Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients

• Published in: AIDS (London) Vol. 19; no. 15; pp. 1607 - 1615
• Main Authors: THOMPSON, Melanie A, KESSLER, Harold A, ERON, Joseph J, JACOBSON, Jeffrey M, ADDA, Nathalie, GONG SHEN, JIAN ZONG, HARRIS, Jeanette, MOXHAM, Cary, ROUSSEAU, Franck S
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 14.10.2005
• Subjects: Adult; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Anti-HIV Agents - blood; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral Therapy, Highly Active; Antiviral agents; Biological and medical sciences; Dioxolanes - administration & dosage; Dioxolanes - adverse effects; Dioxolanes - blood; Dose-Response Relationship, Drug; Female; Genotype; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - isolation & purification; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Linear Models; Male; Medical sciences; Middle Aged; Mutation; Pharmacology. Drug treatments; Purine Nucleosides - administration & dosage; Purine Nucleosides - adverse effects; Purine Nucleosides - blood; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - blood; RNA, Viral - blood; Treatment Outcome; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Infection; Short term; Immunopathology; HIV; Viral disease; Amdoxovir; Antiviral; AIDS; Immune deficiency; Biological activity; DAPD
• ISSN: 0269-9370; 1473-5571
• DOI: 10.1097/01.aids.0000186822.68606.05

To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days. Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.