The U.S. Food and Drug Administration (FDA) has granted approval to Pfizer’s Selzentry (maraviroc), an HIV entry inhibitor that targets the CCR5 receptor on CD4 cells. The drug—the first member of a new class of oral HIV drugs in more than a decade—is approved for patients with HIV strains resistant to multiple antiretrovirals and is expected to be available through pharmacies by mid-September.

Selzentry in Development

Researchers have long known that, in order for HIV to infect a T cell, the virus must first bind with a receptor called CD4 on the cell’s surface (T cells expressing the CD4 receptor are known as CD4 cells). Researchers also suspected that HIV requires the use of a second receptor on the surface of CD4 cells, but this elusive “coreceptor” remained a mystery for more than a decade of intense research.

It wasn’t until 1996 that research groups in New York City, Boston and Bethesda, Maryland, simultaneously discovered what they were looking for: chemokine (C-C motif) receptor 5 (CCR5). In turn, a more complete picture of HIV “fusion and entry” came into view. While HIV first binds with the CD4 receptor, it must then latch on to a coreceptor, either CCR5 or CXCR4, with CCR5 being the most common of the two.

As research into CCR5 continued, a fascinating picture began to form. It turned out that people born with two defective CCR5 receptor genes (dubbed the CCR5 delta-32 mutation)—one from each parent—are highly resistant to HIV (provided that they are exposed to CCR5-tropic HIV, not CXCR4-tropic HIV). There are also people who inherit a defective CCR5 gene from one parent. While they’re still able to contract HIV, studies suggest that they’re more likely to experience slower disease progression than those without the genetic defect.

With these important data, along with additional research suggesting that CCR5 is not vital to health or survival, pharmaceutical and biotech companies scrambled to develop therapeutic compounds that block the CCR5 receptor. In effect, Pfizer’s Selzentry—which made its research debut in 1997 as UK-427,857—is the first approved treatment for HIV that works by targeting a function of normal cells in the body, not the virus itself.

Tests of Efficacy

The FDA approval of Selzentry is based on preliminary results from MOTIVATE-1 and MOTIVATE-2, two Phase III clinical trials pitting Selzentry against placebo. While the studies intend to follow patients for a total of 48 weeks, 24-week results indicated that Selzentry, combined with an optimized background regimen (OBR), is associated with greater viral load reductions and CD4 count increases compared to placebo among HIV-positive patients with limited treatment options due to drug resistance.

Patients in these studies were highly treatment-experienced; 69.7 percent of those on Selzentry and OBR and 66 percent on OBR alone had two or fewer active drugs in their optimized background regimen.

Selzentry is not yet approved for HIV-positive patients beginning antiretroviral therapy for the first time or for those with limited treatment experience. Preliminary data from a study evaluating the drug in patients new to HIV treatment suggest that it is somewhat inferior to standard-of-care Sustiva (efavirenz). However, moderate CD4 count and side-effect benefits were found to be associated with the drug, compared to Sustiva.

Safety Issues

Patients receiving Selzentry in the studies had a rate of discontinuation due to adverse events (3.8 percent), which was the same as the group receiving OBT plus placebo (3.8 percent).  The most common adverse reactions associated with Selzentry therapy in the studies were cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain and dizziness.

Although there was no overall increase in serious liver problems in patients treated with Selzentry in the clinical trials completed to date, liver toxicity has been seen in some patients using the drug. Certain allergy-like signs and symptoms—for example, rash, a drop in the number of eosinophils (a type of white blood cells) or elevated IgE antibodies—prior to the development of liver toxicity may occur. If these signs or symptoms occur while taking Selzentry, Pfizer warns, patients should be evaluated immediately. 

Of note, more cardiovascular events, including heart attacks, were seen in patients receiving Selzentry as compared to placebo. In turn, the manufacturer and the FDA are recommending that the drug be used with caution in patients at increased risk for cardiovascular events.

Because Selzentry blocks the CCR5 coreceptor located on some immune system cells, Pfizer says that there is a potential increase in the risk of developing infections and cancers.

The Trouble With Tropism

Selzentry will only be effective against CCR5-tropic HIV. It will not be effective against virus targeting CXCR4 (and will have a limited effect against HIV with the ability to target both receptors). Because CXCR4-tropic and dual-tropic HIV are more common in people who have been infected for several years—the people who are most likely going to be using Selzentry—a new laboratory test, Monogram Bioscience’s Trofile tropism assay, will be necessary before Selzentry is used, to determine if treatment with the drug will be useful.

Even among patients with CCR5-tropic HIV who begin Selzentry treatment, there is the possibility that their virus will switch to the CXCR4 receptor during therapy, meaning that the addition of Selzentry will no longer have any significant benefit. Much like drug-resistance testing, tropism testing can be ordered by a healthcare provider if Selzentry treatment failure is suspected.

What’s more, because CXCR4-tropic HIV is usually seen in people who have advanced infection, experts have speculated that the emergence of CXCR4-tropic virus during entry inhibitor therapy would result in more rapid disease progression. In another Phase III study, however, patients who experienced a “switch” to CXCR4-tropic virus while taking Selzentry actually ended up with significantly greater CD4 cell counts. In other words, while therapy with a CCR5 inhibitor may not be virologically effective in patients who experience a switch to CXCR4-tropic HIV, it does not appear to be harmful.

Pfizer says that the drug will be available through U.S. pharmacies by mid-September. Outside of the U.S.—Pfizer is in the process of submitting approval applications to regulatory agencies throughout the world—maraviroc is to be sold under the brand name Celsentri.

The Selzentry dose depends on other medications being used in combination with it. With most protease inhibitors, the Selzenty dose should be 150 mg twice daily. With nucleoside reverse transcriptase inhibitors (NRTIs), Aptivus (tipranavir) plus Norvir (ritonavir), and Rescriptor (delavirdine), the dose should be 300 mg twice daily. And when used with Sustiva (efavirenz), provided that protease inhbitors are not also being used in the drug regimen, the dose should be 600 mg twice daily.