• New second-generation NNRTIs: improved resistance and cross-resistance profiles (TuPpA1145)
  Authored by S.Jeffrey, K. Logue, S. Garber, B. Cordova, L. Wallace, D. Baker, S. Erickson-Viitanen, L.T. Bacheler (US)

• Anti-HIV activity and tolerability of DAPD, a novel dioxolane guanine RT inhibitor: preliminary results of a phase I/II clinical trial (TuPpA1146)
  Authored by H. Kessler, J. Eron, M. Thompson, J. Jacobson, S. Deeks, D. Richman, N. Sista, J. Bigley, K. Borroto-Esoda, F. Rousseau (US); F. Raffi (France)

Efforts to develop new drugs within the existing classes continue. Updates on two new NNRTIs from DuPont and a new nucleoside analogue from Triangle Pharmaceuticals were reported in posters at the conference.

One of the limitations of the currently available NNRTIs is the fact that the presence of a single mutation can reduce the activity of these compounds. Hence the search is on for agents in this class that will be effective in people who have developed the major NNRTI resistance mutation known as K103N. Two new, so called second generation NNRTIs, DPC 961 and DPC 083 have been shown to have a long half life in people and have been tested against laboratory isolates of HIV that were made to have different combinations of known NNRTI resistance mutation. When tested against viruses that contained the mutations associated with resistance to efavirenz, both DPC 961 and DPC 083 retained activity in the test tube in the presence of single NNRTI mutations (either K103N, Y181C, or L101I). However, when these drugs were tested against viruses containing secondary mutations, in addition to K103N (high-level efavirenz-resistant viruses), DPC 083 lost activity, while DPC 961 appeared to retain activity. These results are encouraging, however, studies of these drugs in patients who have failed to maintain viral suppression on NNRTI regimens are needed to confirm these preliminary test tube results.

DAPD is a new nucleoside analogue that has been shown to be active against HIV strains resistant to AZT, 3TC and abacavir in vitro. A 14-day Phase I/II study of this promising compound was reported. The study is ongoing and compares four doses (all are twice-daily dosing) of DAPD. The preliminary results show that viral load declines were dose dependent with the best response in the highest dose group (300 mg BID) yielding a 1.5 log drop in HIV RNA. The drug was well tolerated over the short term. Further follow-up and results using higher doses of DAPD in drug resistant patients are awaited.