SAN FRANCISCO — Although nonnucleoside reverse transcriptase inhibitors form one of the mainstays of highly active antiretroviral therapy for HIV, they have a prominent Achilles heel: HIV can develop resistance to the entire NNRTI class with simple, single-point mutations.
Several second-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) are now in clinical trials, Dr. C. Bradley Hare said at a meeting on HIV management sponsored by the University of California, San Francisco. These drugs have been designed to require HIV to develop multiple mutations for resistance to take place.
Dr. Hare of the university discussed the results of current trials for the following compounds:
▸ Etravirine (TMC125). Developed by Tibotec, etravirine showed good in vitro activity against viruses with one of several NNRTI-resistant mutations. In 8-day, phase I, monotherapy studies in NNRTI-naive patients, etravirine resulted in viral loads declining by two orders of magnitude. In NNRTI-resistant patients treated for 8 days, the decline was smaller—one order of magnitude—but still impressive. Dosing is being worked out, but etravirine is likely to require twice-daily dosing. At a dosage of 800 mg b.i.d. in phase II research, etravirine is beating placebo in patients with NNRTI resistance and in patients with three-class drug failure. No hepatotoxicity or CNS toxicity has been observed, but 17% of patients have developed a rash.
▸ TMC278 (not yet named). TMC278, also from Tibotec, has not progressed beyond phase I studies. It has a longer half-life than etravirine, which may allow once-daily dosing. In a 7-day monotherapy trial in 47 patients, all three dose levels of the drug resulted in viral-load declines of more than one order of magnitude. Adverse events were mostly headache and nausea. None of the patients developed NNRTI mutations during the short trial.
▸ Capavirine (AG1549). In early studies, capavirine, developed by Pfizer Inc., was active against some viruses resistant to the first-generation NNRTIs efavirenz and navirapine. It seemed effective as monotherapy in NNRTI-naive patients. But a randomized, phase II study with 179 patients who had failed other NNRTIs was disappointing. Development of the drug was discontinued in 2005.
Dr. Hare disclosed financial ties to Pfizer and other pharmaceutical firms, but not to Tibotec.