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1.
Antiviral Res ; 216: 105660, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37385475

RESUMO

BACKGROUND & AIMS: In the monotherapy arms of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956) evaluating the safety and efficacy of JNJ-56136379 (capsid assembly modulator-class E) with/without nucleos(t)ide analogue (NA), viral breakthroughs (VBT) were observed, leading to JNJ-56136379 monotherapy discontinuation. We present the viral sequencing analysis of JNJ-56136379±NA-treated hepatitis B virus (HBV)-infected patients. METHODS: The HBV full genome was sequenced using next generation sequencing. Baseline amino acid (aa) polymorphisms were defined as changes versus the universal HBV reference sequence (sequence read frequency >15%). Emerging mutations were defined as aa changes versus baseline sequence (frequency <1% at baseline and ≥15% post-baseline). RESULTS: 6/28 JNJ-56136379 75 mg monotherapy arm patients experienced VBT; all 6 had emerging JNJ-56136379-resistant variants T33N (n = 5; fold change [FC] = 85) or F23Y (n = 1; FC = 5.2). 1/32 JNJ-56136379 250 mg arm patients (genotype-E) had <1 log10 IU/mL decline in HBV DNA at Week 4, experienced VBT at Week 8, and carried the I105T baseline polymorphism (FC = 7.9), but had no emerging variants. Eight additional monotherapy-treated patients had shallow second phases of their HBV DNA profile and emerging T33N (n = 7) or F23Y (n = 1) variants. NA initiation (switch [75 mg arm]; add-on [250 mg arm]) in all monotherapy patients with VBT resulted in HBV DNA decline in all patients. No VBT was observed during JNJ-56136379+NA combination therapy. CONCLUSIONS: JNJ-56136379 monotherapy resulted in VBT and was associated with the selection of JNJ-56136379-resistant variants. Efficacy of NA treatment (de novo combination or rescue therapy for VBT) was not impacted, confirming the lack of cross-resistance between these drug classes. CLINICAL TRIAL NUMBER: NCT03361956.


Assuntos
Hepatite B Crônica , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Capsídeo/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Resultado do Tratamento , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Proteínas do Capsídeo/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Farmacorresistência Viral/genética
2.
Antivir Ther ; 28(3): 13596535231174273, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37226302

RESUMO

BACKGROUND: Pimodivir is a first-in-class polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A polymerase complex. The randomized double-blinded placebo-controlled phase 2b TOPAZ study demonstrated antiviral activity and safety of twice daily pimodivir alone (300 mg, 600 mg) or in combination with oseltamivir (pimodivir 600 mg, oseltamivir 75 mg) in adult study participants with acute uncomplicated influenza A. The detailed genotypic and phenotypic characterization of viral variants observed in this study are reported. METHODS: Population sequencing of PB2 and neuraminidase genes, and phenotypic susceptibility testing, were performed using baseline and last virus-positive post-baseline nasal swab samples. RESULTS: Sequencing of baseline samples in 206 of 223 (92.4%) randomized study participants with confirmed influenza A infection identified no polymorphisms at any predefined PB2 positions of interest for pimodivir and no phenotypic reduced susceptibility to pimodivir was observed. Post-baseline sequencing data for 105/223 (47.1%) participants identified emergence of PB2 mutations at amino acid positions of interest in 10 (9.5%) participants (pimodivir 300 mg: n = 3; 600 mg: n = 6; combination: n = 1; placebo: n = 0) and included positions S324, F325, S337, K376, T378, and N510. These emerging mutations were typically associated with decreased pimodivir susceptibility, but not viral breakthrough. No reduced phenotypic susceptibility was observed in the one (1.8%) participant with emerging PB2 mutations from the pimodivir plus oseltamivir group. CONCLUSIONS: Participants with acute uncomplicated influenza A treated with pimodivir in the TOPAZ study infrequently developed reduced susceptibility to pimodivir and combining pimodivir with oseltamivir further decreased the risk of reduced susceptibility development.


Assuntos
Vírus da Influenza A , Influenza Humana , Adulto , Humanos , Oseltamivir/uso terapêutico , Influenza Humana/tratamento farmacológico , Genótipo , Antivirais/farmacologia , Antivirais/uso terapêutico , Vírus da Influenza A/genética
3.
Nature ; 615(7953): 678-686, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36922586

RESUMO

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802-a highly potent DENV inhibitor that blocks the NS3-NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.


Assuntos
Antivirais , Vírus da Dengue , Dengue , Primatas , Proteínas não Estruturais Virais , Animais , Humanos , Camundongos , Antivirais/efeitos adversos , Antivirais/farmacologia , Antivirais/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Dengue/tratamento farmacológico , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/classificação , Vírus da Dengue/efeitos dos fármacos , Relação Dose-Resposta a Droga , Farmacorresistência Viral , Técnicas In Vitro , Terapia de Alvo Molecular , Primatas/virologia , Ligação Proteica/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Replicação Viral
4.
J Med Virol ; 94(7): 3101-3111, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35229317

RESUMO

Although vaccines are currently used to control the coronavirus disease 2019 (COVID-19) pandemic, treatment options are urgently needed for those who cannot be vaccinated and for future outbreaks involving new severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) strains or coronaviruses not covered by current vaccines. Thus far, few existing antivirals are known to be effective against SARS-CoV-2 and clinically successful against COVID-19. As part of an immediate response to the COVID-19 pandemic, a high-throughput, high content imaging-based SARS-CoV-2 infection assay was developed in VeroE6 African green monkey kidney epithelial cells expressing a stable enhanced green fluorescent protein (VeroE6-eGFP cells) and was used to screen a library of 5676 compounds that passed Phase 1 clinical trials. Eight drugs (nelfinavir, RG-12915, itraconazole, chloroquine, hydroxychloroquine, sematilide, remdesivir, and doxorubicin) were identified as inhibitors of in vitro anti-SARS-CoV-2 activity in VeroE6-eGFP and/or Caco-2 cell lines. However, apart from remdesivir, toxicity and pharmacokinetic data did not support further clinical development of these compounds for COVID-19 treatment.


Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Animais , Humanos , Antivirais/farmacologia , Células CACO-2 , Chlorocebus aethiops , Ensaios de Triagem em Larga Escala , Pandemias
5.
J Med Virol ; 93(7): 4454-4460, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33666253

RESUMO

Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID-19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID-19. Itraconazole, an antifungal agent, has been reported to have activity against animal coronaviruses. Using cell-based phenotypic assays, the in vitro antiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Itraconazole demonstrated antiviral activity in human Caco-2 cells (EC50 = 2.3 µM; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC50 = 3.6 µM). Remdesivir inhibited viral replication with an EC50 = 0.4 µM. Itraconazole and 17-OH itraconazole resulted in a viral yield reduction in vitro of approximately 2-log10 and approximately 1-log10 , as measured in both Caco-2 cells and VeroE6-eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS-441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3-log10 drop and >4-log10 drop in Caco-2 cells and VeroE6-eGFP cells, respectively. Itraconazole and 17-OH itraconazole exert in vitro low micromolar activity against SARS-CoV-2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15).


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Furanos/farmacologia , Itraconazol/farmacologia , Pirróis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Triazinas/farmacologia , Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Chlorocebus aethiops , Reposicionamento de Medicamentos , Humanos , Células Vero , Replicação Viral/efeitos dos fármacos
6.
J Med Virol ; 93(6): 3985-3990, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33300183

RESUMO

In AMBER and EMERALD, darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg demonstrated high virological response and low virological failure (VF) through week 96. Week 96 resistance analyses are presented. Post-baseline samples for genotyping/phenotyping were analyzed from protocol-defined-VFs with viral load (VL) ≥ 400 copies/ml at failure/later time points. Post-hoc analyses were deep sequencing (AMBER) and HIV-1 proviral DNA sequencing from baseline samples (VL < 50 copies/ml) (EMERALD). Through week 96 across studies, no darunavir, primary protease inhibitor (PI), or tenofovir resistance-associated-mutations (RAMs) occurred in patients continuing (N = 1125) or switching to D/C/F/TAF (N = 715). M184I/V (emtricitabine RAM) was detected in one patient in each arm of AMBER. In EMERALD D/C/F/TAF patients with prior VF and baseline genoarchive data (N = 98), 4% had darunavir RAMs, 36% emtricitabine RAMs, mainly at position 184 (32%), 4% tenofovir RAMs, and 19% ≥3 thymidine-analogue-associated-mutations at screening. The predicted phenotype showed 0% had reduced susceptibility to darunavir, 37% to emtricitabine, and 22% to tenofovir. All achieved VL < 50 copies/ml at week 96/prior discontinuation, with no VF. D/C/F/TAF has a high barrier to resistance; no darunavir, primary PI, or tenofovir RAMs occurred through 96 weeks in AMBER and EMERALD. In EMERALD, baseline archived darunavir, emtricitabine, and tenofovir RAMs in patients with prior VF did not preclude virologic response.


Assuntos
Alanina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Cobicistat/uso terapêutico , Darunavir/uso terapêutico , Farmacorresistência Viral Múltipla/genética , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Tenofovir/análogos & derivados , Alanina/administração & dosagem , Fármacos Anti-HIV/administração & dosagem , Cobicistat/administração & dosagem , Darunavir/administração & dosagem , Combinação de Medicamentos , Emtricitabina/administração & dosagem , HIV-1/genética , Análise de Sequência de DNA , Comprimidos , Tenofovir/administração & dosagem , Tenofovir/uso terapêutico , Carga Viral/efeitos dos fármacos
7.
HIV Res Clin Pract ; 21(2-3): 83-89, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32715952

RESUMO

BACKGROUND: The efficacy and high barrier to resistance of darunavir have been demonstrated across diverse populations with HIV-1 infection. OBJECTIVE: To evaluate post-baseline resistance among patients in studies of once-daily (QD) darunavir-based regimens and formulations. METHODS: The analysis included treatment-naïve and virologically failing or suppressed patients from 10 phase 2/3 studies (48-192 weeks in duration) of boosted darunavir 800 mg QD-based regimens. Three were phase 3 studies of the QD darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen. Post-baseline resistance was evaluated upon protocol-defined virologic failure (PDVF). Resistance-associated mutations (RAMs) were identified using International Antiviral Society-USA mutation lists. Phenotypic analyses varied across studies. RESULTS: Overall, 250 of 3635 patients in the analysis met PDVF criteria; 205 had post-baseline genotypes/phenotypes. In total, four (0.1%) patients developed (or had identified) ≥1 darunavir and/or primary protease inhibitor (PI) RAM; only one (<0.1%) patient (with prior lopinavir virologic failure) lost darunavir phenotypic susceptibility. Among 3317 patients using nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs; mostly emtricitabine and tenofovir), 13 (0.4%) had ≥1 N(t)RTI RAM (10 with M184I/V). Among patients receiving D/C/F/TAF (n = 1949), none had post-baseline darunavir, primary PI, or tenofovir RAMs; only two (0.1%) patients developed an emtricitabine RAM, M184V/I. CONCLUSIONS: Across a large, diverse population using darunavir 800 mg QD-based regimens and formulations, resistance development remains rare. After clinical trials that span >10 years, loss of phenotypic susceptibility to darunavir was only observed once in a PI-experienced patient and has never been observed in treatment-naïve patients, treatment-experienced PI-naïve patients, or treatment-experienced virologically suppressed patients.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Ensaios Clínicos como Assunto , Darunavir/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Interpretação Estatística de Dados , Esquema de Medicação , Humanos , Comprimidos , Carga Viral/efeitos dos fármacos
8.
Int J Infect Dis ; 97: 7-10, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32479865

RESUMO

OBJECTIVES: Given the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. METHODS: Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection. There are currently no definitive data on the safety and efficacy of DRV/cobicistat for the treatment of COVID-19. The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed. RESULTS: DRV showed no antiviral activity against SARS-CoV-2 at clinically relevant concentrations (EC50 > 100 µM). Remdesivir, used as a positive control, demonstrated potent antiviral activity (EC50 = 0.38 µM). CONCLUSIONS: Overall, the data do not support the use of DRV for the treatment of COVID-19.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Darunavir/uso terapêutico , Pandemias , Pneumonia Viral , Antivirais/uso terapêutico , COVID-19 , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pneumonia Viral/tratamento farmacológico , SARS-CoV-2
9.
J Viral Hepat ; 27(11): 1127-1137, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32579776

RESUMO

Four weeks of once-daily oral JNJ-56136379 (JNJ-6379; 25, 75, 150 or 250 mg), a class-N capsid assembly modulator (CAM-N), was well tolerated with potent antiviral activity in treatment-naïve, chronic hepatitis B e antigen-positive and hepatitis B e antigen-negative patients (NCT02662712). Hepatitis B virus (HBV) genome sequence analysis, using HBV DNA next-generation sequence technology, was performed, and impact of substitutions on efficacy was assessed. Analyses focused on HBV core protein amino acid positions associated with JNJ-6379 and/or other CAMs in vitro resistance, and those within the CAM-binding pocket. 31/57 patients had ≥ 1 polymorphism at any of the core amino acid positions of interest, most frequently at positions 38 (32%), 105 (23%) and 109 (14%). None of these polymorphisms are known to reduce JNJ-6379 in vitro activity (fold change [FC] in 50% effective concentration <3.0). Two JNJ-6379-treated patients carried a Y118F baseline core polymorphism known to reduce JNJ-6379 activity in vitro (FC = 6.6) and had HBV DNA declines of 2.77 (75 mg) and 2.19 log10 IU/mL (150 mg) at the end of treatment. One 75 mg JNJ-6379-treated patient had an emerging T109S substitution (FC = 1.8; HBV DNA decline 3.18 log10 IU/mL). A 25 mg JNJ-6379-treated patient had on-treatment enrichment of Y118F variant (HBV DNA decline 2.13 log10 IU/mL). In conclusion, baseline polymorphisms and enrichment of substitutions reducing JNJ-6379 in vitro activity were rare, with no consistent impact on virological response during a 4-week phase 1b study. Emergence of resistance to longer treatments of JNJ-6379 will be evaluated in phase 2 studies.


Assuntos
Vírus da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , Capsídeo , DNA Viral , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Resultado do Tratamento
10.
AIDS Res Hum Retroviruses ; 36(1): 48-57, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31516033

RESUMO

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL <50 copies/mL) in EMERALD. Through week 48 across both studies, no darunavir, primary PI, or tenofovir resistance-associated mutations (RAMs) were observed in HIV-1 viruses of 1,125 participants receiving D/C/F/TAF or 629 receiving boosted darunavir plus emtricitabine/tenofovir-disoproxil-fumarate. In AMBER, the nucleos(t)ide analog reverse transcriptase inhibitor (N(t)RTI) RAM M184I/V was identified in HIV-1 of one participant during D/C/F/TAF treatment. M184V was detected pretreatment as a minority variant (9%). In EMERALD, in participants with prior VF and genoarchive data (N = 140; 98 D/C/F/TAF and 42 control), 4% had viruses with darunavir RAMs, 38% with emtricitabine RAMs, mainly at position 184 (41% not fully susceptible to emtricitabine), 4% with tenofovir RAMs, and 21% ≥ 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response.


Assuntos
Adenina/análogos & derivados , Cobicistat/administração & dosagem , Darunavir/administração & dosagem , Farmacorresistência Viral , Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Adenina/administração & dosagem , Adulto , Alanina , Fármacos Anti-HIV/administração & dosagem , Esquema de Medicação , Combinação de Medicamentos , Infecções por HIV/epidemiologia , HIV-1/efeitos dos fármacos , Humanos , Inibidores da Transcriptase Reversa/administração & dosagem , Comprimidos/administração & dosagem , Tenofovir/análogos & derivados , Carga Viral/efeitos dos fármacos
11.
HIV Clin Trials ; 18(5-6): 196-204, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29143565

RESUMO

BACKGROUND: Darunavir 800 mg once daily (QD) is indicated for HIV-1-infected treatment-naïve and treatment-experienced (without darunavir resistance-associated mutations [RAMs]) individuals, and has been evaluated in phase 2/3 studies with durations between 48 and 192 weeks. OBJECTIVE: To summarize the development (or identification) of post-baseline resistance (RAMs and antiretroviral phenotypic susceptibility) among patients receiving darunavir QD dosing. METHODS: Seven phase 2/3 studies with available genotypes/phenotypes for subjects treated with ritonavir- or cobicistat-boosted darunavir 800 mg QD regimens were assessed: ARTEMIS (NCT00258557; n = 343), GS-US-299-0102 (NCT01565850; n = 153), GS-US-216-0130 (NCT01440569; n = 313), ODIN (NCT00524368; n = 294), INROADS (NCT01199939; n = 54), MONET (NCT00458302; n = 256), and PROTEA (NCT01448707; n = 273). Genotypic analyses were conducted at baseline (except switch studies enrolling virologically suppressed subjects [MONET, PROTEA]). Criteria for post-baseline resistance testing and evaluation of the development (or identification [switch studies]) of RAMs (respective IAS-USA mutations) varied slightly across studies. RESULTS: Among 1686 subjects treated with darunavir 800 mg QD regimens, 184 had protocol-defined virologic failure; 182 had post-baseline genotypes analyzed. Overall, 4/1686 (0.2%) developed (or had identified [switch studies]) primary protease inhibitor and/or darunavir RAMs (ARTEMIS, n = 1; GS-US-216-0130, n = 1; ODIN, n = 1; MONET, n = 1). Only 1/1686 (<0.1%) subject lost darunavir phenotypic susceptibility (ODIN; possibly related to prior ritonavir-boosted lopinavir virologic failure). Among 1103 subjects using a nucleos(t)ide reverse transcriptase inhibitor (N[t]RTI) backbone, 10 (0.9%) developed ≥ 1 N(t)RTI RAM (8 had the emtricitabine RAM M184I/V). CONCLUSIONS: Darunavir has a high genetic barrier to resistance. Across a diverse population of HIV-1-infected subjects treated with darunavir 800 mg QD regimens, the development of darunavir resistance was rare (<0.1%).


Assuntos
Fármacos Anti-HIV/administração & dosagem , Darunavir/administração & dosagem , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Cobicistat/administração & dosagem , Frequência do Gene , Genótipo , Técnicas de Genotipagem , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Mutação , Ritonavir/administração & dosagem
12.
Virol J ; 14(1): 101, 2017 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-28569206

RESUMO

BACKGROUND: In study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre-existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001. METHODS: HCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post-baseline isolates. RESULTS: The majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3-DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients. CONCLUSIONS: Virologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study. TRIAL REGISTRATION NUMBER: NCT01724086 (date of registration: September 26, 2012).


Assuntos
Antivirais/uso terapêutico , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Ritonavir/uso terapêutico , Simeprevir/uso terapêutico , Sulfonamidas/uso terapêutico , Carbamatos/uso terapêutico , Farmacorresistência Viral , Técnicas de Genotipagem , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Ribavirina/uso terapêutico , Análise de Sequência de DNA , Falha de Tratamento , Valina/análogos & derivados , Valina/uso terapêutico
13.
Open Forum Infect Dis ; 3(2): ofw052, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27186579

RESUMO

Background. The pre-existence of minority hepatitis C virus (HCV) variants and their impact on treatment outcome, as well as the persistence of emerging resistant variants posttreatment in patients failing treatment with simeprevir/peginterferon/ribavirin (SMV/PR), were assessed by deep sequencing (DS). Methods. Population sequencing (PS) and Illumina DS were performed on HCV genotype 1 isolates from patients treated with SMV/PR in Phase 2b (PILLAR [NCT00882908] and ASPIRE [NCT00980330]) and Phase 3 (QUEST-1 [NCT01289782], QUEST-2 [NCT01290679], and PROMISE [NCT01281839]) trials. Results. Minority polymorphisms (ie, detected pretreatment by DS only) reducing SMV activity in vitro were uncommon (3.6%, 19 of 534 patients). These SMV-resistant minority polymorphisms were detected in similar proportions of patients achieving (3.7%) and not achieving (3.3%) sustained virologic response with SMV/PR and generally did not emerge as major variants at time of failure. SMV-resistant variants emerging at time of failure were no longer detected at end of study in 69.3% and 52.0% of the patients by PS and DS, respectively. Conclusions. Minority polymorphisms did not impact outcome of SMV/PR treatment. The majority of emerging variants that became undetectable at end of study by PS were also undetectable by DS. These results suggest no added value of DS for clinical usage of SMV.

14.
Antivir Ther ; 21(4): 317-27, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26566161

RESUMO

BACKGROUND: We assessed etravirine resistance in treatment-experienced, HIV-1-infected children (n=41)/adolescents (n=60) who received twice-daily etravirine 5.2 mg/kg and a background regimen (boosted protease inhibitor plus nucleoside/nucleotide reverse transcriptase inhibitors, optional enfuvirtide/raltegravir) in a Phase II, open-label, multicentre trial (PIANO). METHODS: In addition to phenotypes, viral genotypes were assessed by population and deep sequencing (PS and DS) in virological failures (VFs; baseline and end point) and responders (baseline). Minority resistance-associated mutations (RAMs) were defined as those with frequencies above 1% and not detected with PS. RESULTS: By week 48, 41/101 (40.6%) patients experienced VF; 17/41 (41.5%) VFs and 22/54 (40.8%) responders had ≥1 baseline etravirine RAM by PS, mainly A98G, K101E, V106I and G190A. Baseline minority etravirine RAMs (n) were detected in 8/40 VFs (V90I [2], A98G [1], L100I [1], V106I [1], E138G [1] and Y181C [2]) and 5/38 responders (V90I [3], A98G [1], V106I [1] and E138G [1]). The most frequent emerging non-nucleoside reverse transcriptase inhibitor RAMs detected by PS (≥3 VFs; n) were the etravirine RAMs Y181C (8), V90I (3), L100I (3) and E138A (3). In 15 of 29 (51.7%) VFs with baseline DS/PS and end point PS data, ≥1 emerging etravirine RAM was detected by PS, which was not detected at baseline by DS in most cases (12/15 [80.0%]). In 10/26 (38.5%) VFs with baseline/end point DS data, ≥1 additional emerging minority etravirine RAM was detected. CONCLUSIONS: Patterns of etravirine resistance in adults, adolescents and children experiencing VF are similar. The presence of minority etravirine RAMs at baseline was not consistently associated with treatment failure. ClinicalTrials.gov: NCT00665847.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Piridazinas/uso terapêutico , Adolescente , Fármacos Anti-HIV/farmacologia , Criança , Evolução Molecular , Infecções por HIV/tratamento farmacológico , Humanos , Nitrilas , Piridazinas/farmacologia , Pirimidinas , Falha de Tratamento
15.
J Med Virol ; 88(5): 798-806, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26412111

RESUMO

Minority variants (1.0-25.0%) were evaluated by deep sequencing (DS) at baseline and virological failure (VF) in a selection of antiretroviral treatment-naïve, HIV-1-infected patients from the rilpivirine ECHO/THRIVE phase III studies. Linkage between frequently emerging resistance-associated mutations (RAMs) was determined. DS (llIumina®) and population sequencing (PS) results were available at baseline for 47 VFs and time of failure for 48 VFs; and at baseline for 49 responders matched for baseline characteristics. Minority mutations were accurately detected at frequencies down to 1.2% of the HIV-1 quasispecies. No baseline minority rilpivirine RAMs were detected in VFs; one responder carried 1.9% F227C. Baseline minority mutations associated with resistance to other non-nucleoside reverse transcriptase inhibitors (NNRTIs) were detected in 8/47 VFs (17.0%) and 7/49 responders (14.3%). Baseline minority nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) RAMs M184V and L210W were each detected in one VF (none in responders). At failure, two patients without NNRTI RAMs by PS carried minority rilpivirine RAMs K101E and/or E138K; and five additional patients carried other minority NNRTI RAMs V90I, V106I, V179I, V189I, and Y188H. Overall at failure, minority NNRTI RAMs and NRTI RAMs were found in 29/48 (60.4%) and 16/48 VFs (33.3%), respectively. Linkage analysis showed that E138K and K101E were usually not observed on the same viral genome. In conclusion, baseline minority rilpivirine RAMs and other NNRTI/NRTI RAMs were uncommon in the rilpivirine arm of the ECHO and THRIVE studies. DS at failure showed emerging NNRTI resistant minority variants in seven rilpivirine VFs who had no detectable NNRTI RAMs by PS.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , Sequenciamento de Nucleotídeos em Larga Escala , Rilpivirina/uso terapêutico , Adulto , Substituição de Aminoácidos , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Seleção Genética , Fatores de Tempo , Falha de Tratamento
16.
J Clin Virol ; 72: 133-40, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26513763

RESUMO

BACKGROUND: Monitoring HCV RNA levels during treatment is an important tool for managing protease-inhibitor-based regimens, and different assays used in clinical practice can impact treatment decisions. OBJECTIVES: The concordance of three HCV RNA assays was determined, and their impact on treatment decisions assessed using samples from HCV genotype (GT) 1- and GT4-infected patients treated with the NS3/4A inhibitor simeprevir in combination with pegylated interferon-α/ribavirin. STUDY DESIGN: Plasma samples collected during the simeprevir Phase III studies QUEST-1 and QUEST-2 (GT1), and RESTORE (GT4) were analyzed with the Roche High-Pure-System COBAS(®) TaqMan(®) HCV v2.0 (HPS), the Roche AmpliPrep COBAS(®) TaqMan(®) HCV v2.0 (CAP), and the Abbott RealTime HCV (ART) assay. RESULTS: In GT1, of the 440 samples, 81% were undetectable (rapid virological response; RVR) by HPS at Week 4, 76% by CAP and 44% by ART. In GT4 (103 samples), RVR rates were 67% by HPS and 24% by ART. HCV RNA <25IU/mL at Week 4 was observed for 95-96% and 92% GT1 samples and 86% and 74% GT4 samples by HPS/CAP and ART, respectively. At Week 12, assay concordance for undetectability was high in GT1 and GT4, (95-98% and 93%, respectively). CONCLUSIONS: While different HCV RNA assays can lead to substantially different RVR rates, a good concordance was observed with a cut-off of 25IU/mL. Sustained virologic response rates among GT1 patients achieving RVR or <25IU/mL at Week 4 were high and similar between assays used. At later time points, when viremia is low, assay concordance was high.


Assuntos
Antivirais/administração & dosagem , Monitoramento de Medicamentos/métodos , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , RNA Viral/sangue , Carga Viral/métodos , Ensaios Clínicos Fase III como Assunto , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Humanos , Interferon-alfa/administração & dosagem , Inibidores de Proteases , Estudos Retrospectivos , Ribavirina/administração & dosagem , Simeprevir/administração & dosagem
17.
Antimicrob Agents Chemother ; 59(12): 7548-57, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26392483

RESUMO

Simeprevir (TMC435) is a once-daily, single-pill, oral hepatitis C virus (HCV) NS3 protease inhibitor approved for the treatment of chronic HCV infection. Phenotypic characterization of baseline isolates and isolates from HCV genotype 1-infected patients failing with a simeprevir-based regimen was performed using chimeric replicons carrying patient-derived NS3 protease sequences. Cutoff values differentiating between full susceptibility to simeprevir (≤ 2.0-fold reduction in simeprevir activity) and low-level versus high-level resistance (≥ 50-fold reduction in simeprevir activity) were determined. The median simeprevir fold change in the 50% effective concentration (FC) of pretreatment genotype 1a isolates, with and without Q80K, and genotype 1b isolates was 11, 0.9, and 0.4, respectively. Naturally occurring NS3 polymorphisms that reduced simeprevir activity, other than Q80K, were uncommon in the simeprevir studies and generally conferred low-level resistance in vitro. Although the proportion of patients with failure differed by HCV geno/subtype and/or presence of baseline Q80K, the level of simeprevir resistance observed at failure was similarly high irrespective of type of failure, HCV genotype 1 subtype, and presence or absence of baseline Q80K. At the end of the study, simeprevir activity against isolates that lost the emerging amino acid substitution returned to pretreatment values. Activity of simeprevir against clinical isolates and site-directed mutant replicons harboring the corresponding single or double amino acid substitutions correlated well, showing that simeprevir resistance can be attributed to these substitutions. In conclusion, pretreatment NS3 isolates were generally fully susceptible (FC, ≤ 2.0) or conferred low-level resistance to simeprevir in vitro (FC, >2.0 and <50). Treatment failure with a simeprevir-based regimen was associated with emergence of high-level-resistance variants (FC, ≥ 50).


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Simeprevir/farmacologia , Proteínas não Estruturais Virais/genética , Substituição de Aminoácidos , Farmacorresistência Viral/genética , Expressão Gênica , Genótipo , Hepacivirus/enzimologia , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Testes de Sensibilidade Microbiana , Mutagênese Sítio-Dirigida , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , Polimorfismo Genético , Inibidores de Proteases/farmacologia , Replicon , Falha de Tratamento , Proteínas não Estruturais Virais/metabolismo
18.
J Clin Microbiol ; 53(4): 1264-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25653396

RESUMO

Protease inhibitor (PI)-based response-guided triple therapies for hepatitis C virus (HCV) infection are still widely used. Noncirrhotic treatment-naive and prior relapser patients receiving telaprevir-based treatment are eligible for shorter, 24-week total therapy if HCV RNA is undetectable at both weeks 4 and 12. In this study, the concordance in HCV RNA assessments between the Roche High Pure System/Cobas TaqMan and Abbott RealTime HCV RNA assays and the impacts of different HCV RNA cutoffs on treatment outcome were evaluated. A total of 2,629 samples from 663 HCV genotype 1 patients receiving telaprevir/pegylated interferon/ribavirin in OPTIMIZE were analyzed using the High Pure System and reanalyzed using Abbott RealTime (limits of detection, 15.1 IU/ml versus 8.3 IU/ml; limits of quantification, 25 IU/ml versus 12 IU/ml, respectively). Overall, good concordance was observed between the assays. Using undetectable HCV RNA at week 4, 34% of the patients would be eligible for shorter treatment duration with Abbott RealTime versus 72% with the High Pure System. However, using <12 IU/ml for Abbott RealTime, a similar proportion (74%) would be eligible. Of the patients receiving 24-week total therapy, 87% achieved a sustained virologic response with undetectable HCV RNA by the High Pure System or <12 IU/ml by Abbott RealTime; however, 92% of the patients with undetectable HCV RNA by Abbott RealTime achieved a sustained virologic response. Using undetectable HCV RNA as the cutoff, the more sensitive Abbott RealTime assay would identify fewer patients eligible for shorter treatment than the High Pure System. Our data confirm the <12-IU/ml cutoff, as previously established in other studies of the Abbott RealTime assay, to determine eligibility for shortened PI-based HCV treatment. (The study was registered with ClinicalTrials.gov under registration no. NCT01241760.).


Assuntos
Antivirais/uso terapêutico , Monitoramento de Medicamentos/métodos , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/uso terapêutico , RNA Viral/sangue , Carga Viral/métodos , Quimioterapia Combinada/métodos , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/uso terapêutico , Técnicas de Diagnóstico Molecular/métodos , Estudos Retrospectivos , Ribavirina/uso terapêutico , Resultado do Tratamento
19.
AIDS Res Hum Retroviruses ; 31(6): 628-35, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25684627

RESUMO

HIV-1 samples submitted by clinicians from the United States for routine drug susceptibility testing (PhenoSense GT) were evaluated for genotypic and phenotypic resistance to darunavir and other protease inhibitors (PIs). Among these samples (Monogram Biosciences database January 2006-June 2012; N=78,843), isolates harboring zero IAS-USA darunavir resistance-associated mutations (RAMs) increased from 77.7% in 2006 to 92.8% through the first half of 2012 (H1 2012; upward trend, p=0.0008); a downward trend seen for samples with three or more darunavir RAMs (7.5% in 2006 and 2.6% in H1 2012; p=0.002). Among samples with any PI resistance (N=15,932), samples harboring zero darunavir RAMs gradually increased (39.9% in 2006 vs. 55.0% in H1 2012; upward trend, p=0.005), but three or more darunavir RAMs did not change over time (21.7% in 2006 and 19.2% in H1 2012; p=0.27). During this period, the frequency of the 11 individual darunavir RAMs (IAS-USA 2011 list) decreased among all samples. The frequency of each darunavir RAM in PI-resistant samples decreased or remained relatively stable. The prevalence of samples with phenotypic resistance to darunavir (partial-to-full) decreased over time in all samples (8.2% in 2006 vs. 2.3% in H1 2012), as did resistance to other PIs (p<0.006 for all PIs). Phenotypic resistance to darunavir and other PIs also decreased in PI-resistant samples (darunavir: 23.9% in 2006 vs. 17.1% in H1 2012; p<0.013 for all PIs). Since approval of darunavir in 2006, there was a significant decrease in prevalence of samples with genotypic and phenotypic resistance to darunavir in commercially tested HIV-1 isolates. Furthermore, the prevalence of phenotypic resistance to darunavir was lower than all other PIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Darunavir/farmacologia , Farmacorresistência Viral , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Mutação , Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Prevalência , Estados Unidos/epidemiologia
20.
Antimicrob Agents Chemother ; 59(5): 2746-55, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25712364

RESUMO

In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, the rapid reselection of resistance-associated variants (RAVs) is well known in patients with repeated exposure to the same class of antiviral agents. For chronic hepatitis C patients who have experienced virologic failure with direct-acting antiviral drugs, the potential for the reselection of persistent RAVs is unknown. Nine patients who received 14 days of telaprevir monotherapy were retreated with telaprevir-based triple therapy 4.3 to 5.7 years later. In four patients with virologic failure with both telaprevir-containing regimens, population-based and deep sequencing (454 GS-FLX) of the NS3 protease gene were performed before and at treatment failure (median coverage, 4,651 reads). Using deep sequencing, with a threshold of 1.0% for variant calling, no isolates were found harboring RAVs at the baseline time points. While population-based sequencing uncovered similar resistance patterns (V36M plus R155K for subtype 1a and V36A for subtype 1b) in all four patients after the first and second telaprevir treatments, deep sequencing analysis revealed a median of 7 (range, 4 to 23) nucleotide substitutions on the NS3 backbone of the resistant strains, together with large phylogenetic differences between viral quasispecies, making the survival of resistant isolates highly unlikely. In contrast, in a comparison of the two baseline time points, the median number of nucleotide exchanges in the wild-type isolates was only 3 (range, 2 to 8), reflecting the natural evolution of the NS3 gene. In patients with repeated direct antiviral treatment, a continuous evolution of HCV quasispecies was observed, with no clear evidence of persistence and reselection but strong signs of independent de novo generation of resistance. Antiviral therapy for chronic viral infections, like HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV), faces several challenges. These viruses have evolved survival strategies and proliferate by escaping the host's immune system. The development of direct-acting antiviral agents is an important achievement in fighting these infections. Viral variants conferring resistance to direct antiviral drugs lead to treatment failure. For HIV/HBV, it is well known that viral variants associated with treatment failure will be archived and reselected rapidly during retreatment with the same drug/class of drugs. We explored the mechanisms and rules of how resistant variants are selected and potentially reselected during repeated direct antiviral therapies in chronically HCV-infected patients. Interestingly, in contrast to HIV and HBV, we could not prove long-term persistence and reselection of resistant variants in HCV patients who failed protease inhibitor-based therapy. This may have important implications for the potential to reuse direct-acting antivirals in patients who failed the initial direct antiviral treatment. (The phase IIIb study described in this paper is registered at ClinicalTrials.gov under registration number NCT01054573.).


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Oligopeptídeos/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Método Duplo-Cego , Hepatite C , Humanos
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