ABSTRACT
OBJECTIVES: 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. DESIGN: 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.
Subject(s)
Anti-HIV Agents/administration & dosage , Dioxolanes/administration & dosage , HIV Infections/drug therapy , HIV-1 , Purine Nucleosides/administration & dosage , Reverse Transcriptase Inhibitors/administration & dosage , Adult , Anti-HIV Agents/adverse effects , Anti-HIV Agents/blood , Antiretroviral Therapy, Highly Active , Dioxolanes/adverse effects , Dioxolanes/blood , Dose-Response Relationship, Drug , Female , Genotype , HIV Infections/blood , HIV Infections/virology , HIV-1/drug effects , HIV-1/genetics , HIV-1/isolation & purification , Humans , Linear Models , Male , Middle Aged , Mutation , Purine Nucleosides/adverse effects , Purine Nucleosides/blood , RNA, Viral/blood , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/blood , Treatment OutcomeABSTRACT
We conducted a randomized, open-label, 10-day study that compared the antiretroviral activity of emtricitabine (FTC) 25, 100, and 200 mg once daily and lamivudine (3TC) 150 mg 2 times/day in 82 human immunodeficiency virus (HIV)-infected patients with virus loads >5000 and <100,000 copies/mL who were naive for 3TC and abacavir. All FTC doses demonstrated potent antiretroviral activity. Significantly greater virus suppression was seen at the 200 mg/day dose of FTC than with the lower FTC doses and/or 3TC (P=.02, P=.04, and P=.04, respectively). At the 200 mg/day dose, FTC produced a 1.7-log10 mean reduction in virus load. Trough FTC levels at the 200 mg/day dose exceeded the in vitro 90% inhibitory concentration dose for FTC by 5-fold. The long plasma half-life and the superior antiviral activity versus 3TC of the 200 mg/day FTC dose confirmed the results of other studies and led to the selection of this dose for subsequent therapeutic trials.
