Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebocontrolled study in HIV-1-infected individuals

Robert L. Murphy, Nancy M. Kivel, Carlos Zala, Claudia Ochoa, Phillip Tharnish, Judy Mathew, Maria Luz Pascual, Raymond F. Schinazi

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudinemonophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir In combination with reduced and standard doses of zidovudine. Methods: The study was a double-blind, placebocontrolled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA>5,000 copies/ml. Patients were randomized to 10 days of twicedaily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log10 and area under the virus depletion curve (AUCVL) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. Results: Twenty-four patients were enrolled. The mean VL log10 change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUCVL and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. Conclusion: The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

Original languageEnglish (US)
Pages (from-to)185-192
Number of pages8
JournalAntiviral Therapy
Volume15
Issue number2
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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