The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Slide Session 5: Antiretroviral Therapy: New Agents and Treatment Naïve Patient Populations
February 1, 1999
Reports on several new compounds addressed the growing need to develop drugs with little cross-resistance to the currently available products. Studies focusing on novel agents in the protease class (AG-1776, poster #11 and ABT-378, poster #15) and NNRTI class (AG-1549, poster #12 and DMP-961/DMP-963, poster #13) were presented on the first morning of the conference.
Of these, only ABT-378 has been studied in clinical trials (Abstract #15). Murphy reported on 101 patients who received 24 weeks of ABT-378 (200 or 400 BID) in combination with low dose RTV (100 or 200 BID) given with D4T/3TC in ARV-naïve patients. The 2-protease combination was based on PK studies indicating dramatic enhancement of ABT-378 blood levels when given with low-dose RTV. At entry, patients had a median viral load of approximately 70,000 and CD4 of approximately 350. At 24 weeks, HIV in >90% of patients was undetectable using first generation test and undetectable in 89%, using the ultrasensitive test. CD4 cells increased by about 160 cells. Furthermore, side effects were few and no patient discontinued from study due to ABT-378 side effects. This is the lead product in a group of second generation protease inhibitors with apparently little cross-resistance to the first generation of PI's.
AG-1776 in vitro data was presented (#11). This novel protease shows activity comparable to other potent PI's and is active against all strains of HIV, including HIV-2. It appears highly synergistic with RTV, IDV, and NFV. In this in vitro study, an antivirogram was compiled using viral isolates with known multiple resistance mutations, as well as clinical isolates from known virologic treatment failures. All strains had remarkable susceptibility to AG-1776, suggesting minimal cross-resistance with other PI's. Clinical trials are planned soon.
In vitro studies of AG-1549, a novel NNRTI, demonstrate similar results (#12). Specifically, using an antivirogram, little cross-resistance to the 3 approved NNRTI's was found. Similarly, two other candidate NNRTI compounds -- DMP-961/963 -- were studied in vitro (#13). They, too, showed excellent activity, including against resistant isolates, such as those with the K-103 mutant. In addition, each of these two latter drugs has a prolonged 1/2 life (>24h), suggesting potential ease of administration. All of the newer NNRTI's appear to have little protein-binding of drug.
Thus, compounds are now arriving in early clinical and pre-clinical studies that offer ease of administration, few side effects, and little cross-resistance to current agents. It remains to be seen whether they will remain promising once they are given to large numbers of patients. Preserving the durability of effectiveness of these "second generation" PI and NNRTI's will require concerted efforts from doctors and patients alike.
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