Protease Combinations May Be the Most Effective

John Mellors from the University of Pittsburgh gave one of the most compelling oral presentations at the 4th National Conference on Human Retroviruses and Opportunistic Infections in Washington, D.C. when he addressed the issue of combining two protease inhibitors. The potential advantages which he outlined include the more durable HIV suppression which may be achievable, a delay in the emergence of viral resistance, divergent resistance patterns, favorable drug-drug interactions, the potential for lowering doses and twice daily dosing schedules. The potential disadvantages include the in vitro antagonism which has been observed in some experiments (indinavir + saquinavir), more frequent occurrence of adverse effects, HIV escape into the central nervous system and the greater cost. Dual protease trials are ongoing with ritonavir and saquinavir, nelfinavir and saquinavir, ritonavir and nelfinavir, nelfinavir and indinavir and are planned for 15 additional other combinations.

The clinical trial which has produced most exciting data has been the multicenter study evaluating four dose combinations of ritonavir and saquinavir in protease naive patients with CD4 counts 100-500 cells/mm3. The doses studied included twice daily regimens of saquinavir and ritonavir at either 400 or 600 mg ad a thrice daily regimen with 400 mg twice daily of each drug. The most frequent side effects seen have been diarrhea with the higher dose levels as well as liver function test abnormalities. The highest rate of drug discontinuation has been in the thrice daily regimen. In addition a relationship has been noted between preexisting liver disease (Hepatitis B or C) and subsequent transaminase elevations in the combination trial. Viral load responses have been excellent, with 70-80% of patients remaining below the level of detection at 24 weeks of follow-up and CD4 responses of 90-100 cells. The few patients who were not completely suppressed were investigated for compliance patterns and many were found to be nonadherent to their medication regimens. Of those who were compliant 90% and 97% respectively were < 200 or < 1000 copies/ml. Dr.Mellors also noted that the maximal viral load viral load response is predictive of the durability of the treatment response, with those able to maintain viral levels <200/mm3 maintaining their response for the longest. This argues in favor of trying to achieve the greatest amount of suppression with the most potent agents since it may predict the most durable response and overall achieve the desired goal with the least number of agents and the fewest side effects.