title: VS411 reduced immune activation and HIV-1 RNA levels in 28 days: randomized proof-of-concept study for antiviral-hyperactivation limiting therapeutics.
abstract: BACKGROUND
  A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4(+) T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects.
  
  
  METHODS
  Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests.
  
  
  RESULTS
  VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4(+) T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: -1.47 log(10) copies/mL; CD4(+) T cell count: +135 cells/mm(3)) and fewest adverse events.
  
  
  CONCLUSIONS
  VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component.
  
  
  BACKGROUND
  ITEudraCT 2007-002460-98.
authors.affiliation: ViroStatics srl, Alghero, Italy. info@virostatics.it
authors.forename: Franco
authors.initials: F
authors.lastname: Lori
authors.forename: Davide
authors.initials: D
authors.lastname: De Forni
authors.forename: Elly
authors.initials: E
authors.lastname: Katabira
authors.forename: Denis
authors.initials: D
authors.lastname: Baev
authors.forename: Renato
authors.initials: R
authors.lastname: Maserati
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Calarota
authors.forename: Pedro
authors.initials: P
authors.lastname: Cahn
authors.forename: Marco
authors.initials: M
authors.lastname: Testori
authors.forename: Aza
authors.initials: A
authors.lastname: Rakhmanova
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stevens
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D003692:Delayed-Action Preparations; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D016049:Didanosine / Q000494:pharmacology / Q000627:therapeutic use*; D054306:Dideoxynucleotides / Q000378:metabolism; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D008297:Male; D010919:Placebos; D012367:RNA, Viral / Q000096:biosynthesis* / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D003692:Delayed-Action Preparations; D003838:Deoxyadenine Nucleotides; D054306:Dideoxynucleotides; D004338:Drug Combinations; D010919:Placebos; D012367:RNA, Viral; C559378:VS411 drug combination; C037773:2',3'-dideoxyadenosine triphosphate; D014508:Urea; D016049:Didanosine; C026600:2'-deoxyadenosine triphosphate