Selzentry

Entry Inhibitor

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

Brand Name: Selzentry

Class: CCR5 antagonist (a type of entry inhibitor)

Standard dose: Available in 150 mg and 300 mg tablets. No food restrictions (take with or without food). The recommended dose varies depending on other medications the patient is taking: 150 mg twice daily if taken with a protease inhibitor (except for Aptivus) and Rescriptor; 300 mg twice daily if taken with Aptivus, Viramune, Fuzeon, and all of the NRTIs; 600 mg twice daily if taken with Sustiva, Intelence, rifampin, and some anti-convulsant medications such as phenobarbital, phenytoin, and carbamazepine. Default to the CYP3A inhibitor dose (the PI group) when using medications from different groups (such as a PI with a NNRTI). Concurrent use of Selzentry and other medications that can either inhibit or induce liver metabolism will affect the dose of Selzentry. Your doctor or pharmacist can determine which medications will affect Selzentry.

AWP: $1,147.31/month for 150 mg or 300 mg tablets

Manufacturer contact: Pfizer Laboratories, www.Selzentry.com, 1-800-879-3477 (TRY-FIRST)

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

Potential side effects and toxicity: Most common include cough, fever, cold, rash, muscle and joint pain, stomach pain, and dizziness. Other potential side effects may include liver toxicity; an allergic reaction may happen before the liver problems. It is recommended Selzentry be stopped and your doctor contacted right away if you develop a rash, yellowing of your eyes or skin, and/or dark urine, vomiting, and upper stomach pain. Other rare side effects may include low blood pressure when standing up that could lead to dizziness or fainting, diarrhea, edema (swelling), trouble sleeping, and urinary problems. Immune Reconstitution Inflammatory Syndrome (IRIS) may occur as the immune system regains strength; report symptoms of illness, such as shingles and TB, to health care provider. While no increased risk of infections or cancer was seen in clinical trials, Selzentry affects other immune system cells and could possibly increase the risk of infections and cancer.

Potential drug interactions: Nizoral (ketoconazole), Kaletra, Norvir, Invirase, and Reyataz all increase Selzentry concentrations. Rifampin and Sustiva reduce Selzentry concentrations. Selzentry did not affect the concentrations of oral Versed (midazolam) and oral contraceptives.

Tips: Maraviroc is the first oral entry inhibitor available on the market. It is indicated for the treatment-experienced patient infected only with CCR5-tropic virus. Complex dosing, the need for an expensive tropism test, and competition from recently or soon to be approved drugs, however, have dimmed some of the initial enthusiasm for this drug.

Viral tropism refers to one of the types of HIV that a person can have: CCR5-tropic (R5) virus and CXCR4-tropic (X4) virus. (Tropism is pronounced with a long "o," as in "okay.") HIV latches on to the CD4 receptor on the surface of some human cells (hence, CD4+ T-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, Selzentry 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. In results from various studies, 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). In 2007 the company reported that a switch to X4- or dual-tropic virus was transient and reversible when people went off maraviroc. In studies, a large number of patients were excluded because they did not have exclusive CCR5-tropic virus, limiting the number of patients who could truly benefit from this drug. A sub-analysis reported last year that Selzentry seems to have minimal impact on lipid levels. Selzentry has been studied in treatment-naive patients (first time on therapy) with less than impressive results. It was unable to match Sustiva at viral loads less than 50 copies. For now, this drug seems to be limited to treatment-experienced patients with CCR5-tropic virus.

Doctor

Selzentry (maraviroc) was approved (one tablet twice daily -- no food restriction) for use in combination with other antiretroviral drugs in the treatment of HIV infection in 2007. This antiretroviral is the first oral entry inhibitor produced and is approved only for those who have failed other antiretroviral regimens. In general, this drug has been tolerated, but liver toxicity is a potential problem and liver function should be followed. Maraviroc interacts with a number of PIs and it must be dose adjusted when used with these antiretrovirals. To understand this important drug, you should have knowledge of how it works. For HIV to get into a cell (infect it) it needs to bind to two targets on the cell. Both of these targets are what we call receptors (R). One is the CD4 receptor and the other is called the chemokine receptor. While the virus must use both receptors to get into the cell, for this discussion we will only discuss the chemokine receptor. In general, virus in early infection uses the R5 chemokine receptor (and is called R5 virus) to enter the cell. The virus present in late infection uses the X4 receptor (called X4 virus). Virus in mid-disease can use either the R5 or X4 receptor (DM or dual mixed virus) for cell entry. Maraviroc blocks only the R5 receptor and entry of the R5 virus into a cell. If other virus (X4 or DM) is present, it won't be effective or it works only marginally. Hence an issue with maraviroc, you must know which virus you are dealing with (R5, X4, DM) before using the drug. The Trofile assay can give you this answer. The first version of the assay did not pick up lower levels of X4 virus, but the newer version is said to be more sensitive. Personally, I haven't found many patients (in a salvage situation) with R5 virus and use of the drug in our clinic is relatively small. Oh yeah, it is tempting to substitute maraviroc for T-20, but if the patient has an undetectable viral load, you can't determine if his/her virus is R5 (I hate that!). While this goes against current thought, I believe maraviroc will best serve our patients if used early in infection (seems obvious). Unless we have long-term tolerability data for this drug and other issues are settled, this won't happen. -- Frank M. Graziano, M.D., Ph.D.

Activist

Selzentry, FDA-approved in 2007, is an oral Entry Inhibitor. Although classified as an Entry Inhibitor, this drug is technically a CCR5 antagonist, a "pre-entry inhibitor," if you will. Selzentry works to prevent HIV from binding onto the CCR5 molecule receptor outside of, and thus entering, a healthy CD4 cell. Selzentry requires an expensive test, a tropism assay, to determine if it can be prescribed. Selzentry should only be taken if one has "R5-tropic" virus, not "X4-tropic" or "dual/mixed-tropic" (CXCR4 is the other CD4+ T-cell molecule receptor). And if you have an undetectable viral load or it is less than 1,000, you don't have enough virus for a tropism assay. -- Morris Jackson

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