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A Revolutionary New Way to Fight HIV/AIDS: CCR5 Inhibitors

September 2008

From The Body

Introduction

This video's terrific imagery may help you understand how CCR5 inhibitors work even though the narration is overly technical. To view, click on the image.

Copyright © 2002-2008 Pfizer Inc. All rights reserved. This information is intended only for residents of the United States.

It's an exciting time in the world of HIV treatment. There are more HIV medications available now than ever before. The new generation of medications, ushered in over the past several years, works better against HIV and seems to have gentler side effects than the meds of the 1990s. But with so many new medications to choose from, getting to know the good and bad points of each can be a challenge.

Take, for instance, a completely new family of HIV medications known as CCR5 inhibitors or CCR5 antagonists. CCR5 inhibitors burst onto the scene in 2007, when the first CCR5 inhibitor, Selzentry (maraviroc, Celsentri), was approved in the United States. With Selzentry's approval came a rush of questions from HIV-positive people and health care workers: How do CCR5 inhibitors work? Who should take them? How does a person know if a CCR5 inhibitor will help his or her viral load become undetectable? What are the side effects and other risks associated with them?

Fortunately, all of these questions have answers -- and in this article, you'll learn all you need to know about the basic ins and outs of CCR5 inhibitors.

What Makes CCR5 Inhibitors Unique

Most HIV drugs attack HIV head on. Like an army charging into the enemy, the typical HIV drug takes aim directly at HIV. However, with CCR5 inhibitors, we have a completely new breed of HIV medication. Instead of going on the attack, CCR5 inhibitors protect a person's immune system like a fortress. By attaching to the part of your CD4 cells that HIV targets, a CCR5 inhibitor raises the drawbridge and blocks HIV's entry into CD4 cells. (See "Lowdown on How the Different Types of HIV Medications Work.")

How CCR5 Inhibitors Block HIV

To better understand how CCR5 inhibitors work, let's review the basics about HIV. Once HIV gets into your body, it seeks out your CD4 cells and launches an attack. Its goal: to get inside these cells, take control and turn the cells into HIV factories, spitting out copy after copy of HIV. The CD4 cell that HIV has taken over will eventually die, and the new copies of HIV will go on to infect other CD4 cells.


HIV Virus Life Cycle

Each type of HIV medication blocks HIV in a different way. Here you can see how each of the older classes of HIV drugs interferes with HIV's plans.

Image from www.HIVwebstudy.org, a product of the Northwest AIDS Education and Training Center.

How does HIV get inside your CD4 cells? Scientists have discovered that HIV first grabs hold of a CD4 receptor, a tiny tentacle sticking out of the surface of the cell. (There are many CD4 receptors on a CD4 cell.) Next HIV reaches for a coreceptor, another arm that pokes out of the CD4 cell near the CD4 receptor. The coreceptor acts like a keyhole: Once HIV has released the lock, it's in.

The purple rings are CCR5 inhibitors, which block the coreceptors HIV usually attaches to, preventing the virus from getting inside.

Here is a simulation of a CCR5 inhibitor in action. CCR5 inhibitors (in purple) slide into place within the CCR5 coreceptor on the surface of a CD4 cell. Once they've settled in place, HIV won't be able to lock onto a CCR5 coreceptor anymore, which prevents HIV from entering the CD4 cell and doing its damage.

That's where CCR5 inhibitors meddle with HIV's plans: They plug up that keyhole, preventing HIV from getting inside the cell. Without access to the CD4 cell, it can't set up shop inside the cell, and thus can't harm your immune system or force your cell to pump out more copies of HIV.

In large studies of Selzentry, the medication appeared to do its job exactly as scientists had hoped: When Selzentry was used as part of a specially selected HIV treatment regimen in people whose tests predicted that they would respond to CCR5 inhibitors, Selzentry helped their CD4 count rise and their viral load, the amount of HIV in their blood, fall. (Later in this article, we'll talk more about how doctors can predict who Selzentry will work for.)

Who CCR5 Inhibitors Can Help

No matter how great an HIV medication looks on the drawing board, the reality is that not everybody will be able to benefit from it. The most effective HIV meds we have do a stellar job of fighting the virus, but there will always be some people for whom they just don't work because of HIV drug resistance. When it comes to CCR5 inhibitors, that number is larger than for the average HIV medication and it has nothing to do with resistance. The reason has to do with the way in which CCR5 inhibitors work.

CCR5 inhibitors are named for the coreceptor they block, the CCR5 (sometimes called R5 for short) coreceptor. Some forms of HIV, however, use another coreceptor to enter immune cells: CXCR4 (R4 for short).

Some types of HIV can attach to CCR5 coreceptors, some can attach to CXCR4 coreceptors and others can attach to both.

HIV can use different coreceptors to get inside a CD4 cell. The type of coreceptor HIV uses is called its "tropism."

HIV that uses the CCR5 coreceptor is called CCR5 tropic (or R5 tropic), while HIV that uses the CXCR4 coreceptor is called CXCR4 tropic (or X4 tropic). Some HIV can even use both types of coreceptors; these are called dual-tropic viruses. (If a person has some R5-tropic HIV and some X4-tropic HIV in his or her body, we say that person has mixed-tropic HIV.) CCR5 inhibitors will only work if virtually all of the HIV in your body is CCR5 tropic.

What are the odds your HIV is CCR5 tropic? That depends: Research has shown that people who were recently infected, or people who have little to no resistance to HIV meds, are very likely to have CCR5-tropic HIV. Only about half of so-called "treatment-experienced" people -- people who have already taken a lot of different HIV treatment regimens -- are CCR5 tropic. That's unfortunate, because Selzentry has only been approved for use in treatment-experienced people.

To find out whether a CCR5 inhibitor would work for you, you need to get a tropism test. Above are the results of an actual tropism test.

To find out whether a CCR5 inhibitor would work for you, you need to get a tropism test. Above are the results of an actual tropism test. Click here to view the full test.

Tropism Testing

So how can you tell whether you might benefit from a CCR5 inhibitor? A simple blood test called a tropism test can determine whether your HIV is CCR5 tropic, CXCR4 tropic, dual-tropic or mixed-tropic. In fact, getting a tropism test before you decide whether to start a CCR5 inhibitor is a must, because the drug won't work at all unless you have CCR5-tropic HIV. Fortunately, although tropism testing is expensive, most public and private health insurance plans will cover it.


What If You're Not CCR5 Tropic?

Unfortunately, as we mentioned above, many people -- especially those who have developed resistance to many HIV drugs -- have CXCR4-tropic, dual-tropic or mixed-tropic HIV. A doctor won't prescribe a CCR5 inhibitor if this is the case, because studies have shown that CCR5 inhibitors have no effect on those types of HIV.

Meanwhile, researchers are working hard to figure out whether CCR5 inhibitors will be a good option for people who have never taken HIV meds before. Expect to hear more over the next few years about using CCR5 inhibitors when choosing your first HIV treatment regimen.

Selzentry, the First CCR5 Inhibitor

In August 2007, the U.S. Food and Drug Administration approved the first CCR5 inhibitor, Selzentry, for use in treatment-experienced patients. Studies of Selzentry have mostly focused on people who have been on a lot of different HIV treatment regimens and who have CCR5-tropic HIV. These studies have shown that, when Selzentry is taken in combination with other HIV drugs, the regimen is far more likely to work than if a person took those other HIV drugs without Selzentry.


How Is Selzentry Taken?

Selzentry is a pill that should be taken twice a day. It is available in 150-mg and 300-mg tablets. The proper dose will depend on what other HIV medications you're taking, because different HIV meds can affect how well Selzentry works in your body (and vice versa). For example, if you take a protease inhibitor, such as Prezista (darunavir, TMC114) or Kaletra (lopinavir/ritonavir), your doctor or pharmacist will probably give you a lower dose of Selzentry. If you take Atripla (efavirenz/tenofovir/FTC), Intelence (etravirine, TMC125) or Sustiva (efavirenz, Stocrin), your doctor or pharmacist might give you a higher dose of Selzentry.

HIV medications aren't the only type of drugs that Selzentry may interact with. So, as always, you should make sure your doctor knows about all of the medicines and supplements you use -- whether they're prescription meds or over-the-counter -- before you get a prescription for Selzentry.

As far as researchers know, there are no special risks associated with taking Selzentry while using tobacco, alcohol or recreational drugs. However, all of these substances can harm your body and interfere with your ability to take your HIV meds consistently, so it's also important for you and your doctor to discuss any substances you use before you start Selzentry.

Side Effects

Research on Selzentry to date shows that the drug only causes mild side effects, and even those only occur in some people. People taking Selzentry may experience cough, fever, dizziness, headache, low blood pressure, nausea and bladder irritation.

Fortunately, Selzentry has not been associated with body shape changes or cholesterol/triglyceride problems. However, Selzentry should be used with caution in people who have liver or heart disease, since it can potentially worsen these problems; be sure to talk this over with your doctor.

Also, it's worth noting that Selzentry was approved pretty recently, so we're far from knowing everything there is to know about the drug and its possible side effects. It's also the first CCR5 ever approved on the planet, so there may still be some questions about it. But there are other CCR5 inhibitors under development that have shown excellent results, so this is an exciting new type of medication that most health care providers are learning to use.

For More Information

This article is meant to get you started on the road to learning more about CCR5 inhibitors. If you'd like more information, try visiting these other resources on our site:

Lowdown on How the Different Types of HIV Medications Work

All HIV wants to do is make more copies of itself. Picture it setting up breeding factories inside your CD4 cells.

  • CCR5 inhibitors act like a lock on the factory door that prevents HIV from getting inside.
  • Fusion inhibitors act like a stuck hinge preventing HIV from getting inside the CD4 cell once the door has been opened.
  • Integrase inhibitors act like tricksters who hide the factory's blueprints.
  • NNRTIs and Intelence act like bad supervisors who give the wrong instructions to HIV during the building process.
  • NRTIs act like broken building blocks so that the factory HIV tries to build in your CD4 cells is made with broken bricks.
  • Protease inhibitors act like workers who put defective parts in each new virus being built on the factory's assembly line.


Terms to Know

CCR5 inhibitor - A CCR5 inhibitor, also known as a CCR5 antagonist, is a type of medication that prevents HIV from using the CCR5 coreceptor to enter a CD4 cell.

CCR5 tropic - HIV that can only use CCR5 (or R5) coreceptors.

CD4 cell - A CD4 cell is the type of white blood cell that HIV targets.

Coreceptor - To get inside a CD4 cell, HIV must trigger a coreceptor on the cell's surface. Think of the coreceptor as a keyhole: Once HIV has released the lock, it can slip inside the CD4 cell and do its damage.

CXCR4 tropic - HIV that can only use CXCR4 (or X4) coreceptors.

Dual tropic - HIV that can use both CCR5 and CXCR4 coreceptors.

Mixed tropic - A combination of CCR5-tropic and CXCR4-tropic (and maybe even dual-tropic) HIV.

Tropism - HIV uses two kinds of coreceptors to enter a CD4 cell: CXCR4 and CCR5. The type of coreceptor that HIV uses to enter a cell is called its tropism.




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