New treatment options are needed for individuals with drug resistance to currently available drugs. Several new potentially useful drugs are in development. ABT-378, tipranavir and BMS-232632 are protease inhibitors that look promising against resistant virus in preliminary studies. "632" is dosed once daily. AG1549 is a NNRTI that may have potential in suppressing NNRTI resistant virus and has shown good antiviral activity in early human studies. DuPont has a new NNRTI that is in early development which has a long half-life (150 hours), and in the laboratory appears to be effective against NNRTI resistant virus, but it has yet to be tested in HIV+ individuals. DAPD is a nucleoside which showed good antiviral activity against HIV in early human studies, and showed in preliminary studies to be active against NRTI resistant virus. DAPD may be able to be dosed once daily. PMPA is dosed once daily due to its long half-life of 17 hours. At the currently used doses of PMPA, the nephrotoxicity seen with adefovir does not appear to be as big a problem. T-20 is a fusion inhibitor and a member of a new class of drugs called entry inhibitors. Several entry inhibitors are in much earlier development stages, but T-20 is in more advanced stage of development. It has shown promise in studies for treatment-experienced individuals.

Study GS-98-902 is a phase II, placebo-controlled, double-blinded study evaluating 3 doses of tenofovir disoproxil fumarate (DF). Teneofovir (PMPA) was simply added to stable therapy patients were taking. 189 treatment-experienced patients were enrolled with a mean baseline HIV RNA of 3.7 log copies/ml (5000 copies/ml) and CD4 of 369 cells. HIV RNA results at week 32 showed statistically significant mean HIV RNA log reductions of -0.75, -0.40 and -0.45 for patients in the 300 mg, 150 mg and 75 mg dose groups, respectively.At week 24, the arm previously receiving PMPA placebo added PMPA and showed a 0.5 log decrease in viral load.

HIV reverse transcriptase (RT) and protease genotypic analyses were performed at baseline, early termination and at week 24 from plasma HIV utilizing Visible Genetics technology.

Patients had been on therapy for a mean of over 4 years. Baseline genotypic results were obtained from 187 of 189 patients. Consistent with their extensive treatment experience, 74% of patients had HIV with AZT resistance mutations at baseline (RT codons 41, 67, 70, 210, 215 and 219), 66% had the lamivudine-associated M184V mutation, 48% had both AZT and M184V mutations, 59% had primary PI resistance and 34% had primary NNRTI resistance mutations.

Genotypic data is available for 121 of 189 patients (64%) at week 24. Median viral load in this group was 4700 copies/ml. 12% had undetectable viral load. About 34% (n=42) of the 189 developed additional NRTI-associated mutations, 35 of whom developed typical AZT/thymidine analog-associated RT mutations while taking AZT (n=13), d4T (n=20) or abacavir (n=2). Four patients developed L74V, all of whom were taking ddI or abacavir concomitantly. Three patients developed K65R, an RT mutation which is associated with ddI and abacavir in vivo, but has also been selected by tenofovir in vitro. Although these 3 patients may have been on active tenofovir therapy (blinded analysis), all three patients were also taking ddI or abacavir. However, none of these three patients showed evidence of viral load rebound at week 24. It appears as if the remaining individuals did not develop new mutations.

The study authors concluded that in this analysis of 121 patients, there was no evidence for the development of novel RT mutations associated with tenofovir DF therapy.

RT mutations that developed appeared to be due to the patient's background ART and were not associated with loss of HIV RNA suppression. However, although this data is encouraging and promising larger studies and longer-term use are needed to better assess the utility and resistance profile of PMPA in highly drug resistant individuals.