An oral presentation by Dr. Sham from Abbott laboratories (abstr #14) and a large series of posters (#206-213) presented the first look at ABT-378, a novel protease inhibitor. ABT-38 was designed to overcome some of the limitations of ritonavir, and has several attractive properties. The drug inhibits HIV at concentrations approximately 10 fold lower than the current generation of protease inhibitors. In the test tube, ABT-378 is active against viral strains which are resistant to ritonavir and indinavir due to multiple mutations in the protease gene. Not surprisingly, resistance to ABT-378 could be selected for in the test tube by continued passage at low concentrations of drug. These ABT-378 resistant viruses contained a series of mutations at positions 10, 46, 84, 91, and 47. These strains showed partial resistance to ritonavir and indinavir but remained sensitive to saquinavir.

The half life of ABT-378 would suggest that three time a day dosing would be needed. However, Abbott presented data showing that the clearance of ABT-378 is dramatically decreased with very small doses of ritonavir (also made by Abbott). They suggested that if given with as little as 50 mg of ritonavir daily, ABT-378 could be given as a once a day drug. Certainly, this would be an unusual use for ritonavir.

All of this is based on test tube and animal data. Safety and dose ranging studies in humans are scheduled to begin soon. Caution is wise, since unexpected surprises occur when new drugs are first tried in human volunteers, but this candidate for a new generation of protease inhibitors looks promising.