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 But all three entry inhibitors in clinical trials have run into difficulty, and one has now been withdrawn from development, Dr.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, which are popularly called R5 and X4, respectively. All three current investigational drugs target the R5 receptor.
Some people are known to lack the R5 coreceptor because of spontaneous genetic mutations. They seem to harbor no ill effects from this, leading to speculation that agents that block that receptor are unlikely to have serious side effects. No humans are known to lack the X4 coreceptor, on the other hand, and deleting it in mice is lethal. For that reason, there has been a reluctance to develop drugs that bind to the X4 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 of liver toxicity, all of which involved a threefold increase in ALT and a 1.5-fold increase in bilirubin. In all cases, this elevation in enzymes declined when the drug was removed, and in the one case in which the patient was rechallenged with aplaviroc, the liver toxicity recurred. Further development of aplaviroc has been stopped.
There was hope that entry inhibitors might be a good first-line therapy in treatment-naive patients. But a study comparing Combivir plus efavirenz with Combivir plus vicriviroc in patients who were treatment naive was terminated early because of the clear superiority of efavirenz. Vicriviroc is no longer being developed as a first-line therapy; its use will be only for salvage in patients who have failed earlier regimens.
The case of liver failure in a patient taking maraviroc originally caused concern that studies on this medication would have to be terminated as well. This was despite the fact that the drug has been used in hundreds of treatment-naive and salvage patients with no ill effects. But the patient, a 24-year-old woman, had also been receiving isoniazid and cotrimoxazole for HIV-associated infections. Her ALT levels increased more than fivefold during the 7-week screening period, and her AST increased as well.
On the fifth day of taking maraviroc plus Combivir the patient developed rash and fever, and maraviroc was discontinued. The next day her liver enzymes were significantly elevated (32 times normal). For some reason, despite the known potential for additional liver toxicity, she was given a high dose of acetaminophen (11 g IV) at this time. Her liver enzymes continued to worsen, and on day 16 she received a liver transplant.
“Most people think this Pfizer case is highly, highly unlikely to be related to maraviroc, and I agree,” Dr. Deeks said. “There are a couple of reasons for the liver disease here, so all studies are going forward, at least for the Pfizer drug, for now.”
Dr. Deeks disclosed relationships with several pharmaceutical companies, including being a recipient of research support from GlaxoSmithKline and working as a consultant for Pfizer.