title: Preliminary safety and efficacy data of brecanavir, a novel HIV-1 protease inhibitor: 24 week data from study HPR10006.
abstract: BACKGROUND
  Brecanavir, a novel protease inhibitor (PI), has sub-nM in vitro antiviral activity against multi-PI-resistant HIV-1 and in vitro is >100-fold more potent than previously marketed PIs and approx. 10-fold more potent than the recently marketed PI, darunavir.
  
  
  METHODS
  HPR10006 is an open label, single-arm, descriptive 48 week study, with 8 and 24 week interim analyses. Thirty-one HIV-1-infected patients were enrolled and received brecanavir/ritonavir 300 mg/100 mg twice daily, with two nucleoside reverse transcriptase inhibitors, based on history and genotype.
  
  
  RESULTS
  At baseline, 25/31 had PI-sensitive virus and 6/31 had PI-resistant virus (median of two primary PI and five secondary PI mutations). Median baseline HIV-1 RNA was 5.0 and 4.2 log(10) copies/mL, respectively. Four patients discontinued prior to Week 24. At Week 24, 77% (24/31) had HIV-1 RNA <50 copies/mL regardless of screening genotype, including 5/6 patients with PI-resistant virus (6/6 had HIV-1 RNA <400 copies/mL). Brecanavir/ritonavir was well tolerated with no serious adverse events or clinically concerning changes in laboratory parameters. Of 31 patients, 10 (32%) experienced drug-related Grade 2-4 adverse events [most frequent events were fatigue (13%), dyspepsia (10%) and nausea (10%)]. Baseline isolate brecanavir IC(50) values for all patients ranged from 0.1 to 0.2 nM. Median plasma trough concentration at Week 4 was 150 ng/mL. Correcting the IC(50) (0.2 nM) value for protein binding (6-fold increase in vitro with 50% human serum) gives a corrected inhibitory quotient of 180.
  
  
  CONCLUSIONS
  Brecanavir/ritonavir was well tolerated and showed potent antiviral activity in HIV-1-infected patients harbouring both PI-sensitive and PI-resistant virus, following 24 weeks of dosing.
authors.affiliation: Quest Clinical Research, Department of Medicine, University of California at San Francisco, San Francisco, CA, USA. drjay@questclinical.com
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Lalezari
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Ward
authors.forename: Susan A
authors.initials: SA
authors.lastname: Tomkins
authors.forename: Harmony P
authors.initials: HP
authors.lastname: Garges
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use; D052117:Benzodioxoles / Q000009:adverse effects / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002219:Carbamates / Q000009:adverse effects / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D019438:Ritonavir / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D052117:Benzodioxoles; D002219:Carbamates; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C512121:brecanavir; D016333:HIV Protease; D019438:Ritonavir