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Can the further clinical development of bevirimat be justified? editorial
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Mark A. Wainberga and Jan Albertb
AIDS 2010, 24:000-000
"Recent results have revealed that naturally occurring polymorphisms located within p2, close to the p24 cleavage site, may be present in some individuals, resulting in lower BVM anti-HIV efficacy. In addition, clinical investigators have long suspected that BVM might potentially be less effective in the treatment of patients who have failed a previous protease inhibitor-containing regimen and whose viruses have developed drug resistance mutations within the protease gene"
"Remarkably, they found that 45% of the protease inhibitor-experienced patients also possessed at least one mutation within Gag known to be associated with BVM resistance, and, in some instances, an accumulation of several such mutations was observed. Indeed, a correlation apparently existed between the numbers of protease resistance mutations within a given isolate and the likelihood of accumulation of multiple BVM resistance mutations within Gag. Even more ominously, these investigators also observed that approximately 30% of isolates from drug-naive patients possessed at least one mutation associated with BVM resistance."
"The article by Verheyen et al. in this issue of AIDS does indeed make a compelling case for the use of resistance genotyping prior to the clinical use of BVM as part of an anti-HIV regimen. In reality, though, the fact thatmultiple mutations associated with diminished responsiveness to BVM are located at or close to the p24/p2 cleavage junction has long suggested that BVMis likely to be a drug with a very low genetic barrier for resistance, calling into question the durability of its effectiveness, even when combined with two other excellent drugs in a therapeutic regimen. The truth might now be that the future clinical development of BVM should be abandoned. Hopefully, the companies and scientists responsible for work carried outwith BVMuntil nowwill persist and develop a secondgeneration maturation inhibitor that will not suffer the myriad of resistance-related problems that have long plagued the development of BVM."
from Jules: taking this one step further, by including this drug in a salvage regimen for patients with no or few options puts the patient at risk for failing the entire regimen & the other drugs in the regimen & developing drug resistance to the other drugs in the regimen & potential cross-resistance to the classes of drugs. How effective will the bevirimat resistance test be in identifying old protease mutations that may have faded over time.
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