title: A Phase 1b/2a study of the safety, pharmacokinetics and antiviral activity of BIT225 in patients with HIV-1 infection.
abstract: OBJECTIVE
  BIT225 (N-carbamimidoyl-5-(1-methyl-1H-pyrazol-4-yl)-2-naphthamide), a novel acyl-guanidine, is a novel antiviral drug that blocks Vpu ion channel activity and has anti-HIV-1 activity in vitro. The antiviral effect of BIT225 is most pronounced in cells of the myeloid lineage. With infected circulating monocytes and tissue-resident macrophages representing a key cellular reservoir of HIV-1, BIT225 has a potential role in the eradication of the virus from the host.
  
  
  METHODS
  BIT225-004 is a Phase 1b/2a, placebo-controlled, randomized study of the safety, pharmacokinetics and antiviral activity of BIT225 in 21 HIV-1-infected, ART-naive subjects. Twenty-one subjects were enrolled and received BIT225 (400 mg twice daily) or placebo treatment for 10 days (randomized 2:1). The anti-HIV-1 effect of BIT225 in the monocyte reservoir was measured in CD14+ monocytes isolated from the peripheral blood on days 1 (pre-dose), 5, 10 and 20; isolated monocytes were co-cultured ex vivo with MT4 T cells. De novo HIV-1 replication was measured by p24 activity of released virus into the culture supernatant to day 25 of co-culture. In addition, monocyte samples were collected for analysis by RT-PCR total HIV-1 DNA single-copy assay.
  
  
  RESULTS
  Measurement of HIV-1 directly within the patient's monocyte population indicated that BIT225 treatment significantly reduced the viral burden in myeloid lineage cells, which was more evident in those individuals with the highest viral loads. In addition, BIT225-treated subjects demonstrated a significantly reduced level of monocyte activation (sCD163) compared with the placebo controls.
  
  
  CONCLUSIONS
  This study's unique design demonstrates that BIT225 can significantly reduce the dissemination of HIV-1 from infected monocytes. This has important ramifications for diminishing the seeding/re-seeding of the viral reservoir.
authors.affiliation: Biotron Limited, Suite 1.9, 56 Delhi Road, North Ryde, NSW 2113, Sydney, Australia jwilkinson@biotron.com.au.
authors.forename: John
authors.initials: J
authors.lastname: Wilkinson
authors.affiliation: Biotron Limited, Suite 1.9, 56 Delhi Road, North Ryde, NSW 2113, Sydney, Australia.
authors.forename: Gary
authors.initials: G
authors.lastname: Ewart
authors.affiliation: Biotron Limited, Suite 1.9, 56 Delhi Road, North Ryde, NSW 2113, Sydney, Australia.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Luscombe
authors.affiliation: Biotron Limited, Suite 1.9, 56 Delhi Road, North Ryde, NSW 2113, Sydney, Australia.
authors.forename: Kristin
authors.initials: K
authors.lastname: McBride
authors.affiliation: Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Winai
authors.initials: W
authors.lastname: Ratanasuwan
authors.affiliation: Biotron Limited, Suite 1.9, 56 Delhi Road, North Ryde, NSW 2113, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Miller
authors.affiliation: Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Murphy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006146:Guanidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000821:virology; D010919:Placebos / Q000008:administration & dosage; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D006146:Guanidines; D016655:HIV Core Protein p24; C570889:N-(5-(1-methyl-1H-pyrazol-4-yl)-napthalene-2-carbonyl)guanidine; D010919:Placebos; D011720:Pyrazoles