DAPD is a failed experimental, anti-HIV drug which had demonstrated potent activity against both HIV and hepatitis B virus (HBV) in preliminary studies. It belongs to the class of drugs known as nucleoside analogue reverse transcriptase inhibitors (NRTIs). DAPD is an abbreviation of diaminopurine dioxolone. It is also known as amdoxovir.

Development of DAPD by Gilead was halted in January 2004. The company stated that its other experimental HIV treatments hold greater promise than DAPD, which was formerly developed by Triangle Pharmaceuticals in the United States. Rights to develop the drug will pass back to Emory University and the University of Georgia Research Foundation.

In the body, DAPD is transformed into dioxolane guanine (DXG). While DAPD is a weak inhibitor of HIV, DXG is a potent inhibitor of HIV. Even at high concentrations, DXG is not reported to cause cellular toxicity.

Effectiveness of DAPD

Phase I/II studies investigating the safety, dosing and efficacy of DAPD were conducted in a small number of people. While the drug showed promise as a 'salvage' therapy, it also caused a potentially serious clouding of the eyes of several patients.

For example, in a study in which DAPD was added to ongoing therapy in a group of highly treatment-experienced people, viral load fell by nearly 2 log₁₀ (100-fold) in six people taking the 500mg twice daily dose (Eron 2000). An open-label study, in which people who had taken many different antiretrovirals added DAPD to their regimen, found seven out of 18 had experienced at least a 0.5 log₁₀ reduction in viral load at week 12 (Thompson 2003). This study reported that five people stopped DAPD due to 'lens opacities which did not impact visual acuity.'

Deepite development having been discontinued, two clinical trials of DAPD are ongoing:

• ACTG 5118: T-20 (enfuvirtide, Fuzeon) plus DAPD or placebo.

• ACTG 5165: DAPD plus mycophenolate (CellCept) or placebo.

Resistance

There is evidence that DAPD has activity against virus which is resistant to AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir). Test tube studies suggest that common NRTI resistance mutations, including multi-drug resistance mutations, may not cause high-level cross resistance to DXG, suggesting that it has great potential as a drug for use in salvage therapy. However, the K65R mutation, which is associated with reduced susceptibility to the nucleotide analogue reverse transcriptase inhibitors adefovir (Hepsera) and tenofovir (Viread), and to ddI (didanosine, Videx / VidexEC) and abacavir (Ziagen) also leads to reduced susceptibility to DAPD in some cell lines.

There is some evidence that mutations that cause resistance to the non-nucleoside reverse transcriptase inhibitors (NNRTIs) may enhance the effects of DXG, or re-sensitise viruses to AZT.

The mutation L74V, which confers a slight loss of sensitivity to DAPD, has been observed in vitro. This mutation confers cross-resistance to ddI.

Key research

Thompson (2003) reported preliminary results from DAPD 150 in which 18 highly treatment-experienced people added DAPD (300 or 500mg twice daily) to their existing regimens (which could be optimised at the discretion of the investigator). At baseline, median viral load was about 25,000 and CD4 count was 338. After 12 weeks, median viral change was -0.9 log with 7 achieving at least a half log reduction. Ten patients discontinued the study: 2 due to virological failure, 3 for non-compliance, and 5 due to lens opacities which did not affect vision.

Eron reported on 2 studies in which DAPD (500 mg twice daily) was given to treatment-experienced patients. In one of the studies, DAPD was added to a failing regimen while in the other DAPD was given as single drug therapy following a 'wash-out' period of no treatment. Six people who added DAPD 500 mg twice daily to their existing treatment had an average viral load drop of 1.9 log. This was superior to the 1.0 log decline seen with DAPD monotherapy.

Deeks administered 25, 100, 200, 300 or 500mg twice daily DAPD to 29 treatment-naive individuals in a 14-day monotherapy study. Median viral load reductions were: -0.5 log (n=6), -1 log (n=6), -1.14 log (n=5), -1.5 log (n=6) and -1.46 log (n=6).

References

Borroto-Esoda K et al. The nucleoside reverse transcriptase inhibitor DAPD is active against resistant HIV-1 isolates from patients failing standard nucleoside therapy. Third International Workshop on HIV Drug Resistance and Treatment Strategies, San Diego, abstract 3, 1999.

Deeks S et al. Short-term monotherapy of DAPD in HIV-infected patients. Fourth International Workshop on HIV Drug Resistance and Treatment Strategies, Sitges, abstract O9, 2000.

Eron J et al. Clinical HIV suppression after short term monotherapy with DAPD. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract 690, 2000.

Jeffrey J et al. Amdoxovir, a nucleoside reverse transcriptase inhibitor, is active against HIV mutants resistant to a standard nucleoside therapy. Antiviral Therapy 6 (supp1): 10-11, 2001.

Mewshaw J et al. DAPD: a novel nucleoside inhibitor of HIV-1 replication is active against drug-resistant isolates of HIV-1 from patients failing standard nucleoside therapy, 39th ICAAC, San Francisco, abstract 924, 1999.

Thompson M et al. Preliminary results of dosing of amdoxovir in treatment-experienced patients. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 554, 2003.