RESUMO
The OPTIMIZE study demonstrated noninferior efficacy between telaprevir (TVR) twice daily (bid) vs every 8-h (q8h) administration. This analysis compared the selective pressure of both dosing regimens by characterisation of the hepatitis C virus (HCV) variants emerging in genotype 1 (G1) HCV-infected patients who did not achieve sustained virological response (SVR). HCV NS3â¢4A population sequencing was performed at baseline and time of failure (viral breakthrough, stopping rule or relapse). TVR-resistant variants were classified by fold change in inhibitory concentration (IC50 ). Baseline TVR-resistance was low (<5%) and did not preclude achieving SVR in either arm. The proportion of patients with TVR-resistant variants at time of failure was similar in the bid (15%) and q8h (17%) dosing arms. The majority of variants and virological failures occurred in G1a patients, and mutations V36M, R155K and R155T (G1a), and V36A, T54A and A156S (G1b) were significantly enriched in both treatment arms. The number and type of emerging TVR-resistant variants in non-SVR patients were comparable between treatment arms and were consistent with previous observations. No differences in viral resistance profiles were observed between TVR-based treatment arms in non-SVR patients, indicating a similar selective pressure of TVR bid and q8h dosing.
Assuntos
Antivirais/administração & dosagem , Farmacorresistência Viral , Oligopeptídeos/administração & dosagem , Proteínas de Transporte/genética , Genótipo , Humanos , Incidência , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular , Testes de Sensibilidade Microbiana , Mutação de Sentido Incorreto , Análise de Sequência de DNA , Falha de Tratamento , Proteínas não Estruturais Virais/genéticaRESUMO
Study C209 evaluated the activity of telaprevir in treatment-naïve patients with genotypes 2 or 3 (G2, G3) hepatitis C virus (HCV) infection. Telaprevir monotherapy showed potent activity against HCV G2, but limited activity against G3. This analysis was performed to characterize HCV viral variants emerging during telaprevir-based treatment of G2/G3 HCV-infected patients. Patients were randomized to receive 2 weeks of treatment with telaprevir (telaprevir monotherapy), telaprevir plus peginterferon alfa-2a and ribavirin (triple therapy), or placebo plus peginterferon alfa-2a and ribavirin (control), followed by 22-24 weeks of peginterferon/ribavirin alone. Viral breakthrough was defined as an increase >1 log10 in HCV RNA from nadir, or HCV RNA >100 IU/mL in patients previously reaching <25 IU/mL. Twenty-three patients (47%) had G2 and 26 (53%) had G3 HCV. Viral breakthrough occurred during the initial 2-week treatment phase in six G2 patients (66.7%; subtypes 2, 2a and 2b) and three G3 patients (37.5%; all subtype 3a), all in the telaprevir monotherapy arm. Four breakthrough patients (three G2, one G3) subsequently achieved sustained virologic response (SVR). In all patients with breakthrough and available sequence data, mutations associated with reduced susceptibility to telaprevir in genotype 1 (G1) HCV were observed. No novel G2/G3-specific mutations were associated with telaprevir resistance. The telaprevir resistance profile appeared consistent across HCV genotypes 1, 2 and 3. Although viral breakthrough with resistance occurred in patients receiving telaprevir monotherapy, half of these patients achieved an SVR upon addition of peginterferon/ribavirin highlighting the importance of combination therapy.
Assuntos
Farmacorresistência Viral , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/uso terapêutico , RNA Viral/sangue , Substituição de Aminoácidos , Antivirais/uso terapêutico , Quimioterapia Combinada , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Humanos , Interferon-alfa/uso terapêutico , Mutação , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Análise de Sequência de Proteína , Resultado do Tratamento , Proteínas não Estruturais Virais/genéticaRESUMO
The requirement for multiple mutations for protease inhibitor (PI) resistance necessitates a better understanding of the molecular basis of resistance development. The novel bioinformatics resistance determination approach presented here elaborates on genetic profiles observed in clinical human immunodeficiency virus type 1 (HIV-1) isolates. Synthetic protease sequences were cloned in a wild-type HIV-1 background to generate a large number of close variants, covering 69 mutation clusters between multi-PI-resistant viruses and their corresponding genetically closely related, but PI-susceptible, counterparts. The vast number of mutants generated facilitates a profound and broad analysis of the influence of the background on the effect of individual PI resistance-associated mutations (PI-RAMs) on PI susceptibility. Within a set of viruses, all PI-RAMs that differed between susceptible and resistant viruses were varied while maintaining the background sequence from the resistant virus. The PI darunavir was used to evaluate PI susceptibility. Single sets allowed delineation of the impact of individual mutations on PI susceptibility, as well as the influence of PI-RAMs on one another. Comparing across sets, it could be inferred how the background influenced the interaction between two mutations, in some cases even changing antagonistic relationships into synergistic ones or vice versa. The approach elaborates on patient data and demonstrates how the specific mutational background greatly influences the impact of individual mutations on PI susceptibility in clinical patterns.
Assuntos
Farmacorresistência Viral/genética , Protease de HIV/genética , HIV-1/fisiologia , Mutação/fisiologia , Sequência de Aminoácidos , Clonagem Molecular , Biologia Computacional , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , Humanos , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/genéticaRESUMO
The Clara cell protein, the human counterpart of rabbit uteroglobin, exerts an anti-inflammatory action by interfering in different ways with the cytokine-network. Firstly, CC16 behaves like an anti-cytokine by downregulating the production of IFN-gamma, IL-1 and TNF-alpha by stimulated leukocytes. The extent of inhibition depends on the inducing agent (being maximal when IL-2 is used as inducer) and varies with the applied concentration of CC16. Secondly, the protein reduces the antiviral activity and the augmentation of phagocytosis induced by IFN-gamma. In both cases (inhibition of production and biologic activity) there is a 50% reduction in the presence of 10 ng/ml CC16. The natural and IFN-gamma-enduced cytotoxicity of NK-cells however, are enhanced by the presence of CC16, indicating a more complex interaction of CC16 with the immune-system. The immunosuppressive properties make CC16 a promising agent for the treatment of inflammatory reactions and auto-immune diseases.
Assuntos
Citocinas/biossíntese , Tolerância Imunológica , Proteínas/fisiologia , Uteroglobina , Citotoxicidade Imunológica , Humanos , Células Matadoras Naturais/imunologiaRESUMO
The Clara cell 16 kD protein (CC16), the predominant product of the Clara cells lining the bronchiolar epithelium, is thought to protect the respiratory and urogenital tract from unwanted inflammatory reactions through its immunosuppressive action. In this report, we show evidence that CC16 establishes an anti-inflammatory activity by interfering with the interferon-gamma (IFN-gamma)-mediated actions of the cytokine network. The HuIFN-gamma production of stimulated single-donor peripheral blood mononuclear cells is inhibited by the presence of doses of CC16 in the range of 10(-12) M, with a maximal inhibition (up to 95%) when interleukin-2 is used as a stimulating agent. CC16 also diminishes the biologic activity of IFN-gamma: both the antiviral activity and the stimulation of phagocytosis by IFN-gamma, measured by means of chemiluminescence, are reduced in the presence of CC16. These observations indicate that CC16 acts as an anticytokine and could give new insight in the potential role of the Clara cells.