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HIV entry inhibitors having trouble in trials.(Clinical Rounds)
SAN FRANCISCO -- Efforts to develop entry inhibitors, which constitute the first new class of anti-HIV drugs in years, have hit snags that could delay the entry of these novel agents into the pharmaceutical marketplace.
The debut of entry inhibitors has been eagerly awaited because of preclinical hints that they may be highly effective and have few side effects. But all three entry inhibitors in clinical trials have run into difficulty, and one has now been withdrawn from development, Dr. Steven W. Deeks said at a meeting on HIV management sponsored by the University of California, San Francisco.
GlaxoSmithKline has discontinued development of aplaviroc, which appears to have caused at least five cases of liver toxicity. Schering-Plough's vicriviroc did not perform as well as efavirenz in a head-to-head comparison on treatment-naive patients, and is now being developed only for salvage therapy. And a patient taking Pfizer's maraviroc developed liver failure and required a transplant, although there are indications that other drugs the patient was taking might have been to blame.
Entry inhibitors don't attack the HIV virus directly, explained Dr. Deeks of UCSF. Instead they block a coreceptor on the surface of T cells that the virus requires for entry. Two such coreceptors are known, CCR5 and CXCR4, popularly called R5 and X4. All three current investigational drugs target the R5 receptor.
R5 viruses are associated with slow disease progression and are common in early HIV disease. X4 viruses are associated with rapid disease progression and emerge in late disease. One of the worries in using R5 inhibitors is that they may encourage the earlier emergence of X4 viruses. Indeed, this has apparently happened in five or six patients in the clinical trials, Dr. Deeks said, and this is likely to be associated with more rapid disease progression.
The difficulties that aplaviroc, vicriviroc, and maraviroc have run into are not related to this, however. Aplaviroc has been associated with five cases ...
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Source: HighBeam Research, HIV entry inhibitors having trouble in trials.(Clinical Rounds)