Selzentry (maraviroc)

October 2007     View PDF     En español
Reprinted from www.aidsmeds.com, US

What is Selzentry?
Selzentry is a CCR5-blocking entry inhibitor manufactured by Pfizer. It was approved by the U.S. Food and Drug Administration (FDA) in August 2007. Selzentry is approved for HIV-positive people who have HIV strains that are resistant to multiple antiretroviral drugs. It is not yet approved for people with drug-sensitive HIV strains, such as those starting antiretroviral therapy for the first time.

In countries other than the U.S., maraviroc will be approved and sold under the brand name Celsentri.

Selzentry binds to a protein on the membrane of CD4 cells (T-cells) called CCR5. Once it does this, HIV cannot successfully attach itself to the surface of CD4 cells, and is thus prevented from infecting healthy cells.

Selzentry must be combined with other HIV drugs.

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What is already known about Selzentry?
Selzentry is available in 150 mg and 300 mg tablets and must be taken twice a day. Because of interactions with other medications, including some used to treat HIV, the dose will need to be carefully determined by your healthcare provider. See “What about drug interactions?” below for more information.

Selzentry holds promise for HIV-positive patients who no longer respond to other HIV drugs. Because Selzentry targets HIV differently than most currently available antiretrovirals, chances are that many people living with the virus—regardless of which drugs have failed them in the past—will likely benefit from using Selzentry. Two large clinical trials have determined that Selzentry, when combined with other drugs, is effective for patients whose virus has adapted to other HIV drugs used in the past. However, Selzentry worked best when it was combined with at least two other drugs that the virus was sensitive to (patients who used Selzentry in combination with drugs that their virus was highly resistant to did not experience decreases in their viral load for very long). For this reason, it is best to use drug-resistance testing to determine which drugs your virus is sensitive to; the results will show which antiretrovirals are best to combine with Selzentry.

Selzentry is not yet approved for people with HIV that have no, or limited, resistance to other available antiretroviral drugs. This includes HIV-positive people beginning treatment for the first time. Preliminary data from a study evaluating the drug in patients new to HIV treatment suggest that Selzentry 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.

Selzentry will only be effective at reducing viral load in people with HIV that uses the CCR5 receptor. It will not be effective against virus that uses another CD4 cell coreceptor, called CXCR4 (and the drug will have a limited effect against HIV with that uses both receptors). Because CXCR4-”tropic” and “dual-tropic” HIV is more common in people who have been infected with HIV for several years—the people who are most likely going to be using Selzentry—a laboratory test called a tropism assay is necessary before Selzentry can be used, to determine if treatment with the drug will be useful.

Resistance concerns are twofold: 1) mutations in HIV’s gp120 protein can cause resistance to the drug (but not necessarily to other entry inhibitors); and 2) while taking a CCR5 inhibitor, it is possible that CXCR4-tropic virus will emerge and not be affected by the presence of Selzentry or any other CCR5-blocking entry inhibitor. More data from studies of Selzentry are needed to better understand the risk and impact of resistance-causing mutations and the emergence of CXCR4-tropic HIV while on treatment.

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What about drug interactions?
Selzentry is broken down (metabolized) by the liver, like many medications used to treat HIV and AIDS. This means that Selzentry can interact with other medications. While it is not expected that the drug will lower or raise the levels of any other medications in the body, studies have shown that other drugs can affect levels of Selzentry in the body.

At the time of Selzentry’s approval in August 2007, there were no known “contraindications,” meaning that there are no known medications that must be avoided while taking Selzentry.

Anticonvulsants, such as Tegretol (carbamazepine), Luminal (phenobarbital), and Dilantin (phenytoin), can decrease the amount of Selzentry in the bloodstream. If these medications are used, the maximum Selzentry dose (two 300 mg twice daily) may be necessary.

Other HIV drugs can interact with Selzentry. Some HIV medications are “CYP3A inhibitors,” meaning that they slow the ability of certain enzymes that are responsible for metabolizing, or breaking down, Selzentry in the body. Some HIV medications are “CYP3A inducers,” meaning that they can speed up the metabolism of Selzentry in the body. Still others do not have a significant effect on CYP3A enzymes. The dose of Selzentry will need to be adjusted, depending on which HIV medications are being used:

CYP3A inhibitors: If Selzentry is combined with protease inhibitors (with the exception of Aptivus [tipranavir] plus Norvir [ritonavir]) or Rescriptor (delavirdine), the correct dose is one 150 mg tablet twice a day.

CYP3A Inducers: If Selzentry is combined with Sustiva and other medications—without CYP3A inhibitors—the correct dose is 600 mg (two 300 mg tablets) twice a day.

Other Antiretrovirals: If Selzentry is combined with Aptivus/Norvir, Viramune (nevirapine), Fuzeon (enfuvirtide), or any nucleoside reverse transcriptase inhibitors—without CYP3A inhibitors—the correct dose is one 300 mg tablet twice a day.

Selzentry can interact with some medications used to treat TB, MAC, and other bacterial infections. Rifadin (rifampin) can decrease Selzentry levels, meaning that the Selzentry dose (provided that CYP3A inhibitors are not being used as well) should be 600 mg (two 300 mg tablets) twice a day. Biaxin (clarithromycin) increases Selzentry levels, requiring a Selzentry dose of one 150 mg tablet twice a day.

Selzentry can interact with some medications used to treat thrush (candidiasis) and other fungal infections. Nizoral (ketoconazole) and Sporanox (itraconazole) can increase Selzentry levels in the bloodstream. If these medications are used, the Selzentry dose should be one 150 mg tablet twice a day.

Other medications, including those known to have a strong inhibitory effect on CYP3A enzymes, can interact with Selzentry and may require dosing adjustments. Tell your doctors and pharmacists about all medicines you take. This includes those you buy over-the-counter and herbal or natural remedies. Bring all your medicines when you see a doctor, or make a list of their names, how much you take, and how often you take them. Your doctor can then tell you if you need to change the dosages of any of your medications.

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What is known about side effects?
The most common side effects associated with Selzentry therapy in clinical trials involving treatment-experienced patients were cough, fever, colds, rash, muscle and joint pain, stomach pain, and dizziness.

Although there hasn’t been an overall increase in serious liver problems in patients treated with Selzentry in clinical trials, liver toxicity has been seen in some patients using the drug. Certain allergy-like signs and symptoms—for example, rash, an increase in the number of eosinophils (a type of white blood cell) or elevated IgE antibodies—prior to the development of liver toxicity may occur. If these signs or symptoms occur while taking Selzentry, patients should be evaluated immediately.

In clinical trials, 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, there is a theoretical risk of developing infections and cancers.

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Who should not take Selzentry?
Selzentry is classified by the FDA as a pregnancy category B drug. Pregnancy category B means that animal studies have failed to demonstrate a risk to the fetus, but that there have been no adequate and well-controlled studies in pregnant women. HIV-positive women who become pregnant should discuss the benefits and possible side effects of anti-HIV treatment to help protect their babies from HIV.

It is not known whether Selzentry passes into breast milk and what effect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed.

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Where can I learn more about clinical trials of Selzentry?
If you would like to find out if you are eligible for any clinical trials that include Selzentry, there is an interactive web site run by ACRIA, the AIDS Community Research Initiative of America.

Another useful service for finding clinical trials is AIDSinfo.nih.gov, a site run by the U.S. National Institutes of Health. NIH has "health information specialists" you can talk to at their toll-free number at 800.HIV.0440 (800.448.0440).

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