Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
1.
J Viral Hepat ; 30(1): 19-28, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36201354

RESUMO

ATI-2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI-2173. This was a phase 1b, randomized, double-blind, placebo-controlled trial in treatment-naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.gov: NCT04248426). Patients positive for hepatitis B surface antigen were randomized 6:2 to receive once-daily oral doses of ATI-2173 10, 25, or 50 mg (n = 6 per dose) or placebo (n = 7) for 28 days, with off-treatment monitoring for 24 weeks. Endpoints included PK parameters of ATI-2173 and its metabolite clevudine, maximum reduction from baseline in HBV DNA, and safety and tolerability. Treatment-emergent adverse events occurred in eight patients (47%) receiving ATI-2173 and five (71%) receiving placebo; headache was the most common (n = 4). ATI-2173 PK was generally dose proportional. Systemic clevudine exposure with ATI-2173 dosing was substantially reduced compared with historical values observed with clevudine administration. On Day 28, mean changes from baseline in HBV DNA were -2.72 to -2.78 log10  IU/ml with ATI-2173 and +0.17 log10  IU/ml with placebo. Off-treatment sustained viral suppression and decreases in covalently closed circular DNA biomarkers were observed in most patients; one maintained undetectable HBV DNA at 24 weeks off treatment. In this 28-day monotherapy study, ATI-2173 demonstrated safety and antiviral activity, with sustained off-treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI-2173 with tenofovir disoproxil fumarate in phase 2 studies.


Assuntos
Hepatite B Crônica , Adulto , Humanos , Nucleotídeos/uso terapêutico , DNA Viral , Domínio Catalítico , Antígenos E da Hepatite B , Antivirais/efeitos adversos , Vírus da Hepatite B/genética
2.
Artigo em Inglês | MEDLINE | ID: mdl-32540975

RESUMO

ATI-2173 is a novel liver-targeted molecule designed to deliver the 5'-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5'-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5'-phosphoramidate to deliver the 5'-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5'-monophosphate is converted to the active 5'-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5'-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5'-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5'-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.


Assuntos
Hepatite B Crônica , Hepatite B , Antivirais/farmacologia , Antivirais/uso terapêutico , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Nucleotídeos/uso terapêutico
3.
J Clin Pharmacol ; 49(6): 725-34, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19395586

RESUMO

Telbivudine is a new nucleoside analog indicated for the treatment of chronic hepatitis B infection. A population pharmacokinetic model was developed based on data pooled from 16 early phase studies in 363 healthy participants and patients. Telbivudine was administered as single and/or multiple doses of 25 to 1800 mg daily for up to 28 days. A 2-compartment model with first-order input and lag time provided the best fit to the data. A final model was built with identified covariates, including creatinine clearance on plasma clearance, dose and race on bioavailability fraction, and body weight on central volume of distribution. The final model was applied to simulate steady-state exposure for patients with impaired renal function for various dosing regimens. Results from these simulation analyses support that in patients with moderate to severe renal impairment or end-stage renal disease, reduced daily doses of telbivudine could be an alternative to interval adjustment to achieve exposure comparable to patients with normal renal function or mild renal impairment treated with the full clinical dose.


Assuntos
Antivirais/administração & dosagem , Antivirais/farmacocinética , Nefropatias/metabolismo , Nucleosídeos/administração & dosagem , Nucleosídeos/farmacocinética , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacocinética , Adulto , Idoso , Disponibilidade Biológica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Telbivudina , Timidina/análogos & derivados
4.
Lancet Infect Dis ; 18(6): e183-e192, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29153266

RESUMO

The massive outbreak of Ebola virus disease in west Africa between 2013 and 2016 resulted in intense efforts to evaluate the efficacy of several specific countermeasures developed through years of preclinical work, including the first clinical trials for therapeutics and vaccines. In this Review, we discuss how the experience and data generated from that outbreak have helped to advance the understanding of the use of these countermeasures for post-exposure prophylaxis against Ebola virus infection. In future outbreaks, post-exposure prophylaxis could play an important part in reducing community transmission of Ebola virus by providing more immediate protection than does immunisation as well as providing additional protection for health-care workers who are inadvertently exposed over the course of their work. We propose provisional guidance for use of post-exposure prophylaxis in Ebola virus disease and identify the priorities for future preparedness and further research.


Assuntos
Antivirais/farmacologia , Vacinas contra Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Profilaxia Pós-Exposição , Desenvolvimento de Medicamentos , Humanos
5.
N Engl J Med ; 349(9): 837-46, 2003 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-12944569

RESUMO

BACKGROUND: We compared two strategies for treating patients infected with multidrug-resistant human immunodeficiency virus (HIV). METHODS: Patients with multidrug-resistant HIV and HIV RNA levels of more than 5000 copies per milliliter were randomly assigned to a four-month structured interruption of treatment followed by a change in antiretroviral regimen (treatment-interruption group) or to an immediate change in regimen (control group). Genotypic and phenotypic resistance testing was performed. Disease progression, death, and changes in genotypic resistance, CD4 cell counts, HIV RNA levels, and quality of life were assessed. RESULTS: After a median follow-up of 11.6 months, disease progression or death occurred in 22 of the 138 patients in the treatment-interruption group and in 12 of the 132 patients in the control group (P=0.01), with a hazard ratio of 2.57 (95 percent confidence interval, 1.2 to 5.5) for the treatment-interruption group. There were eight deaths in each group. In the treatment-interruption group, the mutant HIV populations completely or partially reverted to wild type by four months in 64.0 percent of patients. As compared with the control group, the treatment-interruption group had a mean CD4 cell count that was 85 cells per cubic millimeter lower from months 0 through 4 (P<0.001), 47 cells per cubic millimeter lower from months 5 through 8 (P<0.001), and 31 cells per cubic millimeter lower after eight months (P=0.11). The mean HIV RNA levels were 1.2 log copies per milliliter higher (on a base-10 scale) in the treatment-interruption group during months 0 through 4 (P<0.001), but they were not significantly different from those in the control group after month 4. The overall quality of life was similar in the two groups. CONCLUSIONS: In patients infected with multidrug-resistant HIV, structured interruption of treatment was associated with greater progression of disease and did not confer immunologic or virologic benefits or improve the overall quality of life.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Adulto , Contagem de Linfócito CD4 , Progressão da Doença , Esquema de Medicação , Farmacorresistência Viral Múltipla , Feminino , HIV/efeitos dos fármacos , HIV/genética , HIV/isolamento & purificação , Infecções por HIV/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , RNA Viral/sangue
6.
AIDS ; 16(8): 1131-8, 2002 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-12004271

RESUMO

BACKGROUND: To determine the impact of HIV-1 drug resistance at baseline and antiretroviral drug levels (DL) during follow-up on virologic response to the next antiretroviral regimen. METHODS: Baseline genotypic and phenotypic susceptibility was obtained for plasma virus from patients failing a protease inhibitor-containing regimen. Untimed plasma antiretroviral DL were performed and the distribution of DL after 12 weeks of follow-up was classified as above (DLHigh) or below (DLLow) the median. Inhibitory quotients [IQ = (DL at week 12)/(fold change in IC50 to wild-type)] were determined for each drug in the regimen. Primary outcome was change in log10 plasma HIV-1 RNA viral load (DeltaVL) from baseline to 12 weeks. RESULTS: There were 137 patients who had baseline resistance data available for the antiretroviral drugs used in the salvage regimen, and DL at week 12. Each drug with DLHigh was associated with DeltaVL = -0.40 (P = 0.0002) while each drug with DLLow had DeltaVL = -0.16 (P = 0.11). In multivariate models DeltaVL associated with each active drug (defined by genotype) with DLHigh was -0.48 log10 (P < 0.0001), and with each active drug with DLLow was -0.22 (P = 0.03). The DeltaVL was -0.18 if no drugs in the regimen had an IQ > median, compared to -0.58 for one drug, -1.06 for two drugs, -0.86 for three drugs, and -1.44 for four or five drugs with IQ > median (P < 0.0001 for trend). CONCLUSIONS: In salvage therapy, both the number of active drugs and the DL for each drug in the new regimen determine the antiviral response.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Terapia de Salvação , Relação Dose-Resposta a Droga , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/virologia , HIV-1/genética , Humanos , Cooperação do Paciente , Fenótipo , Carga Viral
7.
Artigo em Inglês | MEDLINE | ID: mdl-25808170

RESUMO

The current Ebola virus outbreak is unprecedented in its scope and international impact. Given that there are currently no approved antivirals to treat Ebola virus, there is urgency to conduct more rapid development and evaluation of Ebola antivirals. Recently, the World Health Organization identified a number of antivirals as high priority to include AVI-6002 (AVI-7537 and AVI-7539), BCX4430, brincidofovir, favipiravir, and TKM-100802. This review describes these chemically synthesized inhibitors of Ebola virus, relevant patent development and gives an update on their current status.


Assuntos
Antivirais/uso terapêutico , Ebolavirus , Doença pelo Vírus Ebola/tratamento farmacológico , Adenina/análogos & derivados , Adenosina/análogos & derivados , Amidas/uso terapêutico , Citosina/análogos & derivados , Citosina/uso terapêutico , Descoberta de Drogas , Humanos , Organofosfonatos/uso terapêutico , Patentes como Assunto , Nucleosídeos de Purina/uso terapêutico , Pirazinas/uso terapêutico , Pirrolidinas
9.
J Virol Methods ; 164(1-2): 122-6, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19948190

RESUMO

Allele-specific PCR based on subtype consensus sequences is a powerful technique for detecting low frequency drug resistant mutants in HIV-1 infected patients. However, this approach can be limited by genetic variation in the region complementary to the primers, leading to variability in allele detection. The goals of this study were to quantify this effect and then to improve assay performance.


Assuntos
Primers do DNA/genética , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Reação em Cadeia da Polimerase/métodos , Alelos , Sequência Consenso , Genótipo , HIV-1/isolamento & purificação , Humanos , Polimorfismo Genético , RNA Viral/genética
10.
J Virol ; 80(21): 10794-801, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16928764

RESUMO

Tipranavir is a novel, nonpeptidic protease inhibitor of human immunodeficiency virus type 1 (HIV-1) with activity against clinical HIV-1 isolates from treatment-experienced patients. HIV-1 genotypic and phenotypic data from phase II and III clinical trials of tipranavir with protease inhibitor-experienced patients were analyzed to determine the association of protease mutations with reduced susceptibility and virologic response to tipranavir. Specific protease mutations were identified based on stepwise multiple-regression analyses of phase II study data sets. Validation included analyses of phase III study data sets to determine if the same mutations would be selected and to assess how these mutations contribute to multiple-regression models of tipranavir-related phenotype and of virologic response. A tipranavir mutation score was developed from these analyses, which consisted of a unique string of 16 protease positions and 21 mutations (10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V). HIV-1 isolates displaying an increasing number of these tipranavir resistance-associated mutations had a reduced phenotypic susceptibility and virologic response to tipranavir. Regression models for predicting virologic response in phase III trials revealed that each point in the tipranavir score was associated with a 0.16-log10 copies/ml-lower virologic response to tipranavir at week 24 of treatment. A lower number of points in the tipranavir score and a greater number of active drugs in the background regimen were predictive of virologic success. These analyses demonstrate that the tipranavir mutation score is a potentially valuable tool for predicting the virologic response to tipranavir in protease inhibitor-experienced patients.


Assuntos
Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/genética , HIV-1/enzimologia , HIV-1/genética , Piridinas/farmacologia , Pironas/farmacologia , Farmacorresistência Viral/genética , Genótipo , Protease de HIV/química , HIV-1/efeitos dos fármacos , Humanos , Modelos Biológicos , Modelos Moleculares , Mutação , Fenótipo , Conformação Proteica , Análise de Regressão , Sulfonamidas
11.
J Acquir Immune Defic Syndr ; 43(2): 169-78, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16951642

RESUMO

BACKGROUND: We report the final results of Community Programs for Clinical Research on AIDS (CPCRA-064) study, a multicenter, prospective, randomized, controlled trial that determines the long-term clinical impact of structured treatment interruption (STI) in patients with multidrug-resistant (MDR) HIV-1. METHODS AND RESULTS: Two hundred seventy-four patients on stable antiretroviral therapy with MDR HIV-1 treatment failure were randomized to a 4-month STI, followed by an optimized antiretroviral regimen (STI arm, n = 140) or an immediate change to an optimized antiretroviral regimen (control arm, n = 134). Main outcome measures were progression of disease or death and changes from baseline in HIV RNA levels (log copies/mL) and CD4 cell counts (cells/mm). The median baseline HIV RNA level was 5.0 log copies/mL, the median CD4 count was 147 cells/mm, and the nadir CD4 count was 32 cells/mm. The median follow-up was 37 months. After the STI period, there were no differences in HIV RNA level responses between treatment arms. Differences in CD4 count responses always favored the control arm, with an advantage of 84 cells from 0 to 4 months (P < 0.0001), 50 cells from 4 to 12 months (P < 0.0001), 45 cells from 12 to 24 months (P = 0.006), and 43 cells after 24 months (P = 0.07). Rates in the STI and control arms for first progression-of-disease event or death were 17.5 and 14.3, respectively (hazard ratio = 1.28; P = 0.22). CONCLUSION: STI before changing regimens in patients with MDR HIV-1 treatment failure has a prolonged negative impact on CD4 cell count recovery and does not confer progression of disease or virologic benefits.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Farmacorresistência Viral Múltipla , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Falha de Tratamento , Adulto , Contagem de Linfócito CD4 , Progressão da Doença , Esquema de Medicação , Feminino , HIV/efeitos dos fármacos , HIV/genética , HIV/isolamento & purificação , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Estudos Prospectivos
12.
J Acquir Immune Defic Syndr ; 34 Suppl 1: S21-33, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14562855

RESUMO

All classes of antiretroviral (ARV) therapy have been associated with asymptomatic elevations of alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels, and much less frequently with serious, and at times life threatening, clinical liver hepatotoxicity. The relationship between the risk of developing serious clinical liver injury and the rate and severity of elevated asymptomatic ALT/AST levels is poorly understood. Boehringer Ingelheim has recently completed the Viramune Hepatic Safety Project; its primary objective was to identify risk factors for antiretroviral-associated hepatotoxicity. Data from 1731 nevirapine-treated patients and 1912 control patients who took part in Boehringer Ingelheim-controlled clinical trials as well as 814 nevirapine-treated patients in uncontrolled trials were analyzed. Risk factors for asymptomatic ALT/AST elevations during nevirapine therapy included baseline elevations of ALT/AST levels > 2.5x upper limit of normal (RR = 4.3, p < .01) and co-infection with hepatitis B (RR = 2.3, p < .01) or hepatitis C (RR = 5.2, p < .01). An analysis of ALT/AST elevations > 5x ULN for patients stratified by baseline CD4 cell count demonstrated that men with > or = 400 CD4 cells/mm3 were at increased risk of asymptomatic transaminase elevations while taking nevirapine (RR = 1.6, p < .01). No consistent CD4 cell count cutoff could be identified in women that was associated with an increased risk of ALT/AST elevations. Analyses from five large observational cohorts (N = 8711) demonstrated no significant differences in the rate of serious hepatic events among antiretroviral regimens, including between the non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz. Use of nevirapine was not associated with a significantly increased risk of clinical hepatotoxic events, including liver failure or liver related death, compared to therapy with other antiretroviral drugs.


Assuntos
Infecções por HIV/tratamento farmacológico , Fígado/efeitos dos fármacos , Nevirapina/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Ensaios Clínicos como Assunto , Estudos de Coortes , Humanos , Fígado/enzimologia , Falência Hepática/induzido quimicamente , Falência Hepática/mortalidade , Nevirapina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Risco
13.
J Acquir Immune Defic Syndr ; 35(4): 376-82, 2004 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-15097154

RESUMO

Tipranavir (TPV), a novel nonpeptidic protease inhibitor (NPPI), was administered to treatment-naive HIV-1-infected patients over 14 days in a randomized, multicenter, open-label, parallel-group trial to evaluate the efficacy and tolerability of a self-emulsifying drug delivery system (SEDDS) formulation, in combination with ritonavir (RTV). Of the 31 patients enrolled, 10 were randomized to receive TPV 1200 mg twice daily (TPV 1200), 10 patients received TPV 300 mg + RTV 200 mg twice daily (TPV/r 300/200), and 11 patients received TPV 1200 mg + RTV 200 mg twice daily (TPV/r 1200/200). The median baseline viral load and CD4 cell count were 4.96 log10 copies/mL and 244 cells/mm, respectively. After 14 days, the median decrease in viral load was -0.77 log10 in the TPV 1200 group, -1.43 log10 in the TPV/r 300/200 group, and -1.64 log10 in the TPV/r 1200/200 group. TPV exposure was increased by 24- and 70-fold in the TPV/r 300/200 and 1200/200 groups, respectively, compared with TPV 1200 alone. There were no significant differences across treatment arms with regard to drug-related adverse events. TPV/r appeared to be safe, effective, and well tolerated during 14 days of treatment.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Piridinas/administração & dosagem , Pironas/administração & dosagem , Contagem de Linfócito CD4 , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/toxicidade , HIV-1 , Humanos , Piridinas/farmacocinética , Piridinas/toxicidade , Pironas/farmacocinética , Pironas/toxicidade , RNA Viral/sangue , Ritonavir/administração & dosagem , Sulfonamidas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA