April 30, 2008
The past year has brought so many new drug approvals that even some HIV experts are scratching their heads as they try to figure out how all of these meds work and how they can best be used to treat people with HIV.
Today, we're going to look at one of the new classes, or types, of HIV medications. Called CCR5 inhibitors, this drug class attacks HIV in a totally new way. Helping us to understand this new drug class will be Dr. David Hardy, a researcher and clinician who is the director of the Division of Infectious Diseases at Cedars-Sinai Medical Center in Los Angeles. He is also one of the leading researchers looking at Selzentry (maraviroc, Celsentri), the first CCR5 inhibitor to be approved in the United States. He'll give us the lowdown on how this new drug class works and put it into context.
I think the most important uniqueness of this new class of medications is really just that: It's a brand new class of medications that works by what we call a "new mechanism of action," by the way it stops HIV from getting inside of a human T cell. I think that's really the most important thing here because when a medication works by a new mechanism of action, it is predictably going to be active against viruses that have become resistant or non-responsive to our previous classes of medications.
The CCR5 inhibitors are a class of medications that we've never used before. Just last year, in late 2007, the first medication of its kind, called Selzentry, was approved by the FDA [United States Food and Drug Administration] for use in treatment-experienced HIV-positive persons. This offers a really important new advantage to those persons who have become resistant to the previous classes such as the nucleosides [NRTIs], non-nucleosides [NNRTIs], and protease inhibitors [PIs]. Because this medication works in a new and different way, we would not expect those viruses to be resistant to this new class.
Can you describe a little bit how CCR5 inhibitors work that's different from previous HIV medications?
HIV begins its life cycle when it binds to a CD4 (or T-cell) receptor and one of two co-receptors on the surface of a CD4+ T- lymphocyte. The virus then fuses with the cell. After fusion, the virus releases RNA, its genetic material, into the cell. For more on the HIV life cycle, click here.
One of those steps, the middle step, is one in which the virus has to use a specific kind of receptor on the outside of the cell. The scientific name for it is a chemokine coreceptor. Using a lock-and-key mechanism, the virus has to use a specific type of coreceptor to gain entrance into the cell. The CCR5 inhibitors block that key-and-lock mechanism such that the virus cannot put its key, so to speak, into the lock on the outside of the cell and then interact with the cell in a key-and-lock mechanism sort of way to gain entrance inside the cell.
These new mechanisms of action have been very exciting because our previous classes of anti-HIV medications have worked only after the virus has gotten inside the cell and has already been doing some of its infection processes. This new class of medication works at a much earlier point in the HIV infection cycle so that it blocks the virus's ability to get inside the cell to begin with.
So it's an entry inhibitor.
Exactly. It is classified as a type of entry inhibitor as well as a CCR5 inhibitor.
It's like Fuzeon [enfuvirtide, T-20] in that way.
It is in the same class as Fuzeon. However, Fuzeon works at the third step of the entry process of HIV getting inside of a cell. The two medications -- the CCR5 inhibitor and the fusion inhibitor work in different ways, but they work, as we know so far, probably in complementary ways, where they don't inhibit or compete with each other, but yet, in fact, probably can work together to better block HIV's entry inside of a cell.
Let me just recap this. There are different types of HIV, like HIV-1 and HIV-2, and there are different subtypes of HIV. Now, it turns out, that every single person with HIV has a type of HIV that can enter through different coreceptors on the CD4 cell. Is that right?
That's true. One thing that has been really important as we have studied and learned more about HIV is that it's a little more complex than we thought it was going to be. The important information that you just alluded to there, Bonnie, is the fact that we know HIV changes over time. When someone first becomes infected with HIV, about 98 percent to 99 percent of the time, whether it's sexual transmission, mother-to-child transmission, and in the majority of injection-drug-use transmissions, the type of HIV that causes infection is what's called a "CCR5-using virus." For short, we just call that an R5 virus. This happens in almost all persons that become infected with HIV.
Over time, it's been noted that in some persons, the R5 virus -- meaning one that uses the CCR5 coreceptor to gain entrance into the cell, that lock-and-key mechanism we spoke about before -- that R5 virus will change over time. It seems to change at points in time when the person's T cells are falling and when the person seems to be headed for what we call clinical progression or opportunistic diseases that are associated with HIV and AIDS.
This doesn't occur in everyone we know, but it does occur in some people. This transition is called an R5 to X4 viral change. HIV, at some point in its life cycle, will start using a different coreceptor called the CXCR4 coreceptor. For short, we call that the X4 type of HIV. This switch from R5 virus to X4 virus has usually been associated with a declining course of T cells and declining health, so it's something that we've always been kind of concerned about as a signal of bad things to come. We don't know exactly what causes this to happen. We don't know whether it's the virus that changes and causes the T cells to fall or whether it's perhaps the falling T cells that have some effect on the virus. But we do know that about half the people who do go on to die from HIV will have an R5 to X4 virus switch sometime during their decline in T cells.
How does someone find out what kind of virus they have?
The best way to do that right now is through a test called a tropism test, very much like a phenotype/genotyope test -- in fact, it is a type of phenotype test -- that is run by a laboratory in Northern California called the Monogram Biosciences Laboratory. It can determine whether a person's virus is an R5 virus or an X4 virus. The reason that that laboratory test was developed was to be able to determine whether that person's virus would be susceptible to medications that block the R5 receptor, i.e., the CCR5 inhibitors, the drug class that we talked about earlier in this interview. That test is available widely now throughout the United States and it's one that's being done commonly when patients and their physicians are considering using an R5 inhibitor.
It's a blood test, right?
It is a blood test. It is exactly like a phenotype test. It uses the same laboratory technique that a phenotype uses when one is trying to determine which medications their virus might be susceptible to.
Does this mean you can't have an undetectable viral load when you take this test?
That is true. It's just like other kinds of viral resistance tests that require that a person have a viral load of 500 to 1,000. The test that is done is a tropism test, as it's called, or what's called a Trofile test by the brand name. The person must have a viral load of at least 1,000 for the test to be done well.
I understand that testing is pretty expensive. What if a patient's insurance doesn't cover the testing? Is there any sort of program?
In the state of California where I live, both our ADAP [AIDS Drug Assistance Program] program as well as our Medicaid equivalent here called Medi-Cal are covering the tests in patients whose physicians will order it. Insurance coverage so far has not been a big problem.
Most PPO/HMO insurances are also covering it as well. [For questions about coverage of this test, call the test's maker, Monogram, at 1-800-777-0177 or click here.]
Once you find out what kind of virus you have, then you'll know if you can include a CCR5 inhibitor in your treatment regimen, is that right?
Correct. The clinical studies that have been done to evaluate where the CCR5 inhibitors will work best have studied people who have both what we call CCR5-using, or R5-using, virus and also persons who have another kind of virus that contains the X4 type of virus.
These studies have clearly shown that where the CCR5 inhibitors work best are only with the patients who have the CCR5-using, or what we call R5-using, viruses. The other kind of viruses that use X4 are not inhibited by this new medication. So that's why the test needs to be done, because what the test does basically is something very similar to the genotypes and phenotypes that we've been doing for a while. It helps to better define which medications will work against a person's virus.
So CCR5 inhibitors will not work against your virus if you have the wrong kind of virus?
Correct. The study that actually evaluated that situation in which a CCR5 inhibitor in combination with other anti-HIV medications as part of a HAART [highly active antiretroviral treatment] regimen, or cocktail, showed that the addition of a CCR5 inhibitor to a regimen of other anti-HIV drugs did not add any better viral suppression than adding a placebo if the patient had a X4-containing type virus population.
What if you have a mixed population? Is there such a thing as a little bit of X4 and a little bit of R5?
Yes, there is. There is a type of HIV that is "bi," so to speak, meaning that it can use both the R5 lock-and-key mechanism and it can also use the X4 lock-and-key mechanism. We call those dual viruses. They can go either way, with R5 or with X4.
Then we also know that HIV really exists as a mixed population of viruses oftentimes -- the viral population can contain both R5- and X4-using viruses. So we group those viruses into one big group called dual or mixed viruses.
Whenever any X4-using virus is found in a person's virus, we consider that to be a type of virus in which a CCR5 inhibitor will not work very well. Any dual or any mixed virus population will not have a good result with a CCR5 inhibitor.
Do most people with HIV have all of one type of virus or all of the other type or do most people have a little bit of each? It sounds very confusing. If I was just diagnosed yesterday, what's the likelihood that I'll have mixed-tropic virus?
Click on the image to view. This video's terrific imagery may help you understand how CCR5 inhibitors work even if the narration is overly technical.
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This is something we've also gotten some very good data on. The type of virus a person has changes over time. About 98 percent to 99 percent of people are infected with only an R5 virus. Rarely are people -- only 1 percent to 2 percent -- infected with a virus that contains any X4-using type virus. If someone has never been treated with HIV medications, what we call treatment-naive individuals, studies have shown that somewhere between 85 percent to 95 percent of those persons' viruses will be R5-using viruses only. Where this virus tends to be much more commonly found is in people who have never taken HIV medications before and in people who have T cells that tend to be higher, say, over 200, rather than lower T cells, say, less than 200.
As a population goes through multiple regimens for HIV, multiple cocktails -- say, after three or four regimens that perhaps have not worked or been tolerated -- the percentage who only have R5 virus declines. After people have been on three or four HIV medication regimens, the percentage of those persons who have pure or only R5 virus drops to somewhere between around 50 percent to 60 percent.
Do you think that these types of drugs are destined to be used in first-line or second-line treatment, since most people who are very treatment-experienced cannot take them?
Right now, I should just point out first of all, that when the FDA approved the first CCR5 inhibitor called Selzentry last fall, that the approval was only for persons who were treatment-experienced: those individuals who had, or are known to have, virus resistant to other HIV drug classes -- basically, the ones who need a new class of medications. That's where the CCR5 inhibitor, Selzentry, is now approved for use.
That medication has not been approved for use in the persons you just mentioned, those who have never taken HIV medication before. Although biologically, based on what I mentioned about how common pure R5 virus is based on the number of regimens a person has been on, the more rational group of people to be treated with this kind of medication would be those who have never taken HIV medication before, because more of them, 85 percent to 95 percent, have the kind of virus that this type of medication will suppress.
There is a study that has been ongoing now for about two and a half years that has been studying the use of Selzentry, the first CCR5 inhibitor approved, in treatment-naive persons. The results were that it was almost as good as a Sustiva [efavirenz, Stocrin] plus Combivir [AZT/3TC] regimen, but not considered to be as fully active in terms of suppressing HIV. The FDA has not ruled on whether or not Selzentry can be used in treatment-naive people.
It makes sense that it will be earlier in the game rather than later, because of all the reasons you mentioned.
It does make sense. I should add that in the treatment-naive study with Selzentry versus Sustiva, while the results were very close in terms of suppressing virus, Selzentry was not quite as good as Sustiva. But, on the other hand, the patients who got the Selzentry did have a significantly higher number of T cells after a year's treatment and also had less side effects in terms of the kinds of side effects that usually make people stop taking their medication, particularly the neurologic side effects that can occur with Sustiva.
More and more we are taking a larger perspective on new HIV medications in terms of how well they may raise a T cell count in individuals and also how well they may be tolerated.
Were there any gender or racial differences seen in the responses to Selzentry?
No, there were not. I do have to say that in the large 1,000-patient study of Selzentry that the FDA used to approve Selzentry, the proportion of women was about 10 percent to 12 percent, so the experience with women is much less than the experience with men, as in many other studies of HIV medications. But looking at that 10 percent to 12 percent of women compared to the men in the study, there does not seem to be any evidence of difference in terms of gender. There were somewhere between about 30 percent to 40 percent of people who were not Caucasian in the studies and again, no difference in terms of race or ethnic group either.
What are the most typical side effects with Selzentry?
The large clinical studies that have been completed with Selzentry have been very good studies for trying to determine what side effects may happen when you add that new drug, compared to adding no drug, meaning a placebo. That kind of study design gives us a very good look at the side effects a new drug may add. Basically, the only side effect that patients reported that was more common with Selzentry versus the placebo was a slightly increased number of colds, what we call upper respiratory tract infections: colds, coughs, that kind of thing. Why an increased number of coughs, colds or respiratory tract infections in the head and neck was more common in people taking Selzentry compared to those taking a placebo has not really been clear.
I think the important thing is that there was no greater number of cases of diarrhea, nausea, headache, fatigue, and the common side effects that are sometimes seen with HIV medications. There were also no neurological side effects that were reported in terms of dreaming, in terms of difficulty with sleeping or feeling groggy.
The other side of the coin that's always important for us is to look at the laboratory side effects. So far there has been no evidence, no indication, that Selzentry has been associated with any problems with liver disease or causing liver disease or liver irritation, kidney disease or kidney irritation, or pancreatic irritation or bone marrow suppression, meaning causing anemia or suppressing one's white blood cell count -- the infection-fighting cells.
When I start patients on Selzentry now, when I sit down and talk to them about what they might expect in terms of side effects, I really have very little to tell them. It's been a refreshing and new sort of way of introducing a new drug to a patient because there have really not been a whole lot of side effects that I can think of that they have to be warned about. It's been a significant advancement that this medication does not carry with it any significant side effects so far.
Do we know if Selzentry has any effect on body shape changes, facial wasting, or fat accumulation?
To date there have not been any specific studies about that that I know of. We often first pick up that kind of thing from what we call "anecdotal reports," meaning that someone will say, "I treated five patients with this medication and three of them came back and told me that their faces were getting thin and not looking so good."
Even the anecdotal reports so far -- of the almost 2,000 persons who have been treated with Selzentry in studies -- have not shown any kind of fat-wasting or fat accumulation, the lipodystrophy problems that we've noticed with other HIV medications. So far so good, of course, we haven't seen anything like that. But, of course, the medication has not been studied in a huge number of patients so far or given to a huge number. It was just approved in the U.S. [in August of 2007] and put on the market in September of 2007.
We do know one thing about it that's kind of interesting, and that is one thing that can sometimes or sometimes not be associated with fat changes in the face and body or what we call lipid changes -- changes in the fatty substances in the blood, like cholesterol and what we also call triglycerides. So far, one large study with Selzentry demonstrated that in over a year's period of time, the change in the cholesterol and the triglycerides was really negligible from where the patient started. Even in comparison to a drug that generally does not cause many lipid changes -- the drug Sustiva -- we've seen so far that Selzentry causes even fewer problems with cholesterol and triglycerides than Sustiva does.
Are there any long-term safety issues that we still don't understand about CCR5 inhibitors? I understand that there were some cancer diagnoses in the vicriviroc [SCH 417690; SCH-D] study. Is there a chance that the CCR5 receptor is more important to normal immune function than we think?
That's a very good question, Bonnie. First of all, let me say that with any brand new class of medication, we really do have to take an optimistic watch-and-wait sort of attitude in terms of looking at what side effects might occur over a long time.
For example, no one suspected in 1996 that protease inhibitors -- which work so well in dropping viral load and helping T cells to come back up -- would be associated with the lipodystrophy problems that occurred by 1998 and 1999 in many patients.
In order not to try to make that same kind of mistake, the studies that have been done with Selzentry in most cases, which have lasted somewhere around two and a half to three years for most patients, are going to be continued for a total of five years. This way the patients will stay in the studies and be carefully observed and we can make sure that if any kind of new and different kind of problems we haven't seen before, such as cancers, such as increased infections, such as anything that may pop up later on in the drug's use for long-term therapy, that those will be caught and will be able to be carefully observed in terms of numbers and how many patients it's occurring in.
I can tell you so far, with Selzentry, there has been no sign that any increased cancers have been seen -- either lymphomas or Kaposi's sarcoma, which are commonly seen in persons with AIDS [advanced HIV], or any other kind of skin cancers or other kinds of cancers at all.
You referred to a different, second CCR5 inhibitor called vicriviroc, which is not approved yet. It's still in the development stages. In one small study with that drug, there appeared to be a potential increase in the number of lymphomas in the persons who got the vicriviroc compared to those who received the comparative placebo treatment. Whether or not that's going to be borne out in larger studies has really not been seen at this time. I think with any brand new class of medications, we do have to be cautiously optimistic about watching and waiting to see what, if any, kinds of side effects may occur down the road.
Have the CCR5 inhibitors, whether vicriviroc or Selzentry, been tested with pregnant women?
They have not been tested yet. In initial studies with new medications, especially a new class of medications like this, the FDA in our country prohibits pregnant women from being given those medications until we know whether or not there are any kinds of side effects that may affect the unborn baby.
We do know that Selzentry is classified as what's called a category B medication. On the FDA range from A to F for a medication's ability to cause birth defects in babies -- A being none, F being "do not ever use that medication in a pregnant woman" -- right now Selzentry is considered to be a B. [This means that in animal studies in which pregnant animals (rats, dogs, rabbits) were given Selzentry and had babies, there was no evidence that birth defects occurred in those animals. Because not enough pregnant women have been given this medication, there's still something to be learned, but so far it looks pretty good.
What about people coinfected with hepatitis C? Can they also take CCR5 inhibitors?
So far there's been no problem with that. In the large studies that were responsible for the FDA approving Selzentry, about 15 percent to 16 percent of the people in the studies had either hepatitis B or hepatitis C. The effect on the liver in those persons was not any more severe or problematic than it was in persons who didn't have hepatitis B or hepatitis C. The safety of the medication in all persons, whether they have hepatitis B or C or not, seems to be very good in terms of liver effects.
What is known about CCR5 inhibitors and HIV drug resistance? Can you develop drug resistance to CCR5 inhibitors if you don't take them on time, just like with other HIV drugs? And if you become resistant to one CCR5 inhibitor, does that mean you're going to be resistant to the others?
Again, I think that's one of those questions that I've heard very little good answers for so far. We do know that in a small number of cases in which someone who is taking Selzentry or vicriviroc, and the viral load was suppressed, but then bounced back up -- what we call a rebound in viral load -- that when the studies in the laboratory were done to look at that person's virus, a very small number of them became resistant to the medication.
There have been some limited studies looking at what we call "cross resistance" between one CCR5 inhibitor and another. So far, that has not been something that has commonly occurred and the different CCR5 inhibitors do seem to continue to work even when a virus may become resistant to one. The clinical application of that has really not been seen yet since only one CCR5 inhibitor, Selzentry, has been used in a fairly large number of patients. This is the only one approved by the FDA and now on the market, so the opportunity to treat a person who has failed one CCR5 inhibitor with a second one has really not been possible.
Besides vicriviroc, are there other CCR5 inhibitors currently being developed?
There is another CCR5 inhibitor being developed by a third pharmaceutical company in the United States that looks like it's going to be a once-a-day given medication. It's still in very early studies. I know I saw results last summer from a phase 1 study, which demonstrated that the drug did have some good short-term activity over a 10-day period in suppressing R5-type HIV. I have not seen more studies on that drug to date.
I guess the one thing that may suggest that the drug may be an improvement is that currently Selzentry is licensed to be given as a twice-a-day drug, once in the morning and once at night. The unapproved CCR5 inhibitors still in development -- both vicriviroc and this other drug I mentioned -- are both given once a day.
Are there ongoing studies looking at how well CCR5 inhibitors work, particularly Selzentry, or are all those studies done?
The studies done in treatment-experienced people -- the trials are called the MOTIVATE-1 and MOTIVATE-2 studies -- are going to be continued out through five years. Most patients are somewhere between two and a half to three years into the study right now. Those studies are going to be ongoing for about another two to two and a half years. The studies in the treatment-naive patients -- that is people who have just started treatment -- those studies are about two and a half years mature and the 700 people in those studies are going to be followed for another approximately three years as well.
I don't know exactly how many new studies the company, Pfizer, who makes Selzentry, is planning. I know that they are starting studies in children and adolescents age 16 and less in order to see what kind of effects it has in children. I think they're also looking at studying more women and more persons of color because the first trials did not have adequate representation of those populations.
I think there's also some interest in studying Selzentry in new and different applications. There's a study on the books or on the drawing board to study Selzentry as a vaginal microbicide -- putting it into a gel that can be inserted vaginally, or perhaps even rectally -- that could block the ability of HIV to be sexually transmitted by blocking its ability to attach to a human cell to begin with. Now that the drug has been approved, more and different kinds of studies are being set up for the future.
Why is it going to be studied as a microbicide?
The primary reason that it's being studied as a microbicide is because we know that when transmission of HIV occurs from person to person, particularly in sexual transmission, that the type of virus that is transmitted from person to person is predictably going to be about 98 percent to 99 percent an R5 virus, the type of virus that Selzentry can block. Knowing that that's the kind of virus that gets through the person's skin or mucosa (the lining inside of a vagina, rectum, or mouth), you would particularly want to block the R5 virus. The type of virus that Selzentry can block is an R5 virus. Therefore, using it as a topical microbicide in the vagina or the rectum would seem to make a lot of sense. That's why it's been chosen to be studied for that purpose as well.
Great. Thank you very much, Dr. Hardy. This has been really interesting.
My pleasure, Bonnie. Thank you.