title: Virological efficacy of 24-week fozivudine-based regimen in ART-naive patients from Tanzania and Côte d'Ivoire.
abstract: Use of zidovudine (ZDV) in antiretroviral therapy is limited by toxicity and twice daily (b.i.d.) dosing. Fozivudine (FZD) is a ZDV prodrug, which is activated intracellularly to ZDV-monophosphate especially in mononuclear cells but not in bone marrow cells. FZD promises improved myelotoxicity and once daily (o.d.) dosing.
  
  
  
  Randomized clinical trial.
  
  
  
  We conducted an open-label, phase II, proof-of-concept trial investigating three different FZD doses (800 mg o.d., 600 mg b.i.d., 1200 mg o.d.) versus ZDV (300 mg b.i.d.) in combination with lamivudine and efavirenz in HIV-infected, ART-naive patients from Tanzania and Côte d'Ivoire. The primary objective was to demonstrate virological efficacy after 24 weeks in intent-to treat and per-protocol analysis. Secondary endpoints included safety and pharmacokinetic outcomes.
  
  
  
  Of 119 participants included in the intent-to treat analysis, HIV RNA less than 50 copies/ml at 24 weeks was observed in 64 of 88 (73%) patients in the combined FZD arms versus 24 of 31 (77%) in the ZDV arm (RR 0.94, 95% confidence interval 0.75-1.18). In the per-protocol analysis, responses were 64 of 77 (87%) versus 23 of 29 (79%), respectively (RR 1.09, 95% confidence interval 0.89-1.34). Outcomes were similar between FZD arms. Overall, treatments were well tolerated. Severe or worse anaemia occurred in two cases (one related to FZD, one to ZDV), grade III/IV neutropenia was less frequent in FZD compared with ZDV arms (22 versus 42%, P = 0.035). Pharmacokinetic analysis supported o.d. administration of FZD.
  
  
  
  Virological 24-week efficacy was demonstrated in b.i.d. and o.d. administered FZD-based regimens. Reduced myelotoxicity of FZD needs to be confirmed in a larger trial.
authors.affiliation: aDivision of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany bGerman Center for Infection Research (DZIF), partner site Munich, Germany cProgramme PAC-CI, CHU Treichville, Abidjan, Côte d'Ivoire dService des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan, Côte d'Ivoire eNIMR-Mbeya Medical Research Center (MMRC), Mbeya, Tanzania fService de Pharmacologie et d'Immunoanalyse (SPI), CEA, INRA, Université Paris Saclay, Gif sur Yvette gDepartment of Infectious Diseases, University Hospital Saint-Antoine, Paris, France hChiracon GmbH, Biotechnology Park/TGZ I, Luckenwalde iInstitute for Life Sciences and Environment (i-LSE) GmbH, Heidelberg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Kroidl
authors.forename: Frederic
authors.initials: F
authors.lastname: Ello
authors.forename: Jimson
authors.initials: J
authors.lastname: Mgaya
authors.forename: Tessa
authors.initials: T
authors.lastname: Lennemann
authors.forename: Raoul
authors.initials: R
authors.lastname: Moh
authors.forename: Lucas
authors.initials: L
authors.lastname: Maganga
authors.forename: Serge
authors.initials: S
authors.lastname: Eholie
authors.forename: Alain
authors.initials: A
authors.lastname: Pruvost
authors.forename: Elmar
authors.initials: E
authors.lastname: Saathoff
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Girard
authors.forename: Ralph
authors.initials: R
authors.lastname: Zuhse
authors.forename: Friedrich
authors.initials: F
authors.lastname: von Massow
authors.forename: Xavier
authors.initials: X
authors.lastname: Anglaret
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.forename: Christine
authors.initials: C
authors.lastname: Danel
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects / Q000379:methods*; D007560:Cote d'Ivoire; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008055:Lipids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000072230:Sustained Virologic Response; D013636:Tanzania; D016896:Treatment Outcome; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D044966:Anti-Retroviral Agents; D008055:Lipids; D015215:Zidovudine; C408972:fozivudine tidoxil