July 25, 2007
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Dr. Berger is going to provide an analysis of a few important studies that were presented at IAS 2007. Dr. Berger, let's start with what I think is the biggest news for people living with HIV, and that concerns a study looking at sexual transmission of hepatitis C. Can you talk a little bit about the study?
Bonnie, this study, by Mark Danta,5 is probably one of the most important to come out of the meeting. In most big cities around the United States and, we now know, in Europe, as well, physicians have been noticing that more and more of our HIV-positive patients have become coinfected with hepatitis C. This is a problem because we don't really always know the best way to manage HIV/hepatitis C coinfected patients. It's difficult enough when we have to attack one virus. And it's not as if you can just take pills for hepatitis C as you would for HIV. You can't do that with hepatitis C. We don't have a cocktail, per se, for hepatitis C. We only have two antiviral drugs. One of them is pegylated interferon [brand name: Pegasys (also known as peginterferon alfa-2a), PEG-Intron (also known as peginterferon alfa-2b); IFN is the abbreviation for interferon], which requires individuals to self-inject once a week. The medications themselves are very immunosuppressive. They have lots of side effects. It's not at all a walk in the park. In fact, people who are on hepatitis C treatment often feel like they've aged about 50 years.
The study that was presented at Sydney shows that there has been an increase in hepatitis C incidence during the last few years. Previous to that, we thought that hepatitis C could only be transmitted through intravenous drug use or through a blood transfusion.
But over the last few years we started noticing in the clinic that more and more of our patients were becoming infected with hepatitis C. We know from those patients that most are not intravenous drug users, historically, and have not received any blood transfusions.
Various studies that were done previously showed that, because of changes in behavior among the HIV-positive population, or among men having sex with men, something is changing in terms of the increase in hepatitis C.
In this study Mark Danta and his colleagues actually looked at over 170 patients in Europe who recently became positive for hepatitis C. All of the patients in the study were HIV positive to begin with and are gay men.
The researchers took the blood from these men and did a lot of different genotypic testing. In other words, they mapped out the genes of the hepatitis C virus itself and tried to figure out where those hepatitis C viruses came from within Europe.
They knew that there are different strains of hepatitis C, and that even within those different strains there are different gene maps. By knowing those things, and knowing where things are more common within Europe, or where they found a particular genotype, or a particular gene within Europe, they could try to figure out, if they then found it in another area of Europe, whether it had moved or whether in some cases patients had multiple different genes that were associated with a variety of different countries. In fact, that's what they found.
Unfortunately, many of the patients who were hepatitis C-positive not only had one strain, but had multiple strains. They call them clusters, since there are different genes that are all clustered together. Some of the patients had as many as three or five clusters per area on the hepatitis C virus, which tells us not just the fact that gay men travel, but that individuals when they are traveling are having, most probably, multiple sex partners, or that they are getting infected from individuals that have all those different strains at the same time.
So what are the implications? What does this mean for gay men who are HIV positive and having sex? It means that, if you're a gay HIV-negative man and you're going to have unprotected sex, you not only have to worry about becoming HIV positive, but beware: you can get hepatitis C, as well. Similarly, HIV-positive men are at risk for getting hepatitis C -- and hepatitis C with HIV is a combination that you really don't want to have to deal with. It's definitely a road for quick destruction, if you have both of those viruses. The treatment for hepatitis C, as I said before, is pretty awful.
So this has implications for people who are HIV positive and having unprotected sex.
Yes. A lot of people are barebacking. A lot of gay men think that nothing is really going to happen if they are already positive and they're having sex with another person who's positive, and both of them are undetectable. When, in fact, most individuals that are hepatitis C-positive may not even be aware that they are positive. In addition, this kind of communication or discussion regarding what infections each partner may have is rarely shared prior to having anonymous sex.
But you can easily get hepatitis C by barebacking and along with the barebacking parties that go on in the gay community, a lot of individuals use a lot of recreational drugs, such as crystal methamphetamine, which seems to have steamrolled the epidemic in terms of HIV, as well as hepatitis C, transmissions.
Hasn't there also been news recently about syphilis rates going up in New York and other cities? So it's kind of related, in a way.
It is. Back in Chicago we have seen, over the last few years, a huge increase in syphilis infections. A lot of the patients who present with syphilis don't always know that they have syphilis. They come in sometimes just having routine STD [sexually transmitted disease] testing and we find out that they are syphilis-positive. They never had any symptoms. And unfortunately, a lot of people that do come in with syphilis, not only come in with a particular symptom, but they come in extremely sick. There was a recent study that showed that in people who are now presenting with syphilis, as much as 5 percent of them have syphilis that is affecting the central nervous system, which is what we call tertiary syphilis, or the late stage of syphilis.
What does this mean in terms of monitoring hepatitis C and syphilis? Does this mean, say, if you are a sexually active HIV-positive or HIV-negative gay man, that you should ask your doctor to give you a hepatitis C test every year, as well as a syphilis test?
I think anybody who's sexually active can get any infection. So anyone who's sexually active and HIV negative should probably be tested three or four times a year. When they get their STD testing, they should also ask the doctor not just for their HIV test, but a hepatitis C test, as well. For HIV-positive people who are sexually active, they should also periodically get tested for hepatitis C, as well.
Also, because it's not uncommon for liver enzymes to be increased, on account of taking antiviral medications, hepatitis C infection can go unnoticed. So patients shouldn't always accept the fact that if their liver enzymes are slightly elevated, it's due to the medications that they're taking. They should ask their doctor to also check for hepatitis C. Because often, though it may be a surprise, it's hepatitis C that causes the elevated liver enzymes.
There was another hepatitis-related story about the dangers of treatment interruptions for HIV-positive people who are coinfected with hepatitis B or C. Can you talk a little bit about this study?
Yes. That study, Bonnie, was called the SMART6 study. Last year we had dramatic results from the SMART study. It made a lot of big news. It was a huge study that was very well designed. In fact, more than 5,000 patients took part in it. The focus of the study was to see whether we could have patients taking medications, and then come off their medications for a period of time, what we call a treatment interruption.
During the course of the study, the revelation was the fact that individuals who came off of their HIV medications got sick faster than people who stayed on their medications. The problems that the people off the medications developed were problems that we always thought might have been due to HIV treatment. We found out that they were not due to the medications but were, in fact, due to the HIV being untreated. Those complications were liver problems and kidney problems, as well as heart problems.
So what was presented here at IAS 2007, in terms of hepatitis, was a small subset of the patients who took part in the SMART study who were also coinfected with hepatitis C or hepatitis B.7 The researchers looked at what occurred during the course of the study, in terms of people taking those treatment interruptions. Among the people who were in the treatment interruption arm of the study, these treatment interruptions occurred if their T-cell counts were above 350 cells/mm3. They continued to be monitored while off their medications. If their T cells went below 250, their doctor needed to restart them on medications.
So there was this time in between -- between the above-350 that they were off treatment and the below-250 when they needed to go back on treatment -- during which, as I mentioned, the researchers saw all these complications in people taking interruptions: kidney, liver, as well as cardiac problems.
The researchers looked at the subset of patients who were coinfected with hepatitis. Did those individuals do as well as the people who didn't have hepatitis? Did anything change? Did having hepatitis have any effect on the treatment interruption? In fact, they found that the individuals who were coinfected with hepatitis B actually needed to go on medications much, much faster than the individuals who were not coinfected.
For example, the average amount of time that people were able to be off their medications in the study was approximately 17 months. The average amount of time for someone who had hepatitis B turned out to be only seven months. So that's really a strong statement, in terms of what happens to a person's immune system if they are infected with hepatitis B. It's probably the hepatitis B that caused the rapid deterioration in their T-cell count that impacted on their doctors having to restart the medications that much sooner.
That means that, if you have chronic hepatitis B infection on top of your HIV infection and you're thinking about possibly taking a drug holiday, you need to discuss this with your doctor and take into account the possibility that your T-cell counts may drop very quickly.
I know that, in terms of seeing patients at NorthStar in Chicago, sometimes when patients go off their medications, they all of a sudden think that everything's okay. They don't have to constantly be reminded that they are HIV positive, and they may not even come back to their doctor visits the way they routinely had prior to being on medications.
But if you're not taking medications, perhaps you need to be monitored much more cautiously and closely than someone who's actually taking medications. And if you have hepatitis B, even more closely.
Let's move on. Another study presented at IAS 2007 was the TITAN study that showed that the protease inhibitor Prezista [generic name: darunavir; also known as TMC114] is as good, if not better, than Kaletra [generic name: lopinavir/ritonavir]. What do you think this means for patients?
That study has become the most talked about study here in Sydney, right from the outset. The TITAN study: I love the term "titan." Actually, I think of the battle of the titans -- you know, as in those old movies in which they have monsters fighting each other. But actually, the TITAN1 study is really appropriately named. Because Kaletra has been a titan for a long time in its own right, in the fact that it has always been felt to be one of the biggest, strongest HIV protease inhibitors and is often used upfront as first-line therapy by many doctors, and even when someone is failing their first regimen, physicians often will put them on Kaletra.
Prezista, on the other hand, is a very new protease inhibitor. It has gotten its strengths from the fact that, over the years, HIV-positive people developed more and more resistance to antiviral drugs. Physicians often would not know what to do with those patients -- how to best treat those patients. Often we've stopped trying to get patients to undetectable. We were only trying to maintain their CD4+ or T-cell counts. But when Prezista started being studied in the clinic, we found that actually, despite the fact that individuals had triple-class resistance, or resistance to every medication that was available, they still went to undetectable if they were on Prezista.
And so Prezista made its own niche, in terms of the patient who's been on treatment for a very long period of time. And it has become what doctors call a change in the paradigm in treatment. It changed the fact that we can have the same goal of getting to undetectable for patients who have resistance that we once thought we could only have for treatment-naive patients (people who are just starting on medications).
So these two strong medications were pitted against each other, but not in a patient population that had lots of resistance, but simply in people who maybe were on their first regimen, failed their first regimen, and were looking for what would be the next thing right after that first regimen.
If you were on, for example, Sustiva [generic name: efavirenz; also known by the brand name Stocrin], or say you were on a combination of Truvada [generic name: tenofovir/emtricitabine; also known as TDF/FTC] or Lexiva [generic name: fosamprenavir; also known by the brand name Telzir] or any other combination, and you were failing that regimen, you could have been be a patient, a volunteer, in the study and be randomized to be put on either Kaletra or Prezista. And of course, the doctor didn't choose the medication. It was randomly assigned to each patient. But the patients knew which drug they were taking. The physicians knew which drug the patients were taking.
I should just mention one other thing. Because the patients didn't have a lot of resistance, they really didn't need Fuzeon [generic name: enfuvirtide; also known as T-20]. They didn't need to be on -- they never were on -- Kaletra before this. And they never were on Aptivus [generic name: tipranavir]. They never were on Prezista before the study.
So what did the researchers find during the study? The patients who actually were on Prezista: more of those patients went to undetectable than the patients who were on Kaletra, overall. And it wasn't a very tiny amount. Actually, the difference was approximately 11 percent. So to be didactic about the numbers (and for all of you who are number fans), 60 percent of the patients who were on Kaletra went to undetectable versus 71 percent of the patients on Prezista. That's 11: 71 minus 60 is 11 -- an 11 percent difference.
Is that a statistical difference?
That was felt to be highly statistically significant. The researchers also looked at a number of other things. They looked at the development of resistance in the study. They found that people who were failing Prezista actually developed fewer resistance mutations than the people who were failing Kaletra. People on Kaletra developed more resistance problems.
Another thing that was very interesting is that diarrhea -- what we call grade 2 to grade 4, the cases that require treatment -- was actually twice as common in patients taking Kaletra versus Prezista. So what does that mean? That means that if you're a patient on your first regimen -- say you're on Sustiva or a protease inhibitor-based regimen -- and it looks like your viral load is going up and the regimen isn't working the way it used to work, your doctor needs to look at what medication to choose from next. In the past, your doctor might have considered leaving Prezista for a time further down the road, when you have resistance to everything. But this study actually showed that if you use Prezista at this point, as opposed to Kaletra, you have a better chance of getting to undetectable. If you're one of those people who tend to have diarrhea, or if diarrhea is a problem, you may not want to be on Kaletra; you may want to favor Prezista.
But this whole gestalt of what I just said, about choosing Prezista over Kaletra, is still being talked about. Physicians are going back and forth about how to read the study, looking at different types of patients that were in the study. And it's still being talked about as to whether Prezista is going to be moving up to the forefront, in terms of being used that much earlier.
So stay tuned, in other words, to find out what happens.
Same bat channel, same bat station.
There was another study that looked at Prezista that also included the still-experimental drug etravirine. Can you tell us the importance of this study?
Etravirine -- we would also call it TMC125 -- is a new non-nucleoside. It's a new non-nuke (NNRTI). It's in the same family as Sustiva or Viramune [generic name: nevirapine]. It's been developed because people who have developed resistance to Viramune or Sustiva often have no more non-nukes in the class to go to. In other words, they develop cross-resistance to one or the other drug, and there's no second-generation non-nuke.
So here comes etravirine and it was shown early on that for people who have resistance to Sustiva or Viramune, they can actually go to etravirine without having to absolutely need to go to a protease inhibitor.
But that's not what this study is about, actually. What this study is about is, for people that have resistance to a lot of the medications that are available, not just to the non-nukes, not just to Sustiva or Viramune, but for patients that showed some resistance to protease inhibitors as well, for the people that have that type of problem, in terms of their doctors wanting to choose a combination, that there is another option. In fact, there are a lot of choices now because several of the new drugs are on expanded access programs, as well. And those are choices for doctors that participate in those programs.
For example, the Merck integrase inhibitor MK-0518 [generic name: raltegravir; the brand name is expected to be Isentress] is available on expanded access program. Maraviroc [the brand name is expected to be Selzentry], an entry inhibitor, is also available on expanded access, and so is etravirine. So a doctor can actually choose any of those drugs. They can also use Fuzeon. And so you have got a bunch of new drugs, and some new classes. And how does a doctor figure out which drug to use when you're having resistance?
This is actually the first study2,3 that took two of the newest drugs and put them together, and compared it to one of the drugs alone, with combinations that the doctor choose to use as the background. And it showed that etravirine, if it was paired with Prezista, had very interesting promise. More patients on Prezista plus etravirine did better than those on Prezista by itself with their usual background medications in the cocktail.
So it just provides more hope for people who have resistance. It provides more confidence for doctors in terms of knowing which drug they may want to pair with Prezista. Maybe it's not necessary to go to Fuzeon, which patients need to administer themselves as twice-a-day injections; they can actually choose a twice-a-day pill -- which, obviously, is easier.
How were the side effects on this study? Do you remember?
Yes. Etravirine is extremely well tolerated. The non-nucleoside class has had a reputation, for example, Sustiva causes a lot of what's called central nervous system side effects, brain effects. People know that you take Sustiva at nighttime, before you go to bed. If you don't, you feel like you're a zombie because it causes a lot of sedation. Also, it causes increased dreams, and some people have noticed that they have been a little bit more anxious when they have taken Sustiva. So, researchers looked at these central nervous system side effects and found that etravirine wasn't a problem. They also looked at skin rash problems because Viramune, as well as Sustiva, causes skin rashes. They actually found that etravirine could cause a skin rash. But most of the cases were mild. They were able to actually treat through that. So etravirine looks like a more easily tolerated medication in those respects. And it looks very promising.
Great. And finally, there was a study8,9 that showed that patients will no longer have to deal with hypersensitivity reactions if they take Ziagen [generic name: abacavir], because of a new test that predicts who will get the reaction, and who won't. Can you tell me a little bit about that test?
Yes. The test is actually a milestone, not just in HIV treatment, but also in modern medicine. It's one of the first examples of how we're using the field of mapping out people's genes, and how we can construct treatment based on their genetic makeup. And actually this test, which is called the HLA-B*5701 test, is based on a variant in a person's gene. And for the people who have that variant, they have a much higher rate of developing this severe allergic reaction to Ziagen than people who don't have it. In other words, if you don't have the gene it's extremely unlikely that you'll ever get that reaction. If you do have the gene there's a very high likelihood that you will get it.
So what does this mean? If your doctor is considering whether to put you on Ziagen or Epzicom [generic name: abacavir/lamivudine; also known by the brand name Kivexa], instead of worrying about the possibility of developing this reaction and being unable to use Ziagen again, your doctor can actually do this simple blood test to see if you have this genetic variant. If you do, your doctor will know not to put you on either Ziagen or Epzicom, and will go to a different medication.
On the other hand, if you don't have this gene -- and 95 percent of the population doesn't -- then your doctor can safely put you on Ziagen and it's extremely unlikely that you would get that severe allergic reaction for which Ziagen has a black box warning.
If you are on Ziagen and you've been doing well, you don't need to get this test, because obviously you have not had the reaction and you're home free. There's no reason to draw this test at that point.
One other caveat: If you do the test, looking for this HLA-B*5701, all you need to know are the results of the test. Your doctor can document it very well in the chart. And it's only got to be done once in a lifetime. It doesn't need to be checked every year, or every so many years. It's just one test, once in a lifetime, and you'll know whether Ziagen can potentially cause a problem or not before you even take the drug.
How soon will these tests be rolled out? Can I get it tomorrow at my doctor's office?
You can. In fact, I have been ordering it because we participated in one of the studies. It was part of a study, but some doctors have already begun using it. It's been used in Europe more widely, as well. It's a test that is not unlike the gene typing that's sometimes done prior to transplants. Sometimes we also use gene typing for people with different diseases like lupus or rheumatoid arthritis. Those markers are used as an indicator for those diseases. So this specific test for Ziagen hypersensitivity, or the abacavir hypersensitivity reaction, is available.
Great. Well, I'm afraid we have run out of time, Dr. Berger. Thanks so much for your terrific review of IAS 2007 highlights.
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