Safety and Anti-HIV Activity of Experimental NRTI Amdoxovir  

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) were the first anti-HIV drug class discovered and employed for treatment of HIV infection. Since that time, NRTIs have evolved into a mainstay of current HAART regimens, used often with two NRTIs in combination with a protease inhibitor or a non nucleoside reverse transcriptase inhibitor (NNRTI).

As with most agents employed in therapy for HIV, suboptimal or long-term use of the NRTIs may result in the development of HIV resistant strains, which in turn may lead to virologic failure and clinical decline.

Resistance to antiretroviral agents is often associated with some level of cross-resistance to drugs from the same class. Because of this, the discovery of new agents that are active against drug-resistant strains of HIV is necessary in order to provide viable new treatment options for patients.

Amdoxovir (DAPD), an experimental NRTI, is bioconverted to DXG-TP, which is the active metabolite of the drug. DXG has potent antiviral activity in vitro against clinical isolates of HIV-1 resistant to currently available NRTI, NNRTI and PI . Specifically, DAPD has activity in vitro against clinical isolates containing mutations at positions 41, 67, 70, 184, 215 and 219 of the reverse transcriptase that are resistant to zidovudine/lamivudine and/or stavudine/lamivudine [1].

Melanie Thompson of the AIDS Research Consortium of Atlanta, Georgia and colleagues in the DAPD Study Group sought to evaluate the Pharmacodynamics and safety of escalating doses of amdoxovir monotherapy in treatment-naïve and treatment-experienced HIV patients over a 15 day period. A primary aim of the study was to assess a dose and a doding schedule for amdoxovir for use in future studies of the drug. Results of the study appear in the current issue of AIDS (October 14, 2005). [2]

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.

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.

Based on these findings, the authors conclude, “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 (TAMs) and higher baseline CD4+ cell counts.”

Discussion

Study DAPD-101 demonstrated that amdoxovir produced antiviral activity in all treatment-naive patients and in 24 of 49 (49%) treatment-experienced patients who had at least a 0.5 log₁₀ decline in HIV-RNA at day 15.

In treatment-naive patients receiving short-term amdoxovir monotherapy, a reduction of 1.5 log₁₀ at the highest doses was observed.

In treatment-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients in apparent contradiction to the in vitro virology data [3].

In the stepwise linear regression analysis, in treatment-naive patients, DAPD dose was the only predictive factor for antiviral response. In treatment-experienced patients, the only predictive factors for antiviral response were the presence of TAMs at baseline and baseline CD4+ cell count.

In summary, the authors write, “Results of antiviral activity, safety and pharmacokinetic analyses obtained in this study indicate that amdoxovir has potent antiviral activity in treatment-naive patients. Amdoxovir also demonstrated antiviral activity in heavily treatment-experienced patients, with significant antiviral activity in patients with no TAMs and higher baseline CD4+ cell counts.”

09/30/05

References

1. J L Jeffrey and others. Dioxolane guanosine 5'-triphosphate, an alternative substrate inhibitor of wild-type and mutant HIV-1 reverse transcriptase. Steady state and pre-steady state kinetic analyses. J Biol Chem 278:18971-18979. 2003.

2. M Thompson and others. Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients. AIDS 19(15):1607-1615. October 14, 2005.

3. H Z Bazmi and others. In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (-)-beta-D-dioxolane-guanosine and suppress resistance to 3'-azido-3'-deoxythymidine. Antimicrob Agents Chemother 44:1783-1788. 2000.

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