POSITIVELY AWARE MARCH/APRIL 2011
brand name: Selzentry
common name: maraviroc
class: CCR5 antagonist (a type of entry inhibitor)
manufacturer: ViiV Healthcare | www.viivhealthcare.com, (877) 844-8872
Standard dose: Available in 150 mg and 300 mg tablets. Can be taken with or without food, with no dietary restrictions. 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 Selzentry 150 mg twice daily when combined with a CYP3A inhibitor dose (the PI group) if using medications from multiple classes (such as a PI with a NNRTI). Dose change may be required in kidney disease. 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: $1,101.42 / month for 150 mg or 300 mg tablets
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. New warning added to the drug label last year—should not be used in people with severe renal impairment or end-stage renal disease who are taking potent CYP3A inhibitors or inducers (check with your provider). Immune Reconstitution Inflammatory Syndrome (IRIS) may occur as the immune system regains strength; signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is initiated. Report symptoms of illness, such as shingles and TB, to a 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
Not recommended with rifampin or St. John’s wort. Dose adjustment needed for Biaxin, Dilantin (phenytoin), Tegretol (carbamazepine), phenobarbital, HIV NNRTIs and PIs, Mycobutin, Sporanox (itraconazole), Nizoral (ketoconazole), Vfend, oral contraceptives, and oral Versed (midazolam). See standard dosing section for interactions with other anti-HIV medications.
More information
Maraviroc is the first oral entry inhibitor available on the market. Originally indicated for treatment-experienced patients infected only with CCR5-tropic virus, it is now also FDA-approved for people starting HIV therapy for the first time. Complex dosing, the need for an expensive tropism test, and competition from newer drugs have dimmed some of the initial enthusiasm for this drug. Viral tropism refers to 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 attaches to the CD4 receptor on the surface of some human T-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), thus gaining entry. 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 a negative effect on disease progression or CD4 count 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 with treatment-experienced people, 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 that Selzentry seems to have minimal impact on lipid levels. Selzentry has been studied in treatment-naïve patients (first time on therapy) in the MERIT clinical trial. Although the initial analysis suggested that Selzentry was unable to match Sustiva at viral loads less than 50 copies, a re-analysis of the data using the enhanced Trofile test (Trofile ES) showed the regimens to be comparable (59% for Selzentry vs. 63% for Sustiva in less than 50 copies at 96 weeks). The follow-up results of 96-week data led to its FDA approval for this population. Other CCR5 inhibitors are in the works. See package insert for more complete information on potential side effects and interactions.
Doctor’s comments
Selzentry is an entry inhibitor that acts at an earlier stage of the entry process than Fuzeon: It blocks the binding of the virus to the CCR5 co-receptor on the CD4 cell surface. Since some people have virus that can get into the cell using CXCR4, another co-receptor, Selzentry won’t work against that kind of virus. As a result, it’s necessary to test the “tropism” of the virus before using Selzentry. Only those with purely “R5-tropic” virus should use the drug. The need for this test has been the main obstacle to widespread use of Selzentry, which is an effective, safe and well tolerated agent. The test currently in use in the United States, the Trofile assay, is expensive and time-consuming. Outside of the U.S., cheaper genotypic tests are being used. These may turn out to be good alternatives to Trofile, but we need more data on how well they measure tropism and predict success with Selzentry before they can be recommended. Selzentry has now been approved by the FDA for initial therapy, and people are more likely to have R5-tropic virus at early stages, before they’ve been treated. However, Selzentry is not yet being widely used for that purpose, and for initial therapy, it’s categorized as “acceptable” or “alternative” in the DHHS and IAS-USA guidelines, respectively. —Joel Gallant, MD, MPH
Activist’s comments
For those most in need of a new class of drug, the CCR5 antagonist Selzentry has proven to be a disappointment. It only works in those whose HIV virus has CCR5 receptors, who are not the sickest and who don’t need new drugs the most. Add to that the expensive tropism test required to see if one has the CCR5-tropic virus Selzentry is effective against, complicated interactions with other HIV drugs, and it becomes a difficult drug to use. But its unique mode of activity and few side effects mean that more research is needed to see how best to use this new class of drug. —Jeff Taylor
