The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-␣2a (PEG IFN␣2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-␣2a 180 g/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 g/week PEG IFN-␣2a. In patients with genotypes 1 and 4, the 600-and 1,000-mg combination treatments induced a continuous decay in viral load that reached ؊4.61 ؎ 1.88 and ؊4.75 ؎ 2.19 log 10 IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by ؊5.91 ؎ 1.11 and ؊5.89 ؎ 0.43 log 10 IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN-␣2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day). Conclusion: These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN-␣2a.

The presence of granulocytic ehrlichiae was demonstrated by PCR inIxodes ricinus ticks and wild small mammals in Switzerland in two areas of endemicity for bovine ehrlichiosis. Six ticks (three females and three nymphs) (1.4%) of 417 I. ricinus ticks collected by flagging vegetation contained ehrlichial DNA. A total of 201 small mammals from five species, wood mouse (Apodemus sylvaticus), yellow-necked mouse (Apodemus flavicollis), earth vole (Pitymys subterraneus), bank vole (Clethrionomys glareolus), and common shrew (Sorex araneus), were trapped. The analysis of I. ricinus mammals collected on 116 small mammals showed that nine C. glareolus voles and two A. sylvaticus mice hosted infected tick larvae. In these rodents, granulocytic ehrlichia infection was also detected in blood, spleen, liver, and ear samples. Further examinations of 190 small mammals without ticks or with noninfected ticks showed the presence of ehrlichial DNA in spleen and other tissues from six additional C. glareolus, three A. flavicollis, and one S. araneus mammals. This study suggests thatA. sylvaticus, A. flavicollis, S. araneus, and particularly C. glareolus are likely to be natural reservoirs for granulocytic ehrlichiae. Partial 16S rRNA gene sequences of granulocytic ehrlichiae from ticks and rodents showed a high degree of homology (99 to 100%) with granulocytic ehrlichiae isolated from humans. In contrast, groESL heat shock operon sequence analysis showed a strong divergence (approximately 5%) between the sequences in samples derived from rodents and those derived from samples from questing ticks or from other published ehrlichia sequences. Dual infections with granulocytic ehrlichia andBorrelia burgdorferi were found in ticks and small mammals.

The role of wild mammals, such as roe deer (Capreolus capreolus) and chamois (Rupicapra rupicapra), in the epidemiology of granulocytic ehrlichiae in Switzerland was investigated. We tested blood samples for Ehrlichia phagocytophila genogroup 16S rRNA gene sequences by PCR and for immunoglobulin G antibodies against granulocytic ehrlichiae by indirect fluorescent-antibody assay (IFA). Overall means of 60.9% of 133 roe deer serum samples and 28.2% of 39 chamois serum samples were seroreactive by IFA. PCR results were positive for 18.4% of 103 roe deer serum samples as well. None of the 24 chamois blood samples tested were positive by PCR. Partial 16S rRNA gene and groESL heat shock operon sequences of three roe deer samples tested showed strong degrees of homology (>99.7 and >98.6%, respectively) with the sequences of granulocytic ehrlichiae isolated from humans. These results confirm that chamois, and particularly roe deer, are commonly infected with granulocytic ehrlichiae and provide evidence that these wild mammals are potential reservoirs for granulocytic ehrlichiae in Switzerland.

No abstract

No abstract