Safety and Efficacy of Ombitasvir, Paritaprevir With Ritonavir ± Dasabuvir With or Without Ribavirin in Patients With Human Immunodeficiency Virus-1 and Hepatitis C Virus Genotype 1 or Genotype 4 Coinfection: TURQUOISE-I Part 2.

BACKGROUND: Ombitasvir, paritaprevir with ritonavir, and dasabuvir (OBV/PTV/r ± DSV) ±ribavirin (RBV) are approved to treat hepatitis C virus (HCV) genotype 1 and 4 infection. Here, we investigate the safety and efficacy of OBV/PTV/r + DSV ±RBV for HCV genotype 1, and OBV/PTV/r + RBV for HCV genotype 4, in human immunodeficiency virus (HIV)-1 coinfected patients with or without compensated cirrhosis. METHODS: TURQUOISE-I, Part 2 is a phase 3 multicenter study. Patients with or without cirrhosis were HCV treatment-naive or -experienced, on an HIV-1 antiretroviral regimen containing atazanavir, raltegravir, dolutegravir, or darunavir (for genotype 4 only), and had plasma HIV-1 ribonucleic acid <40 copies/mL at screening. Patients received OBV/PTV/r ± DSV ±RBV for 12 or 24 weeks. RESULTS: In total, 228 patients were treated according to guidelines. Sustained virologic response at posttreatment week 12 (SVR12) was achieved by 194 of 200 (97%) and 27 of 28 (96%) patients with HCV genotype 1 and genotype 4 infection, respectively. There were 2 virologic failures: 1 breakthrough and 1 relapse in a cirrhotic and a noncirrhotic patient with genotype 1b and 1a infection, respectively. One reinfection occurred at posttreatment week 12 in a genotype 1a-infected patient. Excluding nonvirologic failures, the SVR12 rates were 98% (genotype 1) and 100% (genotype 4). Adverse events were mostly mild in severity and did not lead to discontinuation. Laboratory abnormalities were rare. CONCLUSIONS: The OBV/PTV/r ±DSV was well tolerated and yielded high SVR12 rates in patients with HCV genotype 1 or genotype 4/HIV-1 coinfection. The OBV/PTV/r ± DSV ±RBV is a potent HCV treatment option for patients with HIV-1 coinfection, regardless of treatment experience

Catalytic Cycle of Glycoside Hydrolase BglX from Pseudomonas aeruginosa and Its Implications for Biofilm Formation

8 pags., 5 figs.BglX is a heretofore uncharacterized periplasmic glycoside hydrolase (GH) of the human pathogen Pseudomonas aeruginosa. X-ray analysis identifies it as a protein homodimer. The two active sites of the homodimer comprise catalytic residues provided by each monomer. This arrangement is seen in <2% of the hydrolases of known structure. In vitro substrate profiling shows BglX is a catalyst for β-(1→2) and β-(1→3) saccharide hydrolysis. Saccharides with β-(1→4) or β-(1→6) bonds, and the β-(1→4) muropeptides from the cell-wall peptidoglycan, are not substrates. Additional structural insights from X-ray analysis (including structures of a mutant enzyme-derived Michaelis complex, two transition-state mimetics, and two enzyme-product complexes) enabled the comprehensive description of BglX catalysis. The half-chair (H) conformation of the transition-state oxocarbenium species, the approach of the hydrolytic water molecule to the oxocarbenium species, and the stepwise release of the two reaction products were also visualized. The substrate pattern for BglX aligns with the [β-(1→2)-Glc] and [β-(1→3)-Glc] periplasmic osmoregulated periplasmic glucans, and possibly with the Psl exopolysaccharides, of P. aeruginosa. Both polysaccharides are implicated in biofilm formation. Accordingly, we show that inactivation of the bglX gene of P. aeruginosa PAO1 attenuates biofilm formation.The work at the University of Notre Dame was supported by grants from the National Institutes of Health (GM61629 and GM131685), and that in Spain by a grant from MICIU Ministry (BFU2017-90030-P). The authors thank the staff from the ALBA (Barcelona, Spain) synchrotron facility for help in X-ray data collection and CRC of the University of Notre Dame for the computing resources. The authors acknowledge Grant P30 DK089507 from the National Institutes of Health for the BglX transposon mutant of P. aeruginosa

Randomized, double-blind study of stibogluconate plus human granulocyte macrophage colony-stimulating factor versus stibogluconate alone in the treatment of cutaneous Leishmaniasis

Ko, Albert Icksang “Documento produzido em parceria ou por autor vinculado à Fiocruz, mas não consta à informação no documento”.Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-07-13T13:21:50Z No. of bitstreams: 1 Almeida R Randomized, double-blind study of.... .pdf: 76114 bytes, checksum: 8b5c19ceb2448e84f4226674d24b8253 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-07-13T13:38:18Z (GMT) No. of bitstreams: 1 Almeida R Randomized, double-blind study of.... .pdf: 76114 bytes, checksum: 8b5c19ceb2448e84f4226674d24b8253 (MD5)Made available in DSpace on 2017-07-13T13:38:18Z (GMT). No. of bitstreams: 1 Almeida R Randomized, double-blind study of.... .pdf: 76114 bytes, checksum: 8b5c19ceb2448e84f4226674d24b8253 (MD5) Previous issue date: 1999National Institutes of Health grant AI-30639 and by Financiadora de Estudos e Projetos, Centro de Apoio ao Desenvolvimento da Ciência e Tecnologia, and Programa de Apoio aos Núcleos de Excelência.Hospitalar Universitário Professor Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilHospitalar Universitário Professor Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilHospitalar Universitário Professor Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilHospitalar Universitário Professor Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilCornell University Medical College. NY Hospital. Division of International Health and Infectious Diseases. Department of Medicine. New York, NYHospitalar Universitário Professor Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilCornell University Medical College. NY Hospital. Division of International Health and Infectious Diseases. Department of Medicine. New York, NYHospitalar Universitário Professor Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilHospitalar Universitário Professor Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilThe response to recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) in the treatment of cutaneous leishmaniasis was evaluated. Twenty patients with cutaneous leishmaniasis who had lesions for 60 days were enrolled in a double-blind placebo trial of GM-CSF with standard parenteral sodium stibogluconate (20 mg/kg-1/day-1) for 20 days. Ten patients were randomized to receive intralesionally injected GM-CSF (200 microgram) at enrollment and 1 week after, and 10 patients received saline as placebo. GM-CSF- and antimony-treated patients healed faster than patients who received antimony alone (49+/-32.8 vs. 110+/-61.6 days, P<.05). Seven of 10 patients were healed of their lesions before 40 days after therapy in the GM-CSF group, compared with only 1 of 10 patients in the placebo group (relative risk, 7; 95% confidence interval, 1.04-47.00). Thus, GM-CSF plus antimony significantly increased the chance of lesion healing in 40 days