintenance in dual therapy, with favourable results in terms of virological suppression, tolerance improvement and absence of emergence of mutations. Furthermore, atazanavir is the only commonly prescribed PI that can be used after withdrawal of ritonavir, with maintenance of virological suppression whatever the backbone of associated NRTIs. Based on clinical studies, and taking into account the characteristics of the patients included, one may consider that for any patient with a virological suppression on cART for at least 12 months, with the nadir CD4 >100 cells/mm3 and an absence of encephalitis, an LDR-based maintenance therapy including atazanavir can be considered. Cumulative genotypes must be available to make sure that the LDR will not jeopardize future therapeutic options. The final decision regarding the most appropriate LDR must be guided by the objectives shared by the physician and his/her patient.
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Fármacos Anti-VIH/administración & dosificación , Sulfato de Atazanavir/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Quimioterapia de Mantención/métodos , Quimioterapia Combinada/métodos , Humanos , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
Objectives: To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate as a single-tablet regimen (STR) using the PCR signal of the plasma viral load (pVL) assay and determination of plasma drug concentration ( C 24 ). Patients and methods: This was an observational single-centre study enrolling antiretroviral-treated patients with pVL <50â copies/mL initiating elvitegravir-based STR. PCRneg was defined as an undetected PCR signal. Results: One hundred and fifty-one patients were enrolled. At STR baseline, the median time since first ART and time of virological suppression were 5â years (IQR 3-9) and 24â months (IQR 9-44), respectively. By week (W) 48, 26 (17%) of the patients had discontinued STR due to adverse events. The proportion of patients maintaining pVL <50â copies/mL on treatment was 98%, 96%, 93% and 97% at W12, W24, W36 and W48, respectively. Five patients (3.3%) experienced a virological failure and emergence of resistance was observed in two of them with the selection of M184V and N155H mutations. At baseline, W12, W24, W36 and W48, 70%, 57%, 72%, 61% and 74% of the patients with pVL <20â copies/mL had a PCRneg, respectively. The median elvitegravir plasma C 24 value was 648â ng/mL (IQR 348-989; n = 237), with 84% of elvitegravir C 24 values >45â ng/mL, the protein-adjusted IC 95 . Conclusions: In this clinical cohort of virologically suppressed patients switching to STR, most subjects had adequate elvitegravir C 24 values with a high proportion maintaining virological suppression with no residual viraemia until W48.
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Cobicistat/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Quinolonas/uso terapéutico , Tenofovir/uso terapéutico , Carga Viral , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Cobicistat/administración & dosificación , Cobicistat/sangre , Estudios de Cohortes , Emtricitabina/administración & dosificación , Emtricitabina/sangre , Femenino , Infecciones por VIH/sangre , VIH-1/efectos de los fármacos , Humanos , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Quinolonas/administración & dosificación , Quinolonas/sangre , ARN Viral/sangre , Comprimidos , Tenofovir/administración & dosificación , Tenofovir/sangre , Viremia/tratamiento farmacológicoRESUMEN
Background: Obesity has high prevalence among HIV-infected patients. Increased adipose tissue mass affects the pharmacokinetics of numerous drugs, but few data are available for antiretroviral drugs. Objectives: In this study we aimed to explore the pharmacokinetics of antiretroviral drugs and the immuno-virological response in obese patients with HIV infection. Patients and methods: We examined data from 2009 to 2012 in our hospital's database for HIV-1-infected patients who received an antiretroviral drug (abacavir, emtricitabine, lamivudine, tenofovir, efavirenz, etravirine, nevirapine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir or raltegravir). Obese patients were defined as those with BMI ≥30â kg/m 2 and normal-weight patients as those with BMI 19-25â kg/m 2 . Plasma concentrations ( C 12/24 ) were compared for each antiretroviral drug using a Mann-Whitney test. Suboptimal dosing and virological outcome were assessed by logistic regression, adjusting on covariates. Results: We enrolled 291 obese and 196 normal-weight patients. Among the 12 analysed antiretroviral drugs, tenofovir, efavirenz and lopinavir C 12 values were significantly lower in obese than normal-weight patients: 66 versus 86â ng/mL, 1498 versus 2034â ng/mL and 4595 versus 6420â ng/mL, respectively ( P < 0.001). Antiretroviral drug C 12/24 values were more frequently below efficacy thresholds for obese than for normal-weight patients after adjustment for other covariates ( P < 0.001). Although obese patients showed a higher CD4 count than normal-weight patients (510 versus 444â cells/mm 3 , P < 0.001), the groups did not differ in virological failure rate. Conclusions: This study highlights the impact of obesity on antiretroviral drug plasma exposure, but identifies no consequence of this suboptimal exposure on the immuno-virological control in this population.
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Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacocinética , VIH-1/efectos de los fármacos , Obesidad/complicaciones , Carga Viral/efectos de los fármacos , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Índice de Masa Corporal , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/sangre , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/inmunología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Obesidad/virología , ARN Viral/sangre , Adulto JovenRESUMEN
OBJECTIVES: Boosted PIs are commonly prescribed in patients presenting with advanced HIV infection. We assessed the efficacy and tolerability of once-daily ritonavir-boosted atazanavir or darunavir plus two NRTIs in HIV-1-infected ART-naive patients with severe immunosuppression, targeting at least an 85% success rate at week 48. METHODS: This 48 week, open-label, non-comparative, randomized, multicentre trial included ART-naive patients with CD4 cell counts <200 cells/mm(3), with plasma HIV-1 RNA >1000 copies/mL and without genotypic mutations conferring resistance to the study drugs. Patients were randomized (1:1) to receive once-daily atazanavir/ritonavir (300/100 mg) or darunavir/ritonavir (800/100 mg) plus tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine. The primary endpoint was treatment success, defined as plasma HIV-1 RNA ≤50 copies/mL at week 48 and no permanent PI/ritonavir discontinuation. The study was registered with ClinicalTrials.gov (NCT01928407). RESULTS: One hundred and twenty patients were enrolled: 77% were men, 30% were born in Africa and 39% had AIDS. The median baseline CD4 and plasma HIV-RNA values were 69 cells/mm(3) and 5.4 log10 copies/mL. All but four patients received tenofovir disoproxil fumarate/emtricitabine. The week 48 treatment success rate was 66% (95% CI 54%-78%) with atazanavir/ritonavir and 80% (95% CI 68%-89%) with darunavir/ritonavir. The median CD4 cell count increased similarly in the two groups (Δweek 48 to week 0: +194 cells/mm(3)). Adverse events occurred in 23 and 18 patients, respectively. CONCLUSIONS: Despite good adherence, neither study regimen reached the predefined objective, suggesting a need for more potent regimens for patients with advanced HIV infection.