title: Improvement in immune parameters and human immunodeficiency virus-1 viral response in individuals treated with 16alpha-bromoepiandrosterone (HE2000).
abstract: A randomised, double-blind, placebo-controlled study examined the safety, tolerance, immunological effect and anti-human immunodeficiency virus (HIV) activity of sub-cutaneously administered HE2000 (16alpha-bromoepiandrosterone) as monotherapy in treatment-naïve patients with HIV-1. Twenty-four patients received five sequential daily doses of 50 or 100 mg of HE2000 or placebo every 6 weeks for up to three courses, and were followed thereafter for 3 months. HE2000 was safe, with transient injection site reactions being the main side-effect. Peripheral blood samples, collected serially, were analysed for changes in immune cell phenotypes. Significant increases were observed in the numbers of circulating dendritic cells, early activated (CD69+ CD25-) CD8 T-cells and T-NK cells after administration of 50-mg doses of HE2000 (p < 0.05). Gene expression in peripheral blood mononuclear cells was analysed by real-time RT-PCR. Before treatment, HIV-1-infected patients had significantly elevated transcripts for a number of inflammatory mediators (p < 0.012). After 50 mg or 100 mg HE2000, but not after placebo, there were significant sustained decreases in IL-1beta, TNF-alpha, IL-6 and Cox-2 transcripts (p < 0.05). There were no significant differences in CD4 cell numbers, although patients receiving 50-mg doses demonstrated a significant decrease in viral load (- 0.6 log; p < 0.01). Anti-HIV-1 T-cell responses were analysed serially using GAG-peptides to stimulate cytoplasmic IFN-gamma responses. After three courses, the 50-mg dose group demonstrated a significant increase in CD8 T-cell response against two distinct GAG peptide pools (p < 0.03). These findings suggest that immune-based therapies may be able to impact viral load by decreasing inflammation and/or stimulating CD8 T-cells.
authors.affiliation: Hollis Eden Pharmaceuticals Inc., San Diego, CA, USA. creading@holliseden.com
authors.forename: C
authors.initials: C
authors.lastname: Reading
authors.forename: C
authors.initials: C
authors.lastname: Dowding
authors.forename: B
authors.initials: B
authors.lastname: Schramm
authors.forename: A
authors.initials: A
authors.lastname: Garsd
authors.forename: N
authors.initials: N
authors.lastname: Onizuka-Handa
authors.forename: D
authors.initials: D
authors.lastname: Stickney
authors.forename: J
authors.initials: J
authors.lastname: Frincke
mesh_terms: D000328:Adult; D000738:Androsterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D002452:Cell Count; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D004311:Double-Blind Method; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1; D006801:Humans; D007279:Injections, Subcutaneous; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D037181:Lectins, C-Type; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011933:Reagent Kits, Diagnostic; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019562:Viral Load; D000099192:CD69 Antigens
chemical_list: D000738:Androsterone; D019380:Anti-HIV Agents; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051546:Cyclooxygenase 2; D007375:Interleukin-1; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D037181:Lectins, C-Type; D008565:Membrane Proteins; D012333:RNA, Messenger; D011933:Reagent Kits, Diagnostic; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C032020:16-bromoepiandrosterone; C496540:PTGS2 protein, human