Suchergebnisse

AbstractIntroductionA potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug‐resistant virus that could spread and reduce the effectiveness of non‐nucleoside reverse transcriptase (NNRTI)‐based first‐line antiretroviral therapy. We evaluated HIV‐1 seroconversions in MTN‐020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV.MethodsMTN‐020/ASPIRE was a placebo‐controlled, Phase III safety and effectiveness study of DPV ring for HIV‐1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV‐1 drug resistance using both population Sanger sequencing and next‐generation sequencing (NGS) with unique molecular identifiers to report mutations at ≥1% frequency. DPV susceptibility of plasma‐derived recombinant HIV‐1 containing bulk‐cloned full‐length reverse transcriptase sequences from MTN‐020/ASPIRE seroconversions was determined in TZM‐bl cells. Statistical significance was calculated using the Fisher's exact test.ResultsPlasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low‐frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others.ConclusionsHIV‐1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN‐020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk.

Abstract
Bronchopulmonary dysplasia, the most prevalent chronic lung disease of prematurity, is often treated with glucocorticoids (GCs) such as dexamethasone (DEX), but their use is encumbered with several adverse somatic, metabolic, and neurologic effects. We previously reported that systemic delivery of the GC prodrug ciclesonide (CIC) in neonatal rats activated glucocorticoid receptor (GR) transcriptional responses in lung but did not trigger multiple adverse effects caused by DEX. To determine whether limited systemic metabolism of CIC was solely responsible for its enhanced safety profile, we treated neonatal rats with its active metabolite desisobutyryl-ciclesonide (Des-CIC). DEX but not Des-CIC caused a reduction in body weight as well as reduced insulin-like growth factor-1 serum levels and chronic hyperglycemia in neonatal rats. However, Des-CIC was as effective as DEX in reducing the expression of various bleomycin-induced proinflammatory cytokine mRNAs. In vitro studies with various cell types demonstrate the potent GR transactivation and transrepression activity of Des-CIC, although genome-wide transcriptomic analyses reveal differences in DEX vs. Des-CIC responses in neonatal rat lung and liver tissue. Des-CIC is a GR super-agonist as revealed by an in vitro coregulator peptide binding assay. In addition, molecular dynamics simulations revealed unique Des-CIC-dependent allosteric signaling pathways between specific residues in the GR ligand-binding domain and receptor surfaces interacting with coregulator peptides. Thus, Des-CIC is a potential novel selective GR modulator that could impart a favorable therapeutic index for CIC use for even modest durations of GC exposure which could have long-lasting adverse somatic, metabolic, or neurologic effects.