The Body Covers: The 37th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy
DMP-266 Resistance, Interactions, and Clinical Efficacy
September 28-October 1, 1997
Abstracts I-115, I-172, I-174, I-175Several studies at the meeting have dealt with the new non-nucleoside reverse transcriptase inhibitor from Dupont Merck, DMP 266. It now has a name -- efavirenz, and even a brand name -- Sustiva. Doug Mayer from Naval Medical Center presented 48 week data from a study of DMP 266 at a dose of 200 mg once daily in combination with indinavir (Crixivan) at a dose of 1000 mg every 8 hours, compared to indinavir alone at standard dose 101 patients.
All of the patients were naïve to protease inhibitors but 70% had been on nucleosides. After 12 weeks, patients initially randomized to the indinavir alone arm added DMP 266 and d4T. After 36 weeks, an other study suggested that 600 mg of DMP 266 was a better dose, and all patients were changed to DMP 600 mg once daily. In the group that initially received DMP 266 and indinavir, the viral load reduction was about 2.3 log compared to 1.7 log in the indinavir group. After 48 weeks, the median reduction in viral load was -2.4 log for the DMP 266 and indinavir group, and -1.9 in the group that added DMP 266 at week 12. In the group initially receiving combination, 90% had viral loads below 400 (by Roche amplicor) at 48 weeks, compared to about 75%. Using the Roche ultradirect assay with a theoretic cutoff of 20 copies of RNA, 80% and 60% were undetectable. Adverse events consisted of rash in 33%. The rash was usually mild to moderate and dissappeared with continued treatment; 1 patient stopped drug due to rash.
In related studies, the pattern of changes leading to drug resistance was studied in patients who had failed DMP 266 monotherapy at 200 mg/day. Resistance mutations emerged in despite only 14 days of monotherapy. The predominant mutation was a change a position 103. Other mutations were seen at position 188 and 190. When given at 600 mg once daily, DMP 266 appears to maintain blood levels which may be active against some of these mutant strains. Another study looked at the interaction of DMP 266 and nelfinavir (Viracept) in volunteers. Giving the two drugs together resulted in 15% in nelfinavir drug levels (not clinically meaningful) and no change in the DMP 266 levels.
These are very promising results. DMP 266 is a very potent drug and can be given once a day (get used to saying efavirenz or Sustiva). It adds a clinically meaningful benefit to indinavir and d4T, and combination studies with nelfinavir are under way. An expanded access program is being launched and the FDA is expected to review the drug for approval in the beginning of 1998. Rash will be a common problem, but it seems manageable. How best to use this agent is not yet clear; but it should be combined with at least one new POTENT agent, and 2 new drugs will be preferable. Clearly, this drug should never be used as monotherapy.
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