RESUMEN
BACKGROUND: Most guidelines recommend rapid treatment initiation for patients with newly diagnosed human immunodeficiency virus type 1 (HIV-1) infection, but prospective US data are limited. The DIAMOND (NCT03227861) study using darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a phase 3 prospective study evaluating efficacy/safety of a single-tablet regimen in a rapid-initiation model of care. METHODS: Adults aged ≥18 years began D/C/F/TAF ≤14 days from diagnosis without screening/baseline results; as results became available, participants not meeting predefined safety/resistance stopping rules continued. Primary endpoint was virologic response (HIV-1 RNA <50 copies/mL; intent-to-treat; US Food and Drug Administration [FDA] snapshot) at week 48; participant satisfaction was measured via the HIV Treatment Satisfaction Questionnaire status version (HIVTSQs). RESULTS: Of 109 participants, 87% were male, 32% black/African American, median (range) age was 28 (range, 19-66) years, 25% of participants had HIV-1 RNA ≥100 000 copies/mL, 21% had CD4+ cell count <200 cells/µL, and 31% enrolled ≤48 hours from diagnosis. At week 48, 97 (89%) participants completed the study and 92 (84%) achieved HIV-1 RNA <50 copies/mL (FDA snapshot). There were no protocol-defined virologic failures; incidences of adverse events (AEs) and adverse drug reactions (33%) were low, no serious AEs were study drug related, and 1 (<1%) participant discontinued due to study drug related AE(s). The overall HIVTSQs score at week 48 was 58 (maximum: 60). CONCLUSIONS: At week 48, a high proportion of participants starting D/C/F/TAF achieved HIV-1 RNA <50 copies/mL and very few discontinued therapy. D/C/F/TAF was well tolerated, no participants discontinued due to baseline resistance stopping criteria, and high treatment satisfaction among participants was recorded. CLINICAL TRIALS REGISTRATION: NCT03227861.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adenina/análogos & derivados , Adolescente , Adulto , Anciano , Alanina , Fármacos Anti-VIH/efectos adversos , Cobicistat/uso terapéutico , Darunavir/uso terapéutico , Diamante/uso terapéutico , Combinación de Medicamentos , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tenofovir/análogos & derivados , Carga Viral , Adulto JovenRESUMEN
BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a once-daily, single-tablet regimen for treatment of HIV-1 infection. The efficacy/safety of switching to D/C/F/TAF versus continuing boosted protease inhibitor (bPI) + emtricitabine/tenofovir disoproxil fumarate (control) were demonstrated in a phase 3, randomized study (EMERALD) of treatment-experienced, virologically suppressed adults through week 48. The objective of this analysis was to evaluate EMERALD outcomes across subgroups of patients based on demographic characteristics, prior treatment experience, and baseline antiretroviral regimen. METHODS: EMERALD patients were virologically suppressed (viral load [VL] < 50 copies/mL for ≥ 2 months at screening). Prior non-darunavir virologic failure (VF) was allowed. Primary endpoint was proportion of patients with virologic rebound (confirmed VL ≥ 50 copies/mL) cumulative through week 48. Virologic response was VL < 50 copies/mL (FDA snapshot). Safety was assessed by adverse events, renal proteinuria markers, and bone mineral density. Outcomes were examined for prespecified subgroups by age (≤/> 50 years), gender, race (black/non-black), prior number of antiretrovirals used (4/5/6/7/> 7), prior VF (0/≥ 1), baseline bPI (darunavir/atazanavir or lopinavir), and baseline boosting agent (ritonavir/cobicistat). RESULTS: Among 1141 patients in the D/C/F/TAF (n = 763) and control (n = 378) arms, virologic rebound rates (2.5% and 2.1%, respectively) were similar, and this was consistent across all subgroups. Virologic response rates ranged from 91 to 97% (D/C/F/TAF) and 89 to 99% (control) across all subgroups, with differences between treatment arms of 0 and 6%. Adverse event rates were low in both arms and across subgroups. Improvements in renal and bone parameters were observed with D/C/F/TAF across demographic subgroups. CONCLUSIONS: For treatment-experienced, virologically suppressed patients, switching to D/C/F/TAF was highly effective and safe, regardless of demographic characteristics, prior treatment experience, or pre-switch bPI. Trial registration ClinicalTrials.gov Identifier: NCT02269917. Registered 21 October 2014. https://clinicaltrials.gov/ct2/show/NCT02269917.
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Fármacos Anti-VIH/uso terapéutico , Sustitución de Medicamentos , Infecciones por VIH/tratamiento farmacológico , Carga Viral/efectos de los fármacos , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Anciano , Alanina , Terapia Antirretroviral Altamente Activa , Cobicistat/uso terapéutico , Darunavir/uso terapéutico , Combinación de Medicamentos , Emtricitabina/uso terapéutico , Femenino , VIH-1/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteasas/uso terapéutico , Respuesta Virológica Sostenida , Comprimidos , Tenofovir/uso terapéutico , Adulto JovenRESUMEN
Trends in resistance to antiretroviral drugs for HIV-1 may inform clinical support and drug development. We evaluated drug resistance mutation (DRM) trends for nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), and integrase strand transfer inhibitor (INSTI) in a large U.S. reference laboratory database. DRMs with a Stanford HIV Drug Resistance Database mutation score ≥10 from deidentified subtype B NRTI/NNRTI/PI specimens (2006-2017; >10,000/year) and INSTI specimens (2010-2017; >1,000/year) were evaluated. Sequences with NRTI, NNRTI, or PI single- or multiclass DRMs declined from 48.9% to 39.3%. High-level dual- and triple-class resistance declined from 43.3% (2006) to 17.1% (2017), while sequences with only single-class DRMs increased from 40.0% to 52.9%. The prevalence of DRMs associated with earlier treatment regimens declined, while prevalence of some DRMs associated with newer regimens increased. M184V/I decreased from 48.3% to 29.4%. K103N/S/T declined from 42.5% in 2012 to 36.4% in 2017. Rilpivirine and etravirine DRMs E138A/Q/R and E138K increased from 4.9% and 0.4% to 9.7% and 1.7%, respectively. Sequences with ≥1 darunavir DRM declined from 18.1% to 4.8% by 2017. INSTI DRM Q148H/K/R declined from 39.3% (2010) to 13.8% (2017). Prevalence of elvitegravir-associated DRMs T66A/I/K, E92Q, S147G, and the dolutegravir-associated DRM R263K increased. For a subset of patients with serial testing, 50% (2,646/5,290) of those who initially had no reportable DRM subsequently developed ≥1 DRM for NRTI/NNRTI/PI and 49.7% (159/320) for INSTI. These trends may inform the need for baseline genotypic resistance testing. The detection of treatment-emergent DRMs in serially tested patients confirms the value of genotypic testing following virologic failure.
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Farmacorresistencia Viral/genética , Inhibidores de Integrasa VIH/farmacología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/farmacología , Darunavir/farmacología , Didesoxinucleósidos/farmacología , Genotipo , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Mutación , Nitrilos , Oxazinas , Piperazinas , Piridazinas/farmacología , Piridonas , Pirimidinas , Rilpivirina/farmacologíaRESUMEN
Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once-daily single-tablet regimen for the treatment of human immunodeficiency virus-1 infection. Different administration modalities for the D/C/F/TAF fixed-dose combination tablet were explored in this phase 1 randomized, open-label, 3-period, 3-treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference). Pharmacokinetic parameters (noncompartmental analysis; logarithm-transformed) for each component were compared using linear mixed-effects modeling. For the split versus whole tablet, the bioavailabilities (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUClast ]) of each D/C/F/TAF component were comparable. For the crushed versus whole tablet, the bioavailabilities of darunavir, cobicistat, and emtricitabine were comparable, except for a 17% decrease in emtricitabine Cmax ; the relative bioavailability of tenofovir alafenamide decreased by 29% and 19% for Cmax and AUClast , respectively. All intakes were safe and generally well tolerated. In summary, there was no clinically relevant impact on the bioavailability of D/C/F/TAF components when administered as a split tablet compared with a tablet swallowed whole. Administration of a crushed tablet resulted in a modest decrease in tenofovir alafenamide bioavailability; the clinical relevance of this change has not been assessed but is expected to be minimal based on the wide therapeutic window for this agent.
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Adenina/análogos & derivados , Cobicistat/farmacocinética , Darunavir/farmacocinética , Emtricitabina/farmacocinética , Adenina/administración & dosificación , Adenina/farmacocinética , Adulto , Alanina , Disponibilidad Biológica , Cobicistat/administración & dosificación , Estudios Cruzados , Darunavir/administración & dosificación , Combinación de Medicamentos , Emtricitabina/administración & dosificación , Femenino , Voluntarios Sanos , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Comprimidos , Tenofovir/análogos & derivados , Adulto JovenRESUMEN
In the original publication of the article, Table 2 has been published incorrectly.
RESUMEN
The emergence and transmission of antiretroviral drug resistance have been and remain a concern among people living with human immunodeficiency virus (HIV)-1 infection. The protease inhibitor (PI) darunavir has been approved for use in the United States for more than 10 years and has demonstrated a high barrier to resistance. Previous analyses identified significant reductions in the prevalence of samples with darunavir resistance-associated mutations (RAMs) and with phenotypic resistance to darunavir and other PIs between 2006 and 2012. This analysis extends those findings by evaluating darunavir and PI resistance among clinical samples submitted for routine drug resistance testing (combined genotyping and phenotyping) in the United States from 2010 to 2017. Frequencies of 11 darunavir and 23 primary PI RAMs, and phenotypic susceptibility, were assessed yearly among all samples and in a subset of samples with distinct phenotypic resistance to one or more PIs. Among all samples (N = 60,760), the proportion with 0 darunavir RAMs was 91.7% in 2010 and 95.8% in 2017. The proportions of all samples with phenotypic susceptibility to darunavir, atazanavir, and lopinavir were, respectively, 97.4%, 94.2%, and 94.7% in 2010 and 98.6%, 97.7%, and 97.5% in 2017. Among the 4,799 samples with phenotypic resistance to one or more PIs, the proportions with phenotypic susceptibility to darunavir, atazanavir, and lopinavir were, respectively, 73.3%, 41.5%, and 46.0% in 2010 and 70.7%, 53.7%, and 48.8% in 2017. The prevalence of darunavir RAMs among commercially tested HIV-1 samples remained low and generally stable from 2010 to 2017, and high proportions showed phenotypic darunavir susceptibility.
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Darunavir/farmacología , Farmacorresistencia Viral/genética , Inhibidores de la Proteasa del VIH/farmacología , Mutación , Historia del Siglo XXI , Humanos , Concentración 50 Inhibidora , Estados UnidosRESUMEN
INTRODUCTION: We evaluated cardiovascular disease (CVD) risk associated with darunavir treatment and examined the demographic/clinical characteristics of darunavir users based on data from Janssen-sponsored clinical trials, post-marketing pharmacovigilance databases, and administrative claims databases. METHODS: First, selected CVD events [myocardial infarction, stroke, sudden death, invasive cardiovascular procedures (coronary artery angioplasty or bypass, or carotid endarterectomy)] were analyzed in 19 Janssen-sponsored phase 2-4 studies (incidence rates estimated from pooled data; 95% confidence intervals derived from Poisson distribution). Second, analyses were conducted to identify spontaneously reported CVD events in post-marketing pharmacovigilance databases and evaluate disproportional reporting of CVD events for darunavir (using Empirical Bayesian Geometric Mean scores). Third, baseline demographic/clinical characteristics of human immunodeficiency virus-1 (HIV-1)-infected patients in general and new users of darunavir and atazanavir were explored using three US administrative claims databases. RESULTS: Among 19 Janssen-sponsored clinical trials (treatment durations ≤ 6 years), the CVD event rate (95% CI) per 1000 person-years (pooled population; n = 5713) was 6.15 (2.91-11.89), and was lower for patients who used once-daily darunavir/ritonavir 800/100 mg [0.71 (0.16-3.05); n = 1326] versus twice-daily darunavir/ritonavir 600/100 mg [9.21 (4.94-16.04); n = 3058]. Trend analysis of post-marketing pharmacovigilance data showed that cumulative CVD event reporting rates for darunavir users (any dose) generally declined over time. Spontaneously reported CVD events were not disproportionately reported with darunavir versus other protease inhibitors. Compared with the general HIV-1-infected population and atazanavir users, higher proportions of darunavir users were male, older, and had comorbidities associated with CVD risk based on results from US administrative claims databases. CONCLUSIONS: This comprehensive review of Janssen-sponsored clinical trial, post-marketing, and epidemiological data does not suggest that CVD should be considered an important risk for users of darunavir.
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Enfermedades Cardiovasculares/tratamiento farmacológico , Darunavir/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Darunavir/uso terapéutico , Femenino , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: An aging HIV-1-infected population warrants examination of the acceptability of individual antiretroviral regimens. In a previous study of ritonavir-boosted darunavir (ARTEMIS), similar safety/efficacy profiles were observed in younger (≤45 years) and older (>45 years) HIV-1-infected subjects. OBJECTIVE: To evaluate safety and efficacy outcomes in HIV-1-infected younger versus older subjects treated with cobicistat-boosted darunavir. METHOD: In a 48-week, phase 3b, open-label trial, HIV-1-infected adults were administered darunavir 800 mg and cobicistat 150 mg once-daily with 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs). Post hoc analyses examined safety and efficacy outcomes in subjects ≤45 and >45 years. RESULTS: Of 313 subjects, 76% were ≤45 years (median [range] age, 31 [18-45]) and 24% were >45 years (49 [46-72]). Baseline median (range) viral loads were 4.75 (2.6-6.8) and 4.83 (2.7-7.0) log10 copies/mL, and CD4+ counts were 379.0 (5-1473) and 310.5 (6-757) cells/mm3 in younger and older subjects, respectively. Through Week 48, similar proportions of younger and older subjects had ≥1 adverse event (AE; 93% vs 88%), ≥1 grade 2-4 AE possibly related to study drug (13% vs 15%), and discontinued study due to AE (3% vs 3%). At Week 48, 82% of younger and 78% of older subjects had viral load <50 copies/mL (95% CI of the difference: -7.4% to 13.8%). A higher proportion of older versus younger subjects took >4 concomitant medications during the study (69% vs 57%). CONCLUSION: Safety and efficacy profiles of cobicistat-boosted darunavir with 2 N(t)RTIs were similar in HIV-1-infected subjects ≤45 and >45 years.
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Cobicistat/administración & dosificación , Darunavir/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Adolescente , Adulto , Factores de Edad , Anciano , Fármacos Anti-VIH/administración & dosificación , Sinergismo Farmacológico , Femenino , Estudios de Seguimiento , Inhibidores de la Proteasa del VIH/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/análisis , Resultado del Tratamiento , Adulto JovenRESUMEN
BMS-663068 is a phosphonooxymethyl ester prodrug under development for the treatment of HIV/AIDS. The prodrug is designed to overcome the solubility-limited bioavailability of the active moiety, BMS-626529. BMS-663068 is not absorbed from the gastrointestinal (GI) tract and requires enzymatic conversion by alkaline phosphatase to BMS-626529 immediately before absorption. In the light of the known short in vivo half-life of BMS-626529, compartmental absorption modeling was used to predict the potential feasibility of extended-release (ER) delivery to achieve target Cmax :Cmin ratios. To further refine the model with respect to colonic absorption, the regional absorption of BMS-626529 following delivery of BMS-663068 to upper and lower GI sites was characterized through a site of absorption study in human subjects. A refined model was subsequently applied to guide the development of ER tablet formulations. Comparisons of results from the refined model to the in vivo human pharmacokinetic data for three selected ER formulations demonstrate the utility of the model in predicting feasibility of ER delivery and in directing formulation development.
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Fármacos Anti-VIH/farmacocinética , Absorción Intestinal , Organofosfatos/farmacocinética , Piperazinas/farmacocinética , Profármacos/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/sangre , Células CACO-2 , Cápsulas , Estudios Cruzados , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Humanos , Mucosa Intestinal/metabolismo , Modelos Biológicos , Organofosfatos/administración & dosificación , Organofosfatos/sangre , Piperazinas/administración & dosificación , Piperazinas/sangre , Profármacos/administración & dosificación , ComprimidosRESUMEN
The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir's mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents. Here, we show that understanding the effects of daclatasvir in vivo requires a multiscale model that incorporates drug effects on the HCV intracellular lifecycle, and we validated this approach with in vitro HCV infection experiments. The model predicts that daclatasvir efficiently blocks two distinct stages of the viral lifecycle, namely viral RNA synthesis and virion assembly/secretion with mean effectiveness of 99% and 99.8%, respectively, and yields a more precise estimate of the serum HCV half-life, 45 min, i.e., around four times shorter than previous estimates. Intracellular HCV RNA in HCV-infected cells treated with daclatasvir and the HCV polymerase inhibitor NM107 showed a similar pattern of decline. However, daclatasvir treatment led to an immediate and rapid decline of extracellular HCV titers compared to a delayed (6-9 h) and slower decline with NM107, confirming an effect of daclatasvir on both viral replication and assembly/secretion. The multiscale modeling approach, validated with in vitro kinetic experiments, brings a unique conceptual framework for understanding the mechanism of action of a variety of agents in development for the treatment of HCV.
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Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Imidazoles/farmacología , Modelos Biológicos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto , Teorema de Bayes , Carbamatos , Línea Celular , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Femenino , Semivida , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Humanos , Persona de Mediana Edad , Pirrolidinas , ARN Viral/sangre , ARN Viral/genética , Valina/análogos & derivados , Carga Viral/efectos de los fármacos , Ensamble de Virus/efectos de los fármacosRESUMEN
BACKGROUND: BMS-663068 is a prodrug of the small-molecule inhibitor BMS-626529, which inhibits human immunodeficiency virus type 1 (HIV-1) infection by binding to gp120 and interfering with the attachment of virus to CD4+ T-cells. METHODS: Fifty HIV-1-infected subjects were randomized to 1 of 5 regimen groups (600 mg BMS-663068 plus 100 mg ritonavir every 12 hours [Q12H], 1200 mg BMS-663068 plus 100 mg ritonavir every bedtime, 1200 mg BMS-663068 plus 100 mg ritonavir Q12H, 1200 mg BMS-663068 Q12H plus 100 mg ritonavir every morning, or 1200 mg BMS-663068 Q12H) for 8 days in this open-label, multiple-dose, parallel study. The study assessed the pharmacodynamics, pharmacokinetics, and safety of BMS-663068. RESULTS: The maximum median decrease in plasma HIV-1 RNA load from baseline ranged from 1.21 to 1.73 log(10) copies/mL. Plasma concentrations of BMS-626529 were not associated with an antiviral response, while low baseline inhibitory concentrations and the minimum and average steady-state BMS-626529 plasma concentrations, when adjusted by the baseline protein binding-adjusted 90% inhibitory concentration (inhibitory quotient), were linked with antiviral response. BMS-663068 was generally well tolerated. CONCLUSIONS: Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted. Clinical Trials Registration.NCT01009814.
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Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Organofosfatos/uso terapéutico , Piperazinas/uso terapéutico , Adulto , Anciano , Área Bajo la Curva , Quimioterapia Combinada , Femenino , Inhibidores de Fusión de VIH/efectos adversos , Inhibidores de Fusión de VIH/farmacocinética , Infecciones por VIH/sangre , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/genética , Humanos , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Organofosfatos/efectos adversos , Organofosfatos/farmacocinética , Piperazinas/efectos adversos , Piperazinas/farmacocinética , ARN Viral/sangre , Ritonavir/uso terapéutico , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Adulto JovenRESUMEN
UNLABELLED: The influence of naturally occurring polymorphisms on the potency of the HCV nonstructural protein 5A (NS5A) replication complex inhibitor, BMS-790052, was investigated by evaluating hybrid replicons in which the entire NS5A coding region of genotype (GT) la and 1b laboratory (lab) strains (H77c and Con1) were replaced with the corresponding regions of specimens collected from 10 GT-1a- and 6 GT-1b-infected subjects. For baseline (BL) specimens, with no previously observed resistance variants identified by population sequencing, the median 50% effective concentration (EC(50) ) values for BMS-790052 were similar for the clinically derived and lab strains. A Q30R variant was observed at viral breakthrough (VBT) in one of the GT-1a-infected subjects. Because the lowest plasma exposure of BMS-790052 observed in this subject was 117 nM and the median 50% effective concentration value for a GT-1a H77c replicon containing a Q30R substitution is ~7 nM, a rigorous investigation was initiated to determine the basis for resistance. Three approaches were used: (1) replacement of the entire H77c NS5A or (2) replacement of the N-terminal region of NS5A, with sequence from BL and day 14, and (3) substitution of specific amino acids. A BL polymorphism (E62D) did not contribute resistance to BMS-790052; however, the linked variant, Q30R-E62D, conferred high-level resistance in vitro and is likely responsible for VBT in vivo. CONCLUSION: Our data show that a BL polymorphism with minimal effect on the anti-HCV effect of BMS-790052 can affect the emergence of resistance and significantly affect clinical outcome. This work establishes a clear, systematic approach to monitor resistance to NS5A inhibitors in the clinic.
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Antivirales/farmacología , Farmacorresistencia Viral , Imidazoles/farmacología , Polimorfismo Genético , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/genética , Carbamatos , Línea Celular , Genotipo , Humanos , Pirrolidinas , ARN Viral/biosíntesis , Valina/análogos & derivadosRESUMEN
UNLABELLED: The NS5A replication complex inhibitor, BMS-790052, inhibits hepatitis C virus (HCV) replication with picomolar potency in preclinical assays. This potency translated in vivo to a substantial antiviral effect in a single-ascending dose study and a 14-day multiple-ascending dose (MAD) monotherapy study. However, HCV RNA remained detectable in genotype 1a-infected patients at the end of the MAD study. In contrast, viral breakthrough was observed less often in patients infected with genotype 1b, and, in several patients, HCV RNA declined and remained below the level of quantitation (<25 IU/mL) through the duration of treatment. Here, we report on the results of the genotypic and phenotypic analyses of resistant variants in 24 genotype 1-infected patients who received BMS-790052 (1, 10, 30, 60, and 100 mg, once-daily or 30 mg twice-daily) in the 14-day MAD study. Sequence analysis was performed on viral complementary DNA isolated from serum specimens collected at baseline and days 1 (4, 8, and 12 hours), 2, 4, 7, and 14 postdosing. Analyses of the sequence variants (1) established a correlation between resistant variants emerging in vivo with BMS-790052 treatment and those observed in the in vitro replicon system (major substitutions at residues 28, 30, 31, and 93 for genotype 1a and residues 31 and 93 for genotype 1b); (2) determined the prevalence of variants at baseline and the emergence of resistance at different times during dosing; and (3) revealed the resistance profile and replicative ability (i.e., fitness) of the variants. CONCLUSION: Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination therapy.
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Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Imidazoles/farmacología , Imidazoles/uso terapéutico , Proteínas no Estructurales Virales/fisiología , Carbamatos , Método Doble Ciego , Genotipo , Hepacivirus/efectos de los fármacos , Humanos , Imidazoles/administración & dosificación , Fenotipo , Pirrolidinas , ARN Viral/efectos de los fármacos , Replicón/efectos de los fármacos , Valina/análogos & derivados , Proteínas no Estructurales Virales/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
UNLABELLED: The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log(10) IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. CONCLUSION: BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1.
Asunto(s)
Antivirales/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adolescente , Adulto , Antivirales/farmacocinética , Carbamatos , Método Doble Ciego , Femenino , Semivida , Humanos , Imidazoles/farmacocinética , Masculino , Persona de Mediana Edad , Pirrolidinas , ARN Viral/sangre , Valina/análogos & derivados , Carga ViralRESUMEN
The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adolescente , Adulto , Animales , Antivirales/sangre , Antivirales/química , Antivirales/uso terapéutico , Carbamatos , Línea Celular , Chlorocebus aethiops , Farmacorresistencia Viral , Femenino , Genotipo , Células HeLa , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Imidazoles/sangre , Imidazoles/química , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Pirrolidinas , Factores de Tiempo , Valina/análogos & derivados , Células Vero , Carga Viral/efectos de los fármacos , Adulto JovenRESUMEN
Antiretroviral therapy can reduce human immunodeficiency virus type 1 (HIV-1) viremia to below the detection limit of ultrasensitive clinical assays (50 copies of HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4+ T cells, and low residual levels of free virus are found in the plasma. Limited characterization of this residual viremia has been done because of the low number of virions per sample. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4+ T cells in peripheral blood. For each patient, we found some viruses in the plasma that were identical to viruses in resting CD4+ T cells by pol gene sequencing. However, in a majority of patients, the most common viruses in the plasma were rarely found in resting CD4+ T cells even when the resting cell compartment was analyzed with assays that detect replication-competent viruses. Despite the large diversity of pol sequences in resting CD4+ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol sequences. In the most extensively studied case, a predominant plasma sequence was also found in analysis of the env gene, and linkage by long-distance reverse transcriptase PCR established that these predominant plasma sequences represented a single predominant plasma virus clone. The predominant plasma clones were released for months to years without evident sequence change. Thus, in some patients on antiretroviral therapy, the major mechanism for residual viremia involves prolonged production of a small number of viral clones without evident evolution, possibly by cells other than circulating CD4+ T cells. The sequences have been deposited in GenBank. The accession numbers are DQ 391282 to DQ 391351 (for env) and DQ 391352 to DQ 392955 (for RT).
Asunto(s)
Linfocitos T CD4-Positivos/virología , Productos del Gen env/genética , Genes pol/genética , Infecciones por VIH/genética , VIH-1/genética , ARN Viral/genética , Terapia Antirretroviral Altamente Activa , Secuencia de Bases , Evolución Molecular , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Datos de Secuencia Molecular , ARN Viral/sangre , Análisis de Secuencia de ARN , Especificidad de la Especie , Viremia/tratamiento farmacológico , Viremia/genéticaAsunto(s)
Fármacos Anti-VIH/efectos adversos , Enfermedad de Gilbert/complicaciones , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hiperbilirrubinemia/genética , Fármacos Anti-VIH/administración & dosificación , Pruebas Genéticas , Enfermedad de Gilbert/genética , HumanosRESUMEN
BACKGROUND: Effective therapeutic drug monitoring for antiretrovirals requires a better understanding of intraindividual variability in pharmacokinetics. METHODS: We determined concentrations of human immunodeficiency virus (HIV) protease and nonnucleoside reverse-transcriptase inhibitors for 10 patients with undetectable plasma HIV RNA levels who had been receiving stable regimens for > or = 11 months. Plasma samples were collected at the same time of day 3 times per week for up to 4 months. Patients were instructed to take their antiretrovirals at the same time every day. Plasma protease and nonnucleoside reverse-transcriptase inhibitor concentrations were determined using high-performance liquid chromatographic methods. Pharmacokinetic variability was expressed as intraindividual percentage coefficient of variation (ICV), which was calculated as the patient's standard deviation divided by the mean drug concentration for that patient. RESULTS: ICV was determined for 6 drugs for 10 patients, for a total of 17 different patient-drug combinations, using 600 total samples. ICV was unexpectedly high for most patients who were receiving protease inhibitors (ICVs for individual patients taking lopinavir/ritonavir were 24%, 33%, 51%, and 92%; for patients taking nelfinavir/M8 metabolite, they were 30%/44% and 39%/54%; for patients taking ritonavir, they were 34% and 43%; for patients taking saquinavir, they were 52% and 55%). ICVs for patients receiving nonnucleoside reverse-transcriptase inhibitors were lower (for patients receiving efavirenz, they were 7%, 13%, 29%, and 51%; for a patient receiving nevirapine, it was 25%). The median ICV for all patients receiving protease inhibitors (n = 12) was 43.5%, and for all patients receiving nonnucleoside reverse-transcriptase inhibitors (n = 5), the median ICV was 25%. CONCLUSIONS: Intraindividual variability in concentrations of antiretrovirals was surprisingly high in virologically suppressed patients. Possible contributors include food effects, concomitant use of prescription and herbal medications, assay variability, or medication timing, which was assessed by self-report. High intraindividual pharmacokinetic variability may limit the utility of single measurements in therapeutic drug monitoring for some antiretroviral agents.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Síndrome de Inmunodeficiencia Adquirida/sangre , Adulto , Terapia Antirretroviral Altamente Activa , VIH/aislamiento & purificación , Infecciones por VIH/sangre , Inhibidores de la Proteasa del VIH/sangre , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , ARN Viral/sangre , Reproducibilidad de los Resultados , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
Many patients on highly active antiretroviral therapy (HAART) who achieve undetectable HIV-1 RNA levels experience transient episodes of detectable viraemia or blips, suggesting there is incomplete suppression of viral replication. This raises concern that drug resistance mutations could develop and cause eventual treatment failure. However, data from recent studies indicate that most blips are actually random biological and statistical variations around a mean viral load below detectable levels (<50 copies/mL) or due to false elevations of viral load from laboratory processing artefacts. Blips are not typically associated with the development of resistance mutations and most importantly are not associated with virological or clinical failure of previously adequate HAART.
Asunto(s)
Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Carga Viral , Viremia/virología , Replicación Viral/efectos de los fármacos , Terapia Antirretroviral Altamente Activa , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , VIH-1/fisiología , Humanos , Viremia/tratamiento farmacológicoRESUMEN
PURPOSE OF REVIEW: Many patients on highly active antiretroviral therapy with undetectable levels of HIV-1 RNA experience viral load blips. True periods of detectable viremia raise concerns that regimen potency is inadequate to suppress viral replication completely, which could lead to the development of resistance. Because blips are not associated with long-term clinical or virological failure in most studies, there is uncertainty over their clinical significance. RECENT FINDINGS: Recent data help explain the lack of association between blips and clinical or virological failure. Many blips are not an actual rise in viral load, but instead represent normal biological fluctuations around a mean viral load below 50 copies/ml as well as statistical variations around the detection limit of the viral load assay. Some blips may also result from laboratory processing artefacts. Therefore, most blips are not reproducible on duplicate viral load measurements. With frequent viral load measurements, there is less correlation between blips and demographic, treatment, or HIV-associated clinical factors than previously reported. Likewise, many blips are often unrelated to intercurrent illnesses, vaccination, non-adherence, or decreases in antiretroviral drug concentrations. Most importantly, new genotypic resistance mutations do not develop before, during, or immediately after most blips. SUMMARY: Despite recent findings suggesting that many blips are laboratory or statistical aberrations, it remains important to differentiate blips from early virological failure or persistent detectable low-level viremia. Once the episode of detectable viremia is clearly defined as a blip, however, there should be no cause for clinical concern.