Background
Doravirine (DOR) is a nonnucleoside reverse-transcriptase inhibitor. In the phase 3 DRIVE-AHEAD trial in treatment-naive adults with human immunodeficiency virus type 1 (HIV-1) infection, DOR demonstrated noninferior efficacy compared with efavirenz (EFV) and superior profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96.
Methods
DRIVE-AHEAD is a phase 3, multicenter, double-blind, noninferiority trial in antiretroviral treatment-naive adults with HIV-1 RNA ≥1000 copies/mL. Participants were randomized to a daily fixed-dose tablet of DOR (100 mg), lamivudine (3TC; 300 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) (DOR/3TC/TDF) or EFV (600 mg), emtricitabine (FTC; 200 mg) and TDF (300 mg) (EFV/FTC/TDF). The efficacy end point of interest at week 96 was the proportion of participants with HIV-1 RNA levels <50 copies/mL (Food and Drug Administration Snapshot Approach) with a predefined noninferiority margin of 10% to support week 48 results. Safety end points of interest included prespecified neuropsychiatric adverse events and the mean change in fasting lipids at week 96.
Results
Of 734 participants randomized, 728 received study drugs and were included in analyses. At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF vs 73.6% of EFV/FTC/TDF participants, with a treatment difference of 3.8% (95% confidence interval, –2.4% to 10%). Virologic failure rates were low and similar across treatment arms, with no additional resistance to DOR observed between weeks 48 and 96. Prespecified neuropsychiatric adverse events and rash were less frequent in DOR/3TC/TDF than in EFV/FTC/TDF participants through week 96. At week 96, fasting low-density lipoprotein cholesterol and non–high-density lipoprotein cholesterol (HDL-C) levels increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group; the mean changes from baseline in total cholesterol/HDL-C ratio were similar.
Clinical Trials Registration
NCT02403674.
From April 1993 to December 1997, 452 admissions of 231 children with nephrotic syndrome to Chang Gung Children's Hospital were retrospectively reviewed. There were 10 episodes of sepsis and 8 episodes of peritonitis in 18 children, and 14 microorganisms were cultured. Two children died due to Streptococcus pneumoniae sepsis. Gram-positive microorganisms (n=7) and Gram-negative microorganisms (n=7) were found in equal numbers. Enterococcus (1), Streptococcus pneumoniae (4), group D streptococcus (1), and Streptococcus viridans (1) were the Gram-positive microorganisms cultured. Two of 4 cases of Streptococcus pneumoniae sepsis were penicillin resistant. Gram-negative microorganisms included Enterobacter cloacae (1), Klebsiella pneumoniae (1), Escherichia coli (2), Acinetobacter baumannii (1), Neisseria meningitidis (1), and group B salmonella (1). The last three microorganisms have not been previously associated with nephrotic children. Vancomycin therapy to cover penicillin-resistant Streptococcus pneumoniae and a third-generation cephalosporin therapy to cover rare Gram-negative microorganisms should be considered in serious infections of nephrotic children.
SUMMARY
During avian egg production, oestrogen mediates marked increases in hepatic lipid production and changes in the diameter of assembled very-low density lipoprotein (VLDL). A nearly complete shift from generic VLDL (∼70 nm in diameter), which transports lipids to peripheral tissues, to yolk-targeted VLDL (VLDLy) (∼30 nm), which supplies the yolk with energy-rich lipid, has been observed in the plasma of laying domestic fowl. We validated an established dynamic laser scattering technique for a passerine songbird Taeniopygia guttata, the zebra finch, to characterize the dynamics of VLDL particle diameter distribution in relation to egg production. We predicted that non-gallinaceous avian species that have not been selected for maximum egg production would exhibit less dramatic shifts in lipid metabolism during egg production. As predicted, there was considerable overlap between the VLDL particle diameter distributions of laying and non-laying zebra finches. But unexpectedly, non-laying zebra finches had VLDL diameter distributions that peaked at small particles and had relatively few large VLDL particles. As a result, laying zebra finches, in comparison, had diameter distributions that were shifted towards larger VLDL particles. Nevertheless,laying zebra finches, like laying chickens, had larger proportions of particles within proposed VLDLy particle diameter ranges than non-laying zebra finches (e.g. sVLDLy: 50% vs 37%). Furthermore, zebra finches and chickens had similar modal (29.7 nm in both species) and median (32.7 nm vs 29.6 nm) VLDL particle diameters during egg production. Therefore,although zebra finches and chickens exhibited opposing directional shifts in VLDL particle diameter distribution during egg production, the modifications to VLDL particle structure in both species resulted in the realization of a common goal, i.e. to produce and maintain a large proportion of small VLDL particles of specific diameters that are capable of being incorporated into newly forming egg yolks.)
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