RESUMO
GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.
Assuntos
Antivirais/administração & dosagem , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Compostos Macrocíclicos/administração & dosagem , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Idoso , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Antivirais/farmacocinética , Antivirais/farmacologia , Ciclopropanos , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Hepacivirus/isolamento & purificação , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compostos Macrocíclicos/efeitos adversos , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Prolina/análogos & derivados , Quinoxalinas , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND: In hepatitis C virus (HCV) monoinfection, the on-treatment virological response at Weeks 4 and 12 is a strong predictor of treatment outcomes. METHODS: In a retrospective analysis, we examined these responses in 289 HIV-HCV coinfected patients treated with Peg-IFN alfa-2a /ribavirin for 48 weeks in a large randomized, multinational trial (APRICOT). RESULTS: Overall, 21% of patients achieved a rapid virological response at Week 4 and, of these, 88% achieved a sustained virological response. An early virological response at Week 12 was achieved in 71% of patients, and 56% of these patients achieved a sustained virological response. These results are similar to the sustained virological response rates obtained in monoinfected patients who achieve a rapid or early virological response. Patients who did not achieve a rapid virological response but who had unquantifiable HCV RNA or > 3 log10 drop over baseline also had high sustained virological response rates. A total of 46% of patients achieved undetectable HCV RNA (<50 IU/mL) at Week 12. Multiple logistic regression analysis showed that infection with HCV genotype 2/3, low baseline HCV RNA level, and lower age predicted rapid virological response. Infection with HCV genotype 2/3 and low baseline HCV RNA level predicted early virological response. CONCLUSION: A rapid virological response is the best predictor of a sustained virological response, and lack of an early virological response is the best predictor of no sustained virological response. Such results are consistent with findings in HCV monoinfected patients.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/virologia , HIV/crescimento & desenvolvimento , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/virologia , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Humanos , Interferon alfa-2 , Modelos Logísticos , Masculino , Valor Preditivo dos Testes , RNA Viral/sangue , Proteínas RecombinantesRESUMO
Rapid virologic response (RVR) and complete early virologic response (cEVR) are associated with sustained virologic response to hepatitis C virus (HCV) therapy. We retrospectively examined baseline and on-treatment factors associated with RVR (HCV RNA undetectable at week 4) and cEVR (HCV RNA undetectable at week 12, regardless of week 4 response). The analysis comprised 1550 HCV genotype-1 patients from five clinical trials, including three enriched with difficult-to-treat populations, randomized to peginterferon alfa-2a 180 microg/week plus ribavirin 1000-1200 mg/day. Overall, 15.6% achieved RVR and 54.0% achieved cEVR. Baseline factors predictive of RVR were serum HCV RNA
Assuntos
Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Carga Viral , Adulto , Alanina Transaminase/sangue , Antivirais/administração & dosagem , Índice de Massa Corporal , Etnicidade , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Prognóstico , Proteínas Recombinantes , Estudos Retrospectivos , Ribavirina/administração & dosagem , Resultado do TratamentoRESUMO
AIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in US American minority populations of African or Native American descent than it is in European Americans. However, the proportion of this epidemiological difference that can be ascribed to genetic or environmental factors is unknown. To determine whether genetic ancestry is correlated with diabetes risk in Latinos, we estimated the proportion of European ancestry in case-control samples from Mexico and Colombia in whom socioeconomic status had been carefully ascertained. METHODS: We genotyped 67 ancestry-informative markers in 499 participants with type 2 diabetes and 197 controls from Medellín (Colombia), as well as in 163 participants with type 2 diabetes and 72 controls from central Mexico. Each participant was assigned a socioeconomic status scale via various measures. RESULTS: Although European ancestry was associated with lower diabetes risk in Mexicans (OR [95% CI] 0.06 [0.02-0.21], p = 2.0 x 10(-5)) and Colombians (OR 0.26 [0.08-0.78], p = 0.02), adjustment for socioeconomic status eliminated the association in the Colombian sample (OR 0.64 [0.19-2.12], p = 0.46) and significantly attenuated it in the Mexican sample (OR 0.17 [0.04-0.71], p = 0.02). Adjustment for BMI did not change the results. CONCLUSIONS/INTERPRETATION: The proportion of non-European ancestry is associated with both type 2 diabetes and lower socioeconomic status in admixed Latino populations from North and South America. We conclude that ancestry-directed search for genetic markers associated with type 2 diabetes in Latinos may benefit from information involving social factors, as these factors have a quantitatively important effect on type 2 diabetes risk relative to ancestry effects.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Hispânico ou Latino/estatística & dados numéricos , Fatores Socioeconômicos , Colômbia/epidemiologia , Diabetes Mellitus Tipo 2/economia , Diabetes Mellitus Tipo 2/genética , Humanos , México/epidemiologia , Grupos Raciais/estatística & dados numéricos , Estados Unidos/epidemiologia , População BrancaRESUMO
The clinical relevance of occult hepatitis B virus (HBV) infection, defined as detectable HBV DNA serum/liver, in the absence of hepatitis B surface antigen (HBsAg), is unclear. We determined the prevalence of serum occult HBV infection in HIV/HCV co-infected patients enrolled in APRICOT, a randomized multinational trial that investigated the efficacy and safety of peginterferon alfa-2a (40 kDa) plus ribavirin for treatment of HCV. We also examined the effect of prior HBV exposure to liver histology at baseline. Only HBsAg-negative patients were eligible. At screening, serum HBV DNA was assessed by commercial assay (detection limit = 200 copies/mL). Patients were divided into four serological groups: anti-HBs+/anti-HBc+; anti-HBs-/anti-HBc+; anti-HBs+/ anti-HBc-; anti-HBs-/anti-HBc-. Baseline liver biopsy grade and stage were compared among groups. Serum HBV DNA was undetectable in all patients, (n = 866). Results of anti-HBs and anti-HBc was available for 176 patients: 60 (34.1%) anti-HBs+/anti-HBc+; 60 (34.1%) anti-HBs-/anti-HBc+; 11 (6.3%) anti-HBs+/anti-HBc-; 45 (25.6%) anti-HBs-/anti-HBc-. There were no differences among the groups in the histological grade or stage at baseline liver biopsies. Occult HBV infection in serum was not detected in this large immunocompetent cohort. Moreover, prior exposure to HBV did not appear to have any affect on baseline liver histology.
Assuntos
Infecções por HIV/complicações , Hepatite B/complicações , Hepatite B/diagnóstico , Hepatite C/complicações , Adulto , Biópsia , DNA Viral/sangue , Feminino , HIV/imunologia , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepacivirus/imunologia , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Fígado/patologia , Fígado/virologia , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.