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New antiretroviral agents: bright lights on the horizon
Reported by David Margolis, MD, University of Texas, Southwestern Medical Center
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One of the early highlights of the 10th CROI was the Tuesday morning session covering new antiretrovirals, during which an array of new drug candidates were reviewed. The benefits of two decades of experience with HIV, coupled with advances in virology, protein structure modeling, and high throughput drug candidate screening were apparent. Although many potential new drugs will likely fall prey to problems with side effects or delivery as they are brought into clinical trials, some of the problems that have dogged older agents are now "engineered" out of this years' freshman class. While new drugs cannot be on the shelf until the fat lady at the FDA sings, the fact that the pipeline appears full allows optimism.
A new chemical class of non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs), the benzophenone NNRTIs were presented by Larry Boone of Glaxo SmithKline. Like Sustiva, Rescriptor, and Virammune, these drugs bind directly to the HIV RT enzyme and are potent inhibitors of HIV replication with IC50s (the drug concentration that inhibits 50% of HIV production) in the low nanomolar range. Three candidates GW 4751, 3011, and 4511 were shown. The IC50 of resistant viruses selected in the lab was only 10-15-fold increased, an improvement over the current NNRTIs. Further, these drugs retained nearly full activity against viruses highly resistant to current NNRTIs. A novel 106A mutation appeared important in the development of resistance to these drugs, and it was difficult for the virus to develop resistance to these drugs in lab experiments, implying the potential of clinical utility. Standard laboratory assays to predict drug side effects have not turned up major warning signs so far. Of course, more testing and eventually human trials are ahead. It is also unclear if viruses resistant to current NNRTIs will have a head start on developing resistance to the benzophenones.
Happily, Roche re-entered the HIV drug-making business with a new protease inhibitor (PI), RO-033-4649. Again, human studies have yet to begin, but pre-clinical testing suggests that this protease inhibitor should be highly potent, easily taken by mouth, and should have manageable and predictable interactions with other drugs. The major feature of this PI was its potent and persistent activity against HIV with high-level resistance to current protease inhibitors. A panel of 50 "nasty viruses" selected from the archives at Virologics were inhibited by 4649. The average IC50 against these viruses was only 100 nM, and two-thirds of these resistant viruses had less than a 10-fold increase in resistance to 4649 ("low-level" resistance).
Early results from a clinical trial of the Tibotec PI, TMC 114, were presented. 50 patients who had failed several PIs were studied. Of these, 46% had virus resistant to all PIs and only 26% had virus sensitive to more than 1 PI. TMC 114 was given twice a day in doses of 300, 600, or 900 mg boosted by 100 mg of ritonavir. For the first 2 weeks of the study, boosted TMC was the only new drug these patients received. As proof of antiviral activity in this setting, HIV viral load dropped a mean of 1.35 logs in the 14 days after TMC was added. 5 subjects had severe adverse events during the short study period, mostly GI or central nervous system side effects. One patient had an episode of hepatitis. Further studies of TMC 114 are ongoing, and antiviral activity over the longer term in the setting of pre-existing PI resistance will be important to confirm.
A new drug that inhibits HIV integration into the human genome, V165, was presented by scientists at the Rega Institute in Belgium. Although the drug appears potent, its mechanism of action is not yet clear, and further testing may be required before human trials can begin. Maeada from Kumamoto University in Japan presented data on a new molecule AK602, capable of blocking HIV entry into the cell via blockade of HIV's use of the chemokine R5 receptors. Chemokine receptors are the second key, in addition to the CD4 receptor, that the virus uses to gain access to the human cells.
Scientists from Panacos Pharmaceuticals discussed PA-457, an apparently unique drug that inhibits one of the last steps in HIV virion assembly. Again, while early studies suggest that the drug may be non-toxic, the exact mechanism of its action is unclear. Further studies will likely be required before human testing can begin.
The Pfizer group from the UK reported on UK-427,857, a name said to have no nationalistic overtones. Again, preclinical studies give hope that this agent will become a well tolerated and potent twice a day oral drug that can block the use of the chemokine R5 receptor by HIV. Human testing in HIV+ individuals has started.
Finally Diego Miralles from Trimeris presented the results of the use of the next-generation fusion inhibitor, son-of-T20, T-1249. T-1249 was substituted for T-20 at a dose of 192 mg/day to the therapy of 50 patients failing T-20. The results of a planned interim analysis of the first 25 patients was shown. Median time on T-20 after virological failure at enrollment in the T1249 study was 56 weeks (range 28-136). Of these first 25 patients, 24 had plasma virus recovered that allowed a resistance test; all had T-20 resistance. During the 10 day study period, the median (95% CI) log10 HIV RNA decline from baseline was -1.12. Fifteen (63%) patients had at least a 1.0 log10 and 19 (79%) patients had at least a 0.5 log10 drop in HIV RNA. Patients who had been failing T-20 for a shorter time appeared to have better responses (7/7 patients achieved >1 log10 decrease in HIV RNA; median decrease in HIV RNA -1.6 log10). There were serious adverse events, but none were judged possibly related to T-1249.
Although early diagnosis and access to quality care are still problems in the developed world, and access to care is an issue everywhere else, the steady advances in better drugs in proven classes, and new classes of antiretrovirals suggest that in the best of worlds drug-resistant HIV may be held at bay for years to come.
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