Photo not available due to experimental status

Brand Name: Not yet established

Common Name: maraviroc (formerly UK-427,857)

Class: entry inhibitor—experimental CCR5 antagonist

Standard Dose: Not yet determinded. Once and twice daily doses being studied.

Manufacturer contact: Pharmacia and Upjohn Company, a Pfizer company, www.pfizer.com,
1 (212) 573–1000

AIDSInfo:1 (800) HIV–0440 (448–0440), www.aidsinfo.nih.gov

No maraviroc related liver damage or cancers found in studies.

Aptivus/Norvir had no interactions with maraviroc in healthy (HIV-negitive) volunteers. Sustiva reduced maraviroc concentrations by 50%, while Viramune and Kaletra increased maraviroc concentrations. The official dosing recommendations for these combinations will be known once the drug is approved.

Maraviroc is expected to go into expanded access (free drug for people in medical need, before FDA approval) this year; visit www.maraviroceap.com. Maraviroc is one of the truly new drugs that advanced patients are in so desperate need of—and it’s not the only one, making 2007 an especially promising year (see article "The Times They Are A-Changing"). But maraviroc is not without problems. One, it relies on tropism, and two, other drugs of its type have been discontinued or curtailed during development in late 2005—not a happy sign.

Tropism refers to one of the types of HIV that a person can have: CCR5-tropic (R5) virus and CXCR4-tropic (X4) virus. HIV latches on to the CD4 receptor on the surface of some human cells (hence, CD4+ cells), and then it latches on to one of the two co-receptors on the surface of the cells, CCR5 (R5) or CXCR4 (X4). These two chemokine co-receptors basically invite HIV to come inside. As the name “CCR5 inhibitor” suggests, maraviroc inhibits (blocks) CCR5, shutting down this point of entry for the virus. (The co-receptor inhibitors are also called “antagonists,” as in “CCR5 antagonist.”) X4 virus is associated with advanced HIV disease. HIV infection may involve viruses that infect only CCR5 cells, only CXCR4, both of these types of cells (dual tropic), or a mix (mixed tropic). Most people are infected with CCR5 virus and then over time more CXCR4 and mixed viruses accumulate. Results presented at 2006 IAS indicated that Pfizer did not find that blocking R5 with maraviroc caused virus to shift to X4 or show any other negative effect in so-called “dual tropic” people (their virus can use either R5 or X4). On the other hand, viral load drops were not great, although better than placebo plus optimized therapy. That wasn’t unexpected in this population, for which maraviroc is not aimed, but it’s disappointing nevertheless. Remember that these people had virus that could use either R5 or X4 for entry to the cell, so that could be expected to blunt the response. T-cells, however, went up by about twice as much as with placebo (dummy pill) plus optimized background therapy (around 60 v. 36). Co-receptor inhibitors are part of the HIV entry inhibitor class of drugs—they work in different ways to stop the virus from infecting the cell. People with genetically inherited absence of CCR5 receptors have been found to be highly resistant to HIV infection. Nevertheless, whether there are longterm effects of blocking this immune system chemokine receptor remain to be seen. The co-receptor antagonists hit the body’s cells (have a cellular target), which is exciting and is something to keep in mind for the future. A weird observation in genetically-altered mice was increased risk of West Nile virus.

A test to measure tropism is available and may become important for co-receptor therapy.

This drug (which at the time of this writing is still undergoing clinical trials) is a new type of drug called a CCR5 antagonist—which is an entry inhibitor like Fuzeon but works at a completely different point outside of the cell. Maraviroc is the only one out of three CCR5 players who started out of the gate around the same time that has made it this far (GSK’s got dropped due to toxicity and Schering’s is floundering for the same reasons). Maraviroc works by binding to one of the co-receptors (CCR5) that HIV uses to gain entry into the T-cell. The problem is, not all HIV uses the same receptor to gain entry. Some HIV (usually the more advanced and seemingly more virulent strains) use the other receptor called CXCR4. So in order to use this drug you have to have a test called a tropism assay first to see what type of HIV you carry (by the way boys and girls, tropism is a big new word that we are all going to learn a lot more about in the coming year so pay attention). When a tropism assay is conducted, it can tell you whether or not your particular virus likes to use the front door or the back door—or both…Ooh! This is explained as CCR5-tropic, CXCR4-tropic, or mixed/dual tropic (meaning you have both). This drug works best if you have CCR5-tropic virus, and will not work at all if you have CXCR4-tropic virus. There is some lingering concern about what will happen if this drug is used on someone who has dual or mixed tropic or CCR5-only tropic virus. Will the pressure created cause the virus to shift from being a more mellow CCR5 virus to a more virulent X4 one? Because the jury is still out on this and other concerns, this drug will most likely be approved for use in treatment experienced patients. All in all, this is one class of drug that you will want to keep your eyes on in the coming year.—Cathy Olufs