Influenza A/H1N1 vaccine in patients treated by kidney transplant or dialysis: a cohort study.

BACKGROUND AND OBJECTIVES: In 2009, the pandemic influenza A/H1N1 accounted for worldwide recommendations about vaccination. There are few data concerning the immunogenicity or the security of the adjuvanted-A/H1N1 vaccine in transplanted and hemodialyzed patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Sera from 21 controls, 53 hemodialyzed (HD) patients, and 111 renal transplant recipients (RT) were sampled before (T0) and 1 month after (T1) a single dose of Pandemrix® vaccine (GSK Biologicals, AS03-adjuvanted). We measured the neutralizing antibodies against A/H1N1/2009, the geometric mean (GM) titers, the GM titer ratios (T1/T0) with 95% confidence intervals, and the seroconversion rate (responders: ≥4-fold increase in titer). The HLA and MICA immunization was determined by Luminex technology. RESULTS: The GM titer ratio was 38 (19 to 78), 9 (5 to 16), and 5 (3 to 6) for controls, HD patients, and RT patients, respectively (P < 0.001). The proportion of responders was 90%, 57%, and 44%, respectively (P < 0.001). In RT patients, the prevalence of histocompatibility leukocyte antigen (HLA) class I, histocompatibility leukocyte antigen class II, and MHC class I-related chain A immunization, was, respectively, 15%, 14%, and 14% before and 14%, 14%, and 11% after vaccination (P = 1, 1, and 0.39). CONCLUSIONS: The influenza A/H1N1-adjuvanted vaccine is of limited efficacy but is safe in renal disease populations. The humoral response is lower in transplanted versus hemodialyzed patients. Further studies are needed to improve the efficacy of vaccination in those populations.

Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.

We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.