Should I Be on HIV Entry Inhibitors?

Novel drugs block HIV from entering and infecting cells

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HIV entry inhibitors (also known as a fusion inhibitors) are a class of antiretroviral drug used to treat HIV. The active molecules of the drug are able to stop HIV from multiplying by attaching themselves to certain proteins on the surface of a cell. These are the proteins that HIV needs to "unlock" to in order to enter a cell. Without the means to do so, HIV cannot replicate and create multiple copies of itself.

People who are resistant to other classes of HIV drug may benefit from the entry inhibitors as they can generally overcome drug-resistant HIV mutations. This is especially good news for anyone who has been on treatment for years and has found themselves with fewer and fewer treatment options.

Currently, there are two HIV entry inhibitors approved by the U.S. Food and Drug Administration (FDA): Selzentry (maraviroc) and Fuzeon (enfuvirtide).

Maraviroc and CCR5 Receptor Antagonists

A CCR5 receptor antagonist is a type of entry inhibitor that prevents HIV from binding to a protein on a CD4 T-cell called the CCR5. The CCR5 receptor is one of the primary entry points for HIV, particularly in early-stage infection. By preventing this attachment, HIV is unable to enter the host and hijack its genetic machinery.

Also known as an entry inhibitor, the CCR5 receptor antagonist is different from other classes of antiretrovirals insofar as it doesn't target the virus directly but instead attaches to the surface of the host cell.

It also differs in how it can benefit some people and not others. This is because HIV can vary from person to the next. Some types of HIV will bind to a host using the CCR5 receptor; others will use what is called a CXCR4 receptor for entry.

(Typically speaking, CCR5 is seen more in early infection while CXCR4 in seen in later-stage disease.) 

To determine this, doctors will use a genetic test called a trofile assay is confirm the tropism (orientation) of your specific virus. If the test is positive for CCR5, the virus is said to be "CCR5 tropic," meaning that it will be responsive to a CCR5 antagonist drug. By contrast, CXCR4-tropic virus will not be affected by the drug.

While a number of CCR5 antagonists have been developed only one has actually reached the market:

  • Aplaviroc (code name GSK-873140) was discontinued during clinical trials in 2005 as as result of serious liver toxicities.
  • Maraviroc (available under the brand names Selzentry in the U.S. and Celsentri abroad) was approved in March 2007 for use in previously treated patient
  • Vicriviroc (code name SCH 417690) was abandoned by the manufacturer in 2010 after it failed to meet efficacy targets set by the manufacturer.

The one approved drug, maraviroc, was shown to achieve complete suppression of the virus in 60 percent of people with deep resistance to other HIV drugs. People on the drug need to be monitored closely as it can cause serious liver toxicity in some. Others may experience skin rash and other allergic reactions.

Fuzeon and the Development of Fusion Inhibitors

Fusion is a stage in the life cycle of HIV that enables the virus to bind to a host cell prior to entering it. A fusion inhibitor works by binding to the gp41 protein on the surface of the host cell and preventing it from fusing with HIV. Without this fusion, HIV replication is stopped and infection is averted.

At present, fusion inhibitors have been designed to be delivered by injection rather than as an oral drug. This, combined with the high cost of treatment (approximately $25,000/year), have limited the drug's use to salvage therapy (when all other treatment options have been exhausted).

A number of fusion inhibitor candidates have been developed, although only one has actually reached the marketplace:

  • Enfurvitide (available under the brand name Fuzeon) was approved by the FDA in 2003 for use in treatment-experienced patients.
  • T-1249 was discontinued by the manufacturer due in part to lackluster response to Fuzeon.
  • TRI-1144 and TRI-199 have both been in development since 2003 and have yet to enter large-scale clinical trials.

The one approved fusion inhibitor, enfurvitide, requires twice-daily injection. Side effects can include insomnia, muscle pain, depression, cough, tingling skin sensation, shortness of breath, weight loss, and the hardening of skin at the injection site.

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Article Sources

  • Biswas, P.; Tambussi, G.; and Lazzarin, A. "Access denied? The status of co-receptor inhibition to counter HIV entry." Expert Opinion in Pharmacotherapy. 2008; 8(7):923-933.
  • FDA. "Drug Approval Package: Fuzeon (enfuvirtide) for injection." March 13, 2003.
  • Food and Drug Administration (FDA). "FDA Approves Novel Antiretroviral Drug." Silver Spring, Maryland; August 6, 2007.