Treatment of chronic hepatitis C in patients unresponsive to interferon. Interest of re-treatment combining interferon induction therapy and ribavirin (a multicenter pilot study)

Aim About 45% of patients with chronic hepatitis C are unresponsive to the present reference treatment combining pegelated interferon plus ribavirin; before pegylated interferon was available the non-response rate was around 60%. This open multicenter pilot study, initiated before pegylated interferon became available, was designed to evaluate, in patients unresponsive to interferon monotherapy, the rate of biological and virological response and side-effects of the ribivirin- alpha 2b interferon combination. Methods The combination protocol was ribavirin (1 to 1.2 g/d) plus alpha 2b interferon at induction doses (9 MU/d the first week; 4.5 MU/d the eleven following weeks; 3 MU/2 days the 36 following weeks). Results Among the 27 included patients, 17 (63%) were viremia-negative (PCR) after 12 weeks of treatment, 9 (33%) were complete responders (undetectable viremia and normal transaminases) at the end of treatment (48 weeks) and of follow-up (72 weeks). Patients with non-1, non-4 genotypes who derived full benefit from this therapeutic strategy (6/7 (86%) were complete responders: 4/5 with genotype 3 and 2/2 with genotype 5). Quality-of-life was impaired during treatment, especially during the first 12 weeks of high-dose interferon therapy. Conclusion While waiting for new therapeutic possibilities, these good results suggest interferon induction at the beginning of treatment remains a valid option

Antiviral effect of ribavirin in early non-responders to interferon monotherapy assessed by kinetics of hepatitis C virus RNA and hepatitis C virus core antigen

BACKGROUND/AIMS: To evaluate the efficacy of ribavirin, given in second intention in non-responders to interferon alone, by studying viral kinetics. METHODS: We conducted a trial including 203 patients with chronic hepatitis C, naïve of treatment. Patients were treated with interferon three times a week with or without ribavirin and amantadine according to response. Viral kinetics were assessed by serial measurements of HCV RNA (bDNA 3.0 and Monitor 2.0) and a new assay, trak-C, able to quantify total Hepatitis C virus (HCV) core antigen. RESULTS: A significant initial drop in HCV RNA or HCV core antigen, under interferon alone, was associated with response to therapy, -4.85+/-1.33 log for HCV RNA in sustained responders versus -1.86+/-1.53 log for others groups, P<0.001. In patients receiving ribavirin in second intention, we also observed a similar drop in HCV RNA and HCV core antigen, predictive of sustained response, -2.67+/-1.26 log for HCV RNA in sustained responders versus -0.44+/-0.49 log in non-responders, P<0.001. CONCLUSIONS: Ribavirin has probably an additional antiviral effect in interferon treated patients. Kinetics of HCV RNA and HCV core antigen under treatment are highly predictive of a sustained virological response

Efficacy and Safety of Glycoprotein IIb/IIIa Inhibitors on Top of Ticagrelor in STEMI: A Subanalysis of the ATLANTIC Trial

BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPIs) in combination with clopidogrel improve clinical outcome in ST-elevation myocardial infarction (STEMI); however, finding a balance that minimizes both thrombotic and bleeding risk remains fundamental. The efficacy and safety of GPI in addition to ticagrelor, a more potent P2Y12-inhibitor, have not been fully investigated. METHODS: 1,630 STEMI patients who underwent primary percutaneous coronary intervention (PCI) were analyzed in this subanalysis of the ATLANTIC trial. Patients were divided in three groups: no GPI, GPI administration routinely before primary PCI, and GPI administration in bailout situations. The primary efficacy outcome was a composite of death, myocardial infarction, urgent target revascularization, and definite stent thrombosis at 30 days. The safety outcome was non-coronary artery bypass graft (CABG)-related PLATO major bleeding at 30 days. RESULTS: Compared with no GPI (n\u2009=\u2009930), routine GPI (n\u2009=\u2009525) or bailout GPI (n\u2009=\u2009175) was not associated with an improved primary efficacy outcome (4.2% no GPI vs. 4.0% routine GPI vs. 6.9% bailout GPI; p\u2009=\u20090.58). After multivariate analysis, the use of GPI in bailout situations was associated with a higher incidence of non-CABG-related bleeding compared with no GPI (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.32-6.64; p\u2009=\u20090.03). However, routine GPI use compared with no GPI was not associated with a significant increase in bleeding (OR 1.78, 95% CI 0.88-3.61; p\u2009=\u20090.92). CONCLUSION: Use of GPIs in addition to ticagrelor in STEMI patients was not associated with an improvement in 30-day ischemic outcome. A significant increase in 30-day non-CABG-related PLATO major bleeding was seen in patients who received GPIs in a bailout situation

Prehospital ticagrelor in ST-segment elevation myocardial infarction

Background:The direct-acting platelet P2Y receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown. Methods: We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours' duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days. Results: The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition use

Genetic hitchhiking and resistance evolution to transgenic Bt toxins: insights from the African stalk borer Busseola fusca (Noctuidae)

Since transgenic crops expressing Bacillus thuringiensis (Bt) toxins were first released, resistance evolution leading to failure in control of pests populations has been observed in a number of species. Field resistance of the moth Busseola fusca was acknowledged 8 years after Bt maize was introduced in South Africa. Since then, field resistance of this corn borer has been observed at several locations, raising questions about the nature, distribution and dynamics of the resistance trait. Using genetic markers, our study identified four outlier loci clearly associated with resistance. In addition, genetic structure at neutral loci reflected extensive gene flow among populations. A realistically parameterised model suggests that resistance could travel in space at speed of several kilometres a year. Markers at outlier loci delineated a geographic region associated with resistance spread. This was an area of approximately 100 km radius, including the location where resistance was first reported. Controlled crosses corroborated these findings and showed significant differences of progeny survival on Bt plants depending on the origin of the resistant parent. Last, our study suggests diverse resistance mutations, which would explain the widespread occurrence of resistant larvae in Bt fields across the main area of maize production in South Africa

DNA Physical Properties and Nucleosome Positions Are Major Determinants of HIV-1 Integrase Selectivity

Retroviral integrases (INs) catalyse the integration of the reverse transcribed viral DNA into the host cell genome. This process is selective, and chromatin has been proposed to be a major factor regulating this step in the viral life cycle. However, the precise underlying mechanisms are still under investigation. We have developed a new in vitro integration assay using physiologically-relevant, reconstituted genomic acceptor chromatin and high-throughput determination of nucleosome positions and integration sites, in parallel. A quantitative analysis of the resulting data reveals a chromatin-dependent redistribution of the integration sites and establishes a link between integration sites and nucleosome positions. The co-activator LEDGF/p75 enhanced integration but did not modify the integration sites under these conditions. We also conducted an in cellulo genome-wide comparative study of nucleosome positions and human immunodeficiency virus type-1 (HIV-1) integration sites identified experimentally in vivo. These studies confirm a preferential integration in nucleosome-covered regions. Using a DNA mechanical energy model, we show that the physical properties of DNA probed by IN binding are important in determining IN selectivity. These novel in vitro and in vivo approaches confirm that IN has a preference for integration into a nucleosome, and suggest the existence of two levels of IN selectivity. The first depends on the physical properties of the target DNA and notably, the energy required to fit DNA into the IN catalytic pocket. The second depends on the DNA deformation associated with DNA wrapping around a nucleosome. Taken together, these results indicate that HIV-1 IN is a shape-readout DNA binding protein

T Lymphocytes Promote the Antiviral and Inflammatory Responses of Airway Epithelial Cells

T cells modulate the antiviral and inflammatory responses of airway epithelial cells to human rhinoviruses (HRV)