Objective: 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.
Design: Randomized clinical trial.
Methods: 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.
Results: 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.
Conclusion: 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.
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.
Correspondence to Arne Kroidl, Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Leopoldstrasse 5, 80802 Munich, Germany. Tel: +49 89 2180 17601; e-mail: firstname.lastname@example.org
Received 31 August, 2016
Revised 25 November, 2016
Accepted 26 November, 2016
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