RESUMO
Tenofovir alafenamide fumarate is a lipophilic prodrug of tenofovir which is preferentially metabolized in lymphatic tissue resulting in high concentrations of tenofovir (TFV) and its active diphosphate metabolite inside the cells that replicate HIV. Due to its selectivity for these tissues, lower total doses of TAF can be administered relative to tenofovir disoproxil fumarate (TDF) which results in improved bone and renal biomarkers. Tenofovir alafenamide fumarate has become the "backbone" of multiple combination products for the treatment of HIV, combined with emtricitabine for PreP and as a monotherapy for the treatment or HBV.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adenina , Alanina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Fumaratos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Tenofovir/análogos & derivados , Tenofovir/uso terapêuticoRESUMO
OBJECTIVES: Accurate assays for hepatitis C virus (HCV) quantitation and genotyping are important for the management of HCV infection. In this study, we evaluated the performance of cobas HCV and cobas HCV GT assays (Roche) for HCV quantitation and genotyping on the cobas 4800 System. METHODS: We compared the performance of the cobas HCV assays with another commercial system (Abbott m2000) using a panel of well-characterized patient samples and proficiency testing samples. RESULTS: The limit-of-detection of the cobas HCV assay in our center was higher (15 IU/mL) than the manufacturer claim (9.2 IU/mL). The assay showed high analytical specificity, accuracy, precision, and linearity. Performance was congruent with the RealTime HCV assay (Abbott). For genotyping, the cobas HCV GT assay only showed moderate agreement with the RealTime HCV Genotype II assay (kappa = 0.550). The cobas assay outperformed the RealTime assay for typing HCV genotypes 1b and 6 (p = 0.033). CONCLUSION: Our results confirm that the cobas 4800 System is a reliable platform for HCV quantitation and genotyping. The cobas HCV GT assay is a good choice for genotype 1b/6 endemic areas in east Asia, clearly outperforming the RealTime HCV Genotype II assay.
Assuntos
Genótipo , Técnicas de Genotipagem , Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/virologia , Técnicas de Genotipagem/métodos , Técnicas de Genotipagem/normas , Humanos , RNA Viral , Kit de Reagentes para Diagnóstico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Carga ViralRESUMO
Several commercial PCR kits are available for detection of herpes simplex virus (HSV) and varicella zoster virus (VZV), but the test performance of one CE-marked in vitro diagnostic kit-RealStar® alpha Herpesvirus PCR Kit-has not been well studied. This study evaluated the performance of RealStar® alpha Herpesvirus PCR Kit 1.0 on the LightCycler® 480 Instrument II for detection and differentiation of HSV-1, HSV-2, and VZV in human clinical specimens. We evaluated the analytical sensitivity of the RealStar® and in-house multiplex real-time PCR assays using serial dilutions of nucleic acids extracted from clinical specimens. The analytical sensitivity of the RealStar® assay was 10, 32, and 100 copies/reaction for HSV-1, HSV-2, and VZV, respectively, which was slightly higher than that of the in-house multiplex real-time PCR assay. Reproducibility of the cycle threshold (Cp) values for each viral target was satisfactory with the intra- and interassay coefficient of variation values below 5% for both assays. One-hundred and fifty-three clinical specimens and 15 proficiency testing samples were used to evaluate the diagnostic performance of RealStar® alpha Herpesvirus PCR Kit against the in-house multiplex real-time PCR assay. The RealStar® assay showed 100% sensitivity and specificity when compared to the in-house assay. Cp values of the RealStar® and in-house assays showed excellent correlation. RealStar® alpha Herpesvirus PCR is a sensitive, specific, and reliable assay for the detection of HSV-1, HSV-2, and VZV, with less extensive verification requirements compared to a laboratory developed assay.
Assuntos
Herpesvirus Humano 1/genética , Herpesvirus Humano 2/genética , Herpesvirus Humano 3/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , DNA Viral/genética , Herpes Simples/virologia , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Human adenoviruses are common causes of community-acquired respiratory tract and enteric infections. Severe disseminated infections with high mortality rates may be seen in immunocompromised individuals. An accurate and cost-effective quantitative assay is essential not only for laboratory diagnosis of adenoviral infections, but also for monitoring of response to antiviral treatment. The diagnostic performance of an in-house quantitative polymerase chain reaction assay was compared to a commercial system. METHODS: The analytical sensitivity, specificity, linearity, precision and accuracy of an in-house adenovirus quantitative polymerase chain reaction assay were evaluated against the RealStar® Adenovirus PCR Kit (Altona Diagnostics GmbH, Hamburg, Germany), using 122 clinical specimens and 18 proficiency testing samples. RESULTS: Linear regression analysis of the quantitative results by the in-house assay showed the dynamic range from 2.60 to 9 log10 (plasma) and 2.94 to 9 log10 (viral transport medium) copies/mL, with the coefficient of determination (R2) of 0.996 and 0.998, respectively. A dilution series demonstrated the limits of detection and lower limits of quantification for plasma were 2.06 log10 and 2.60 log10 copies/mL and those for viral transport medium were 2.31 log10 and 2.94 log10 copies/mL respectively. The precision of the in-house assay was highly reproducible among runs with coefficients of variance ranging from 0.07 to 3.21% for plasma and 0.17% to 2.11% for viral transport medium. A comparison of 52 matched samples showed an excellent correlation between the quantitative viral loads measured by the in-house assay and the RealStar® Adenovirus PCR Kit (R2 = 0.984), with an average bias of - 0.16 log10 copies/mL. CONCLUSIONS: The in-house adenovirus assay is a sensitive and reliable assay with lower cost for the detection and quantification of adenoviral DNA when compared to the RealStar® Adenovirus PCR Kit.
Assuntos
Infecções por Adenoviridae/virologia , Adenovírus Humanos/isolamento & purificação , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Carga Viral/métodos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: HHV-6 reactivation in immunocompromised patients is common and may be associated with serious morbidity and mortality; therefore, early detection and initiation of therapy might be of benefit. Real-time PCR assays allow for early identification of HHV-6 reactivation to assist in providing a timely response. Thus, we compared the performance of an in-house developed HHV-6 quantitative PCR assay with a commercially available kit, the RealStar® HHV-6 PCR Kit. METHOD: The analytical sensitivity, analytical specificity, linearity, precision and accuracy of the in-house developed HHV-6 qPCR assay were evaluated. The diagnostic performance of the in-house HHV-6 qPCR assay was compared with the RealStar® HHV-6 PCR Kit, using 72 clinical specimens and 17 proficiency testing samples. RESULTS: Linear regression analysis of the quantitative results showed a dynamic range from 2 to 10 log10 copies/ml and a coefficient of determination (R2) of 0.999 for the in-house assay. A dilution series demonstrated a limit of detection and a limit of quantification of 1.7 log10 and 2 log10 copies/ml, respectively. The precision of the assay was highly reproducible among runs with coefficients of variance (CV) ranging from 0.27% to 4.37%. A comparison of 27 matched samples showed an excellent correlation between the quantitative viral loads measured by the in-house HHV-6 qPCR assay and the RealStar® HHV-6 PCR Kit (R2=0.926; P<0.0001), with an average bias of -0.24 log10 copies/ml. CONCLUSIONS: The in-house developed HHV-6 qPCR method is a sensitive and reliable assay with lower cost for the detection and quantification of HHV-6 DNA when compared to the RealStar® HHV-6 PCR Kit.
Assuntos
Herpesvirus Humano 6/genética , Herpesvirus Humano 6/isolamento & purificação , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Infecções por Roseolovirus/virologia , Biópsia , DNA Viral , Humanos , Fígado/patologia , Fígado/virologia , Kit de Reagentes para Diagnóstico , Infecções por Roseolovirus/diagnóstico , Sensibilidade e Especificidade , Carga Viral/métodosRESUMO
BACKGROUND: Emtricitabine with tenofovir disoproxil fumarate is a standard-of-care nucleoside reverse transcriptase inhibitor (NRTI) backbone. However, tenofovir disoproxil fumarate is associated with renal and bone toxic effects; the novel prodrug tenofovir alafenamide achieves 90% lower plasma tenofovir concentrations. We aimed to further assess safety and efficacy of fixed-dose combination emtricitabine with tenofovir alafenamide in patients switched from emtricitabine with tenofovir disoproxil fumarate. METHODS: In this controlled, double-blind, multicentre phase 3 study, we recruited virologically suppressed (HIV RNA <50 copies per mL) patients with HIV aged 18 years and older receiving regimens containing fixed-dose combination emtricitabine with tenofovir disoproxil fumartate from 78 sites in North America and Europe. Patients were randomly assigned (1:1) to switch to fixed-dose 200 mg emtricitabine with 10 mg or 25 mg tenofovir alafenamide or to continue 200 mg emtricitabine with 200 mg or 300 mg tenofovir disoproxil fumarate, while remaining on the same third agent for 96 weeks. Randomisation was done by a computer-generated allocation sequence and was stratified by the third agent (boosted protease inhibitor vs other agent). Investigators, patients, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary outcome was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the US Food and Drug Administration snapshot algorithm with a prespecified non-inferiority margin of 10%. The primary efficacy endpoint was analysed with the per-protocol analysis set, whereas the safety analysis included all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02121795. FINDINGS: We recruited patients between May 6, 2011, and Sept 11, 2014; 780 were screened and 668 were randomly assigned to receive either tenofovir alafenamide (n=333) or tenofovir disoproxil fumarate (n=330). Through week 48, virological success (HIV-1 RNA <50 copies per mL) was maintained in 314 (94%) of patients in the tenofovir alafenamide group compared with 307 (93%) in the tenofovir disoproxil fumarate group (difference 1·3%, 95% CI -2·5 to 5·1), showing non-inferiority of tenofovir alafenamide to tenofovir disproxil fumarate. Seven patients in the tenofovir alafenamide (2%) and three (1%) in the tenofovir disoproxil fumarate group discontinued due to adverse events. There were no cases of proximal renal tubulopathy in either group. INTERPRETATION: In patients switching from emtricitabine with tenofovir disoproxil fumarate to emtricitabine with tenofovir alafenamide, high rates of virological suppression were maintained. With its safety advantages, fixed-dose emtricitabine with tenofovir alafenamide has the potential to become an important NRTI backbone. FUNDING: Gilead Sciences.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Tenofovir/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Alanina , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Método Duplo-Cego , Emtricitabina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tenofovir/administração & dosagem , Tenofovir/efeitos adversosRESUMO
BACKGROUND: Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate. METHODS: In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736. FINDINGS: Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6-6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group. INTERPRETATION: Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING: Gilead Sciences.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Tenofovir/uso terapêutico , Adenina/administração & dosagem , Adenina/uso terapêutico , Adulto , Alanina , Contagem de Linfócito CD4 , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral , Carga ViralRESUMO
BACKGROUND: Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens. METHODS: In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445. FINDINGS: We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks. INTERPRETATION: Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile. FUNDING: Gilead Sciences.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Carbamatos/administração & dosagem , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Organofosfonatos/administração & dosagem , Quinolonas/administração & dosagem , Tiazóis/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adulto , Alanina , Fármacos Anti-HIV/efeitos adversos , Artralgia/induzido quimicamente , Densidade Óssea/efeitos dos fármacos , Contagem de Linfócito CD4 , Carbamatos/efeitos adversos , Cobicistat , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Emtricitabina , Feminino , Infecções por HIV/virologia , Cefaleia/induzido quimicamente , Humanos , Rim/efeitos dos fármacos , Masculino , Náusea , Organofosfonatos/efeitos adversos , Quinolonas/efeitos adversos , Transtornos Respiratórios/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Tenofovir , Tiazóis/efeitos adversos , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: The safety and efficacy of tenofovir disoproxil fumarate (TDF) in HIV-1-infected children have not been evaluated in a randomized controlled trial. METHODS: Subjects (2 to <16 years) on a stavudine (d4T) or zidovudine (ZDV) containing regimen with HIV-1 RNA <400 copies/mL were randomized to either switch d4T or ZDV to TDF or continue d4T or ZDV. The primary endpoint was the proportion of subjects with HIV-1 RNA < 400 copies/mL at Week 48 with a prespecified noninferiority margin of 15%. After the 48-week randomized phase, eligible subjects were rolled over to an extension phase. RESULTS: Ninety-seven children (48 TDF vs. 49 d4T or ZDV) were randomized and treated. The percent of subjects who maintained virologic suppression in the TDF versus d4T or ZDV group at Week 24 were 93.8% versus 89.8% (difference 4.0%; 95% confidence interval:: -6.9% to 14.9%) and at Week 48 were 83.3% versus 91.8% (difference: -8.5%; 95% confidence interval: -21.5% to 4.5%; missing = failure, intent-to-treat analysis). No subjects discontinued study drug because of an adverse event in the 48 weeks of randomized phase. Four subjects discontinued TDF because of proximal renal tubulopathy in the extension phase. CONCLUSIONS: Our study did not demonstrate noninferiority of TDF versus d4T or ZDV at Week 48. Overall safety and tolerability of TDF in children were consistent with adults. TDF may be considered as an alternative to d4T or ZDV in HIV-infected children.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Organofosfonatos/uso terapêutico , Estavudina/uso terapêutico , Zidovudina/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adolescente , Fármacos Anti-HIV/efeitos adversos , Criança , Pré-Escolar , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Organofosfonatos/efeitos adversos , RNA Viral/sangue , Estavudina/efeitos adversos , Tenofovir , Resultado do Tratamento , Carga Viral , Zidovudina/efeitos adversosRESUMO
BACKGROUND: Here, the baseline and emergent resistance to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) versus efavirenz (EFV)/FTC/TDF in HIV-1-infected antiretroviral-naive adults through 144 weeks from the randomized, ongoing, Phase III study GS-US-236-0102 is described. METHODS: HIV-1 protease (PR) and reverse transcriptase (RT) were sequenced at screening; patients with HIV-1 resistant to EFV, FTC or TDF were excluded. Genotypic/phenotypic analyses were performed at virological failure confirmation and baseline for PR, RT and integrase (IN) for patients with virological failure and for patients with HIV-1 RNA≥400 copies/ml at weeks 48, 96, 144 or early study drug discontinuation. Retrospective, baseline, IN genotyping was conducted for EVG/COBI/FTC/TDF patients. RESULTS: In the EVG/COBI/FTC/TDF group through week 144, HIV-1 from 10 patients (2.9%; 10/348 treated patients) developed primary IN strand transfer inhibitor (n=9) and/or nucleoside RT inhibitor resistance substitutions (n=10). The emergence of resistance decreased over time with 8, 2 and 0 patients developing HIV-1 resistance through week 48, post-week 48-96 and post-week 96-144, respectively. Emergent substitutions were E92Q (n=7), N155H (n=3), Q148R (n=1) and T66I (n=1) in IN, and M184V/I (n=10) and K65R (n=4) in RT. All 10 isolates had reduced susceptibility to EVG, FTC or TDF. Virus with EVG phenotypic resistance had cross-resistance to raltegravir. In the EFV/FTC/TDF group, virus from 14 patients (4.0%; 14/352 treated patients; 4 during weeks 96-144) developed a resistance substitution to EFV (n=14; K103N: n=13), FTC (M184V/I: n=4) or TDF (K65R: n=3). CONCLUSIONS: Resistance development to EVG/COBI/FTC/TDF was infrequent through 144 weeks of therapy and decreased over time, consistent with durable efficacy.
Assuntos
Terapia Antirretroviral de Alta Atividade , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Alcinos , Benzoxazinas/administração & dosagem , Cobicistat/administração & dosagem , Ciclopropanos , Emtricitabina/administração & dosagem , Feminino , Genótipo , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Mutação , Quinolonas/administração & dosagem , Tenofovir/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
In HIV-1-infected treatment-naive patients with mild-to-moderate renal impairment [creatinine clearance (CrCl): 50-89 mL/min], elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB, n = 33) achieved high rates of virologic success (78.8%; 95% confidence interval: 61.1% to 91.0%) and was well tolerated through week 48. Four patients discontinued study drug due to an adverse event and none due to proximal renal tubulopathy. As expected, decreases in CrCl were noted as early as week 2, after which they stabilized. The renal safety profile of STB in patients from this study is consistent with the long-term experience in a large number of patients with CrCl ≥70 mL/min.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/patologia , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Carbamatos/efeitos adversos , Carbamatos/uso terapêutico , Cobicistat , Estudos de Coortes , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Emtricitabina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Organofosfonatos/uso terapêutico , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Tenofovir , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To describe baseline and emergent HIV-1 resistance to elvitegravir/ cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) and ritonavir-boosted atazanavir/emtricitabine/tenofovir DF (ATV+RTV+FTC/TDF) in HIV-1-infected, treatment-naïve subjects through 144 weeks. METHOD: This was a randomized, double-blind, phase 3 study. HIV-1 protease (PR) and reverse transcriptase (RT) were sequenced at screening. Genotypic and phenotypic analyses were performed at virologic failure confirmation and retrospectively at baseline for PR, RT, and integrase (IN) for patients with virologic failure through week 144. RESULTS: In the EVG/ COBI/FTC/TDF group through week 144, HIV-1 from 8 patients (2.3%; 8/353 treated patients) developed primary IN strand transfer inhibitor (INSTI) (n = 6) and/or nucleoside RT inhibitor (NRTI) resistance substitutions (n = 7). The emergence of resistance decreased after the first year, with 5 patients developing HIV-1 resistance through week 48, 1 from weeks 48-96, and 2 from weeks 96-144. Emergent substitutions were E92Q, N155H, or Q148R (n = 2 each) and T66I or T97A (n = 1 each) in IN and M184V/I (n = 7) and K65R (n = 1) in RT. All 8 isolates had reduced susceptibility to EVG, FTC, or TDF. Virus with EVG phenotypic resistance showed cross-resistance to raltegravir. In the ATV+RTV+FTC/TDF group, HIV-1 from 2 patients (0.6%; 2/355 treated patients; both at week 144) developed the resistance substitution M184V/I in RT. CONCLUSIONS: Resistance development to EVG/COBI/FTC/TDF was infrequent (2.3%) through 144 weeks of therapy and decreased over time, consistent with durable efficacy.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adenina/administração & dosagem , Adenina/análogos & derivados , Adenina/uso terapêutico , Sulfato de Atazanavir , Carbamatos/administração & dosagem , Carbamatos/uso terapêutico , Cobicistat , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Farmacorresistência Viral/genética , Quimioterapia Combinada , Emtricitabina , HIV/efeitos dos fármacos , HIV/genética , Humanos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Organofosfonatos/administração & dosagem , Organofosfonatos/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Quinolonas/administração & dosagem , Quinolonas/uso terapêutico , RNA Viral/genética , RNA Viral/isolamento & purificação , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Tenofovir , Tiazóis/administração & dosagem , Tiazóis/uso terapêuticoAssuntos
Fármacos Anti-HIV/administração & dosagem , Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , Comprimidos/administração & dosagem , Adolescente , Adulto , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Masculino , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. OBJECTIVE: This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. METHODS: This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (≥3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. RESULTS: At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. CONCLUSIONS: Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Alcinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Benzoxazinas/uso terapêutico , Ciclopropanos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Antagonismo de Drogas , Emtricitabina , Feminino , Infecções por HIV/epidemiologia , HIV-1/genética , HIV-1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Organofosfonatos/administração & dosagem , Organofosfonatos/efeitos adversos , Organofosfonatos/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , RNA Viral , Rilpivirina , Tenofovir , Estados Unidos , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer with no antiretroviral activity in vitro. METHODS: An international, randomized, double-blind, double-dummy, active-controlled trial was conducted to evaluate the efficacy and safety of COBI versus ritonavir (RTV) as a pharmacoenhancer of atazanavir (ATV) in combination with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in treatment-naive patients. The primary end point was a human immunodeficiency virus type 1 (HIV-1) RNA load of <50 copies/mL at week 48 by the Food and Drug Administration snapshot algorithm; the noninferiority margin was 12%. RESULTS: A total of 692 patients were randomly assigned to a treatment arm and received study drug (344 in the COBI group vs 348 in the RTV group). At week 48, virologic success was achieved in 85% of COBI recipients and 87% of RTV recipients (difference, -2.2% [95% confidence interval, -7.4% to 3.0%]); among patients with a baseline HIV-1 RNA load of >100 000 copies/mL, rates were similar (86% vs 86%). Similar percentages of patients in both groups had serious adverse events (10% of COBI recipients vs 7% of RTV recipients) and adverse events leading to discontinuation of treatment with the study drug (7% vs 7%). Median increases in the serum creatinine level were 0.13 and 0.09 mg/dL, respectively, for COBI and RTV recipients. CONCLUSIONS: COBI was noninferior to RTV in combination with ATV plus FTC/TDF at week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the 2 regimens were comparable. Once-daily COBI is a safe and effective pharmacoenhancer of the protease inhibitor ATV.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Carbamatos/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Oligopeptídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Piridinas/uso terapêutico , Ritonavir/uso terapêutico , Tiazóis/uso terapêutico , Adenina/administração & dosagem , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Sulfato de Atazanavir , Carbamatos/administração & dosagem , Cobicistat , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Emtricitabina , Feminino , Inibidores da Protease de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , Humanos , Masculino , Oligopeptídeos/administração & dosagem , Organofosfonatos/administração & dosagem , Piridinas/administração & dosagem , Ritonavir/administração & dosagem , Tenofovir , Tiazóis/administração & dosagem , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
We report week 96 results from a phase 3 trial of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF, n = 348) vs efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF, n = 352). At week 48, EVG/COBI/FTC/TDF was noninferior to EFV/FTC/TDF (88% vs 84%, difference +3.6%, 95% confidence interval: -1.6% to 8.8%). Virologic success (HIV-1 RNA <50 copies/mL) was maintained at week 96 (84% vs 82%, difference +2.7%, 95% CI: -2.9% to 8.3%). Discontinuation due to adverse events was low (5% vs 7%). Median changes in serum creatinine (mg/dL) at week 96 were similar to week 48. These results support the durable efficacy and long-term safety of EVG/COBI/FTC/TDF.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV , Carbamatos , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Organofosfonatos , Oxazinas , Quinolonas , Tiazóis , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Carbamatos/uso terapêutico , Creatinina/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Combinação Efavirenz, Emtricitabina, Fumarato de Tenofovir Desoproxila , Combinação Elvitegravir, Cobicistat, Emtricitabina e Fumarato de Tenofovir Desoproxila , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Masculino , Organofosfonatos/administração & dosagem , Organofosfonatos/efeitos adversos , Organofosfonatos/uso terapêutico , Oxazinas/efeitos adversos , Oxazinas/uso terapêutico , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , RNA Viral/sangue , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
This ongoing, randomized, double-blind, active-controlled phase 3 international trial demonstrated the noninferior efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) compared with atazanavir boosted by ritonavir (ATV/RTV) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) at 48 weeks. Here, we report the week 96 results. Of 708 treated subjects, virological success (Food and Drug Administration snapshot) was maintained at week 96 with EVG/COBI/FTC/TDF and ATV/RTV + FTC/TDF (83% vs 82%, difference 1.1%, 95% confidence interval -4.5% to 6.7%). Study drug discontinuations due to adverse events were low (4% vs 6%). Median increases from baseline in serum Cr (mg/dL) in EVG/COBI/FTC/TDF vs ATV/RTV + FTC/TDF at week 96 (0.12 vs 0.08) were similar to those at week 48 (0.12 vs 0.08). EVG/COBI/FTC/TDF showed similar mean decreases (%) in bone mineral density from baseline vs ATV/RTV + FTC/TDF (hip: -3.16 vs -4.19, P = 0.069; spine: -1.96 vs -3.54, P = 0.049). Overall, week 96 results support durable efficacy and safety of EVG/COBI/FTC/TDF in HIV-1-infected patients.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Sulfato de Atazanavir , Bilirrubina/sangue , Densidade Óssea/efeitos dos fármacos , Carbamatos/uso terapêutico , Cobicistat , Intervalos de Confiança , Creatinina/sangue , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Emtricitabina , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Oligopeptídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Piridinas/uso terapêutico , Quinolonas/uso terapêutico , RNA Viral/sangue , Ritonavir/uso terapêutico , Tenofovir , Tiazóis/uso terapêutico , Triglicerídeos/sangueRESUMO
BACKGROUND: The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection. METHODS: This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1:1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586. FINDINGS: 1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89·5%] vs 308 patients [86·8%], adjusted difference 3·0%, 95% CI -1·9% to 7·8%). Both regimens had favourable safety and tolerability; 13 (3·7%) versus 18 (5·1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 µmol/L vs 260 µmol/L, p=0·006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 µmol/L vs 7 µmol/L). INTERPRETATION: If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment. FUNDING: Gilead Sciences.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Sulfato de Atazanavir , Carbamatos/administração & dosagem , Cobicistat , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Combinação de Medicamentos , Emtricitabina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Organofosfonatos/administração & dosagem , Piridinas/administração & dosagem , Quinolonas/administração & dosagem , Ritonavir/administração & dosagem , Tenofovir , Tiazóis/administração & dosagemRESUMO
BACKGROUND: The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection. METHODS: In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796. FINDINGS: 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI -1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 µmol/L, IQR 5 to 20 vs 1 µmol/L, -6 to 8; p<0·001). INTERPRETATION: If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection. FUNDING: Gilead Sciences.