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September 26, 2007

The Trouble With Tropism

by David Evans

For HIV-positive people in need of new treatment options, last month’s arrival of Selzentry (maraviroc) in the United States was a sight for sore eyes. The new drug, manufactured by Pfizer, is the first in a whole new class of antiretrovirals—called “CCR5 antagonists”—to gain approval from the Food and Drug Adminstration (FDA). In 1996, scientists discovered how HIV binds with and subsequently infects CD4 cells with the use of a co-receptor dubbed CCR5 (R5 for short). Selzentry, a product of this research and also approved this week as Celsentri in the European Union, halts HIV from attaching itself to CD4 cells at the R5 site, thus blocking cellular entry of the virus and preventing HIV replication.

Historically, the time period from a discovery in the laboratory to drug approval is lightening quick for HIV medications compared with those developed for many other illnesses, and the recent approval of Selzentry illustrates this dramatically. It took a mere 10 years to bring a drug to market from the day that the CCR5 co-receptor and its role in HIV replication were discovered.

While the rapid approval of the drug seems like a great thing, there are some uncertainties about the long-term impact of Selzentry and other R5 antagonists. The questions that remain have to do with what is known as “tropism” or, the virus’s preference for the co-receptor it uses to enter the CD4 cell.

The R5 protein is one of two co-receptors for HIV dotting the surface of CD4 cells. The other is known as CXCR4 (or X4 for short). Different forms of HIV have different tendencies, or tropism, for the different co-receptors. Some HIV is “R5-tropic,” meaning that it uses the R5 co-receptor to enter the cell. There's also “X4-tropic” virus, meaning HIV prefers using the X4 co-receptor to gain entry. To make matters more confusing, the virus can experience tropism switches (for example, it could initially prefer R5 and change to use X4).

Such switches, it turns out, might be a problem. Studies have found that X4-tropic HIV may actually lead to faster progression to AIDS. Therefore, if the use of an R5-targeting entry inhibitor like Selzentry causes HIV to switch its tropism and promote the growth of X4-using virus, there will be questions about the long-term risks of this drug and others that work in a similar fashion.

Fortunately, the experience of Selzentry in clinical trials completed to date has been extremely favorable. While Selzentry treatment does, in fact, appear to be associated with tropism switches, there’s no evidence to suggest that patients have been harmed by this.  

In order to help you better understand how entry inhibitors work and to help you make your own treatment decisions regarding entry inhibitors, we take you through the thinking behind the development of a drug like Selzentry.

Cost of Entry

Like all viruses, HIV must first bind with its cellular target if it is to establish infection. Researchers have long known about one receptor, called CD4, on T cells that HIV has a particular attraction to (hence the name CD4 cells). However, scientists also suspected that the virus must latch on to another cell-surface molecule to gain entry and begin replicating.

It wasn’t until 1996 that three different labs reported finding not one, but two, coreceptors: R5 and X4. Picture it like this: CD4 is the doorknob and the coreceptors are the locks on a T cell’s front door—its membrane. HIV, with its own mix of proteins studding its surface, uses CD4 to grab hold of the cell and either R5 or X4—depending on its tropism—to unlock the cell’s membrane to rudely let itself in. 

Ben Cheng, a long-time AIDS activist and the deputy director of the Forum for Collaborative HIV Research in Washington, DC, remembers the excitement the papers generated. “People were just really enthusiastic about the finding…because nobody understood how HIV got into cells, particularly CD4 cells,” he says “This increased everybody’s knowledge of the HIV life cycle.”

Cellular Preference

Once researchers knew about R5 and X4, they set out to determine if differences in tropism had different affects on the way HIV damages the immune system. They soon found that HIV tends to evolve down one of two paths. If the virus goes one way, it develops a preference, or tropism, for cells with R5 on their surface. If it goes the other way, it uses X4.

There are also people who have detectable levels of dual-tropic virus, referring to HIV that can target either R5 or X4. Then there are people with mixed populations of virus detectable in their blood, involving a blend of R5- and X4-tropic virus. Dual-tropic and mixed-population virus are often categorized together as “dual/mixed” HIV.

HIV’s tropism matters a great deal. Studies show that R5-tropic virus is easier to transmit, is more commonly found early on in HIV disease and is generally associated with higher CD4 cell counts and lower viral loads. On the other hand, X4-tropic virus is usually found only when HIV disease has progressed and people’s CD4 cell counts have dropped. Several studies, including one recently reported at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), have found that approximately half of HIV-positive people not yet on treatment with X4-tropic or dual/mixed virus have more rapid disease progression.

What causes the shift in viral tropism, and whether it is a cause or an effect of disease progression, still eludes scientists. Also, the majority of people who progress to AIDS never have a detectable R5-to-X4 tropism switch. When asked to explain this perplexity, Cheng says, “I think nobody really understands why. It’s probably because HIV uses whatever path that is easiest to replicate. And if it’s easier through the CCR5 pathway then it will continue doing that. But nobody knows what the trigger [for a tropism switch] is.”

Born Lucky

A second major finding about the viral co-receptors has come to have even greater importance, and led directly to the development of R5-blocking entry inhibitors, including Selzentry.

Soon after the discovery of CCR5, researchers found that a small percentage of people—usually those of northern European descent—are born with a genetic mutation, known as the delta-32 deletion, that greatly affects the amount of this coreceptor on CD4 cells.

People who inherit this mutation from both parents are highly resistant to HIV infection, notably R5-tropic virus. They can, however, become infected with X4-tropic virus, but this happens rarely. People who inherit the mutation from only one parent can become infected with R5-tropic virus, but seem to experience a much slower disease progression course—their viral load remains low and CD4s remain high for many years, sometimes indefinitely.

There appear to be few negative health consequences for people whose CD4 cells can’t produce effective R5. Though some studies have found that they might have a slightly greater susceptibility to infections like West Nile virus, herpes and hepatitis C, they are otherwise generally healthy.

These findings spurred researchers to wonder if therapeutically blocking CCR5 in people who hadn’t inherited the delta-32 deletion might be just as safe and effective at fighting HIV.

”Here’s a demonstration in nature of people who seemed to be immunologically healthy despite their inability to make this protein, to generate R5,” comments Roy Gulick, MD, director of the Cornell HIV clinical trials unit in New York and a researcher of R5 entry inhibitors. “That made people more confident in seeking out drugs that could block the receptor.”

Potential Promise and Problems

Soon after the co-receptors’ discovery, three major pharmaceutical companies—Pfizer, GlaxoSmithKline, and Schering-Plough—began searching for a drug that could bind to R5 thus blocking HIV from entering the CD4 cell. By 2003, three companies were testing the proper dosing, effectiveness and safety of their drugs in small groups of people. Pfizer’s Selzentry is one such compound, and Schering’s vicriviroc is still being tested. GSK’s compound fizzled out in early studies.

Although researchers and activists were excited by the promise of these R5 antagonists, they also had a major worry. If a drug were to block all the R5 receptors in a person with HIV, they wondered, would that cause X4 tropic virus to emerge and result in rapid disease progression?

That, Dr. Gulick says, was the lingering question. “There was a theoretical concern that if you blocked the receptor and suppressed R5 virus, that could lead to an X4 dominance and disease progression. Fortunately, in the clinical trials to date we have not seen this happen.”

While tropism switches have been documented in Selzentry and vicriviroc clinical trials, they haven’t been linked to more rapid disease progression. In fact, several studies have found that people with X4-tropic and dual/mixed virus before or during treatment do get some benefit from taking a CCR5 entry inhibitor. Although such people often aren’t able to keep their viral loads undetectable, they do appear to have modest CD4 count gains and are able to ward off new AIDS-related health problems.

Research also shows that HIV reverts back to R5-tropic virus in the majority of patients who discontinue Selzentry, after experiencing a tropism switch while on treatment with the drug in clinical trials. This might mean that R5 antagonists could be used again in the future, although clinical trials haven’t yet tested this theory. 

Testing to the Fore

HIV tropism isn’t just the stuff of research—it has important implications when it comes to the use of Selzentry and other CCR5 entry inhibitors in the real world. Approximately 40 to 50 percent of people who have used antiretrovirals in the past have dual/mixed and X4-tropic virus. Because these are the HIV-positive people who will most likely be using Selzentry to construct effective treatment options, laboratory testing to determine their HIV’s tropism is essential to determine if they’ll actually benefit from the drug before it is started.

The test, Monogram Bioscience’s Trofile assay, is now available to patients and doctors considering Selzentry or enrollment in a clinical trial of another R5 (or X4) entry inhibitor, or who are just curious. By using a blood sample in which HIV is detectable, the test provides three relatively simple results: that the patient’s virus is R5-tropic, X4-tropic or dual/mixed.

A potential drawback of the test is that it can fail to detect X4-tropic virus if it makes up less than 10 percent of the blood sample’s HIV population. This can lead some people who have low levels of X4-tropic or dual/mixed virus to conclude that they have only R5-tropic virus. According to the company, the Trofile assay has a turnaround time of 14 to 16 days after they receive a blood sample. The list price for the test is $1,960, though the company has been successful getting some insurers and state programs to cover it.

Hopefully, it will soon be possible for people to get even more accurate results about their viral tropism. Data regarding a more sensitive test from the same company that makes the Trofile assay were recently reported. Also, Pathway Diagnostics recently announced that they have a tropism test of their own, called SensiTrop, boasting a lower cost and much faster turnaround time (two to four days for results). Whether it's as or more accurate than Monogram's Trofile assay has yet to be determined. 

Promise Fulfilled

The promise of this new class of drugs was fulfilled in August 2007 when the FDA approved Selzentry for use in people who are heavily treatment-experienced. Earlier this month, Schering announced that vicriviroc has entered Phase III clinical trials. Unlike Selzentry, which must be taken twice a day, vicriviroc is being studied as a once-a-day drug. And a handful of other R5-blocking agents—as well as X4 entry inhibitors—are in earlier stages of development.

Dr. Gulick finds the approval of Selzentry optimistic and says, “It’s the 23rd antiretroviral drug approved. Because of its unique mechanism of action it offers hope to a lot of people with drug resistant virus now…it’s truly a great time in HIV medicine, because we have a number of tools available now, all at one time, for people who are heavily treatment-experienced.”


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