First medication in new class of ARTs poised to be available for salvage therapy

Tropism testing helps determine best patients for drug

HIV clinicians will have a powerful new weapon in the AIDS arsenal when the first CCR5 antagonist receives marketing approval from the Food and Drug Administration. Approval was expected to be given sometime in July or August.

Maraviroc, which is expected to be marketed by Pfizer under the trade name of Celsentri, targets the earliest stage yet in the HIV infection cycle.

"Maraviroc is the first in a class that works by stopping HIV from being able to attach to a human cell prior to infecting the cell," says W. David Hardy, MD, director of the Division of Infectious Diseases and the AIDS Program at Cedars-Sinai Medical Center in Los Angeles, CA. Hardy also is an associate professor of medicine in residence at the Geffen School of Medicine at the University of California — Los Angeles.

Research showed that patients treated with maraviroc alone had a viral load decrease of 1.7 logs at 10 days, Hardy says.

"That shows it has a high activity and potency in those patients with CCR5-tropic virus," he says. "That's at the same order as what we'd seen earlier with protease inhibitors and that we're now seeing with integrase inhibitors."

In another study, patients who were given either an optimized background antiretroviral (ART) regimen plus maraviroc once a day or twice a day had twice as good viral suppression and twice as good a rise in CD4 cell counts as patients who received the optimized background ART regimen plus placebo, Hardy says.

"The viral load dropped from 0.8 to 1.1 log greater than those on placebo," he adds. "Maraviroc showed high potency at 24 weeks of treatment."

The other good news is the safety profile for ART regimens that include maraviroc are identical to the safety profile of ART regimens plus placebo, Hardy says.

"That's very exciting because side effects have been a real problem for HIV patients," he says. "As we add more drugs we get more side effects, but in this case we saw that the side effects did not increase, and that includes the liver side effects."

Also, there was no increase in kidney toxicity, lipid adverse events, and bone marrow toxicity, Hardy says.

"The good news is that within 24 weeks of treatment, this drug was effective in terms of doubling its response rate, but without the additional side effects," he adds.

It's taken many years for HIV researchers to develop this type of drug, says Hardy, who has investigated HIV/AIDS since 1983.

"After 10 years or more of research, the detailed molecular biology of how HIV identifies, attaches to, and then inserts itself inside of a human cell has been discovered and clearly described," Hardy explains.

This background work has made it possible for investigators to discover a way to stop the virus from being attached to a cell and exploit this discovery, he says.

"CCR5 antagonists are a brand-new type of medication in the over-arching class of entry inhibitors," Hardy says. "There are a growing number of compounds called entry inhibitors, and maraviroc is the first one to come before the FDA as a CCR5 antagonist."

The first entry inhibitor to be marketed in the United States is enfuvirtide (Fuzeon), a fusion inhibitor, which blocks the fusion of the cell membrane and viral envelope.

Maraviroc also is the first HIV drug to inhibit a human target instead of a viral target, Hardy says.

"It is blocking on the human side the interaction between a viral protein and a human protein, which couple up for the virus to attach to a cell and get inside," Hardy explains. "Previously, all of our targets utilized as anti-HIV inhibitors have been viral targets."

Maraviroc is unique in other ways, as well. For example, it is used in conjunction with a diagnostic test called tropism testing to determine whether a specific patient's HIV infection would be susceptible to the drug.

When HIV first infects a cell, it can use either the CCR5 in its second attachment step, or it can use the CXCR4 molecule, or it can use both. HIV that uses solely the CCR5 molecule is called CCR5 tropic; HIV that uses both is called dual-tropic, and HIV that uses solely the CXCR4 is CXCR4 tropic, which is a small minority of infections, Hardy says.

Patients who have dual tropic or CXCR4 tropic virus wouldn't derive as much benefit from maraviroc, so clinicians will need to test patients prior to prescribing the drug. The test that's available for tropism testing is called Trofile, developed and marketed by Monogram Bioscience of South San Francisco, CA. Trofile was used by Pfizer during clinical trials of maraviroc.

"We started working on this technology in 2000," says Christos Petropoulos, PhD, vice president of research and development and chief scientific officer of Monogram Biosciences.

"We anticipated this class of drug and used related technology to look at drug resistance to the fusion inhibitor [Fuzeon]," Petropoulos says. "The goal is to identify CXCR4 tropic viruses that are not going to respond to Celsentri, and our method is close to 95 percent sensitive."

With an enhanced technology, the company expects to increase the tropism test's sensitivity level to 95-99 percent, he adds.

"We were working on this test, and Pfizer approached us in 2002 or 2003 and said, 'We heard you have this technology and what can we do to help?'" Petropoulos recalls. "So we collaborated with Pfizer scientifically."

The tropism test is as simple as viral load or genotype testing, Petropoulos says.

Providers take a blood sample and send it to Monogram Biosciences or to a large reference lab. The results are available on-line in about two weeks, he says.

Results from Pfizer's trials showed that patients who have CXCR4 tropic virus or dual tropic virus and were treated with maraviroc had no viral load reduction when compared to placebo, Petropoulos notes.

"Patients did seem to have increasing CD4 cell counts over the placebo arm, so there may be immunological benefit," he adds. "But a lot more work needs to be done before you can make that conclusion, and this was only 24 week data."

The research thus far suggests that providers will need to conduct a tropism test prior to prescribing maraviroc and perhaps during treatment when treatment failure occurs because there's evidence that HIV can switch tropism as patients become experienced in conventional ART, Petropoulos and Hardy say.

"If a patient is on the drug and has a failure, providers can look at it and see whether the drug tropism has switched," Hardy says.

"We don't know what causes a virus to switch from one type of tropic virus to another kind of tropic virus," Hardy adds.

By using the tropism assay, researchers know that among ART-naïve patients, from 85 to 90 percent will have a CCR5-only tropic virus and 10 to 15 percent will have dual-mixed tropic virus, while only about 1 percent will have CXCR4-only tropic virus, Hardy says.

These percentages change as patients become treatment experienced. The more ART regimens a patient has, the more likely it appears to be that his tropism has shifted, he says.

The percentage of treatment-experienced patients with pure CCR5 tropic virus drops down to 50 to 60 percent, with the percentage of dual-mixed tropic virus increasing to 40 to 45 percent, and the number with CXCR4-only tropic virus increasing to 2 to 3 percent, Hardy says.

"As a patient's CD4 t-cell count drops either with or without treatment, there also seems to be the same kind of shift," Hardy adds. "Patients develop some presence of CXCR4 tropic virus as the CD4 cell count gets lower and lower."

Pfizer's initial application for FDA approval is for treatment-experienced patients, but maraviroc could eventually be a good drug for treatment-naïve patients, as well, Hardy says.

More data about the drug's impact on treatment naïve patients are needed before this is possible, he says.

Another factor in maraviroc being offered first to treatment-experienced patients is that their options are much more limited, Hardy says.

"There are lots of different regimens available and very potent ones and well-tolerated ones, and it is a crowded area for treatment-naïve patients," Hardy explains.

Alternately, patients who have been treated on ARTs and are experiencing treatment failure have very limited treatment options, he adds.

"On a personal note, every single one of the patients I have placed on maraviroc has become [HIV] undetectable," he says. "It's the first time I've seen every single patient respond in this fashion, and it's been very rewarding to see that happen."

The study's been unblinded and Hardy knows which patients have received it once a day, twice a day, and which were on placebo, and all except the placebo patients have had an excellent response, he says.

"My perspective on this medication is that it will be a significant addition initially to our armamentarium for experienced patients who need a new medication," Hardy says. "The only qualifier is that they need to have HIV that is CCR5 tropic as defined by an assay, because we can't make that statement about patients who have dual-mixed virus or CXCR4 tropic virus."

An FDA panel of outside experts had recommended that the FDA approve maraviroc, but the FDA delayed its approval, which had been expected in June, 2007, and instead issued an approvable letter and asked for additional information from Pfizer. The drug already is available in 30 countries through the expanded access program and, also, is pending approval by the European Union.