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


METHODS
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Thompson
Melanie A
MA
AIDS Research Consortium of Atlanta, Georgia, USA.
Kessler
Harold A
HA
Eron
Joseph J
JJ
Jacobson
Jeffrey M
JM
Adda
Nathalie
N
Shen
Gong
G
Zong
Jian
J
Harris
Jeanette
J
Moxham
Cary
C
Rousseau
Franck S
FS
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D023241:Antiretroviral Therapy, Highly Active; D004148:Dioxolanes / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011684:Purine Nucleosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D004148:Dioxolanes; D011684:Purine Nucleosides; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C098393:amdoxovir