May 2008 Podcast — Top 10 HIV Stories of the Past Year: An Interview With David Wohl, M.D. — By Bonnie Goldman
Posted by pozlife on July 2, 2008
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Dr. David Wohl is a clinician and researcher at the University of North CarolinaEvery day a barrage of HIV research is published and presented around the world. Even if you were to read all the journal articles and research meeting coverage related to HIV, how should you evaluate the importance of individual studies? That’s when it helps to know someone who is himself knee-deep in the research.
Dr. David Wohl is a researcher and clinician at the University of North Carolina, and he’s also an expert in our “Ask the Experts” forums. For years now, Dr. Wohl has been writing our year-end review of the top HIV medical stories for health care professionals on our sister site The Body PRO.
Dr. Wohl has the unique ability to put the advances of HIV medicine in perspective, and he does so with humor and with wisdom. But most importantly, he tries to make the material accessible to everyone. If you’re interested in discovering the very latest in cutting-edge HIV research, read or listen to our interview, or if you just want the nitty gritty, take a look at our summary.
A Cavalcade of New HIV Meds
What do you think is the most important area of HIV treatment research today?
Figuring out when, and with what, to start HIV treatment
Developing new meds for people with HIV drug resistance
Finding ways to fight HIV besides antiretrovirals
Creating HIV meds that don’t cause difficult side effects
Finding causes for metabolic and cardiovascular problems in HIVers
Learning how gender and race affect the way HIV and meds work
Finding a cure
None of these
Welcome, Dr. Wohl. Tell me, what did you think was the number one HIV research study of 2007?
There were actually a bunch of important research studies. The big story is that there are new drugs, and they work really well. In 2007 there were a few different studies of new drugs that are opening up a whole new opportunity for people with HIV infection.
I’ve heard people say that it’s just like it was in 1996, when HAART [highly active antiretroviral therapy] was approved. There’s a lot of hope now in the air because of all these new drugs.
I think the difference between 1996 and 2008 is that we’re smarter. That doesn’t mean we’re smart, it just means we’re smarter. I think we’ve learned a lot from our mistakes, from the science that’s gone on, and from our patients. What we’re seeing now is a new day in HIV care, where there are some more options, and they’re not what I call “me too” drugs. They’re not retooled versions of old drugs. These are actually new compounds that can work against the virus. I don’t know if it’s completely analogous, but in many ways it is like 1996 for someone who hasn’t had very much in the way of options, but now does and is really committed to taking his or her therapy. We have to remember that a person can have all the new drugs in the world and they can all be potent, but unless the person is committed to taking his or her medicines and taking them as directed, it doesn’t matter how novel and new or potent it is.
Can you list these new drugs?
There are several of them. The first one that I want to mention is Isentress [raltegravir, MK-0518].1,2 This is a totally new drug in a new category of drugs. It works on an enzyme called integrase, which was never targeted before. It works within the HIV virus to keep the HIV virus from making more copies of itself.
Another one is called Selzentry [maraviroc, Celsentri].3,4 Selzentry is a very new type of drug; it blocks the entry of HIV into the cell by blocking a receptor that the virus needs to get into the cell. Very exciting.
Another new medicine that is now available is Intelence [etravirine, TMC125].5,6 It’s part of a new generation of non-nucleoside reverse transcriptase inhibitors. The previous generation of non-nucleosides includes Viramune [nevirapine] and Sustiva [efavirenz, Stocrin].
Another new medicine that I think is exciting is called Prezista [darunavir, TMC114]. It’s a potent protease inhibitor that works against protease inhibitor-resistant virus.7
These are four really exciting new drugs that are making a tremendous difference for people who have experience with HIV drugs and have resistant virus.
One thing we’re seeing consistently throughout these studies is that the more new drugs that are active against your virus, the better, and the greater the chance that your viral load will become undetectable.
There are really good data to show that, in people who are HIV infected and who have resistant virus, each of these drugs — in combination with other drugs — can get their viral load undetectable. One thing we’re seeing consistently throughout these studies is that the more new drugs that are active against your virus, the better, and the greater the chance that your viral load will become undetectable. This is true even if you have dripping red genotypes that show so much resistance that nothing else is predicted to work.
What we’re seeing is that when you have two, or possibly even three, newer agents that work against your virus, it works great. Before we had these newer medicines, there just wasn’t a critical mass. There weren’t enough new medicines to craft a regimen that was likely to work in people whose HIV was already resistant to a lot of HIV medications. With these newer drugs, there’s now more to pick from. Two, or even three, active medications should work against a person’s virus. It opens up tremendous new opportunities for people who, before these drugs came about, didn’t have any opportunities.
Are these drugs going to be used at all for people just starting therapy?
There’s always an interest among the manufacturers of drugs like these to try to get the use of their drugs to expand beyond one niche. A drug comes out that’s used in what we call salvage therapy — meaning people who need new drugs to rescue them because they have resistant virus and the other drugs aren’t working — and then the manufacturer tries to get it to work in a treatment-naive person. “Treatment-naive people,” that’s our jargon for people who’ve never been on HIV therapy before. It makes sense, because then the drug manufacturer gets a broader market for its product. In every single one of these cases, there’s some interest in using these medications early on.
For different drugs, there’s a different amount of data supporting them. We know that there’s a big interest in using Prezista early on, because it’s a protease inhibitor and we do use protease inhibitors early in HIV therapy, including as initial therapy.8 That’s a no-brainer.
I think there certainly is interest in using more novel agents such as Selzentry and Isentress early on, and studies are ongoing of those medicines.9 For Selzentry, there was one study that looked at it against Sustiva early in HIV therapy.10 It didn’t do as great as Sustiva, but it looked pretty decent. I think it’s encouraging.
Intelence is a drug that people will also look at for initial treatment. The answer to your question is definitely yes.
Too Many HIV-Positive People Get Diagnosed Late
Let’s move on to the number two most important study of 2007.
Is this the dawn of a new era in HIV care? I think arguably it is. But one thing we’re still dealing with is too many people are coming in too late to HIV care.
There was a very important study done by the Johns Hopkins group.11 The investigators looked at the immune status of people presenting for care in their clinic in Baltimore. The bottom line was that over time, we really haven’t seen improvements in this. In fact, if anything, we’re seeing people come in with lower CD4 cell counts. There are data that have been presented before that indicate that the average T-cell count of people presenting for care in the United States is under 200.12 It’s about 187.
What the Hopkins group was able to do was to look at their patient population over different chunks of time.11 They found that, again, people are entering care who have never been on HIV therapy before, with decreasing CD4 cell counts.
This is really concerning, because it means people are showing up late. It means people are not getting tested earlier in the course of their HIV infection. We know that people who start therapy at lower CD4 cell counts have a greater risk of side effects, and may not respond as well as people who have higher CD4 cell counts.
So it’s very concerning. It shows that we are not doing a good job of offering HIV testing and having people utilize HIV testing on a more regular basis.
So this is a failure in HIV prevention?
I think this is a failure in HIV detection.
Certainly there is, taking a step back, a failure in prevention and that’s why people are getting infected. But what we’re seeing here is that we are not doing a very good job of diagnosing infection as evidenced by the fact that:
1. Twenty-five to 30 percent of people with HIV in this country do not know they’re HIV infected,13 and
2. People who are diagnosed are getting diagnosed pretty late in the course of their disease.
That has implications not only for that person’s health, but also for the public health. That means under-diagnosis leads to people having sex with people and possibly transmitting their virus unbeknownst because they didn’t know they were HIV infected.
I think there are a few different dimensions here that are very concerning. In this analysis, it’s very interesting that being older, being male, and being African American were independently associated with having a lower CD4 cell count on presentation. That tells us that not only is there a problem, but that there’s a problem among certain subpopulations that’s very concerning.11
Did the researchers suggest anything?
The glaring neon light shining here is that we should be doing more testing. The CDC [U.S. Centers for Disease Control and Prevention] came out with some important recommendations, saying that anyone who’s in medical health care should be tested for HIV.14
I think that’s really important. I think we should have routine HIV testing. You visit your doctor for your annual physical and the doctor offers you an HIV test. If you have risk behaviors, the doctor should continue to offer you that regularly.
I think we’re under-testing people, and we’re not using our health care system as a tool. It’s a very important tool in HIV prevention when used to detect people with HIV. We’ve done it with pregnant women; pregnant women know that when they come into perinatal clinics, they’re going to be offered HIV testing. We need to have that happen for people coming in to get their blood pressure checked, their cholesterol checked.
Heart Attack and HIV Meds: Not a Black-and-White Issue
On to number three.
Number three has to do with an ongoing concern regarding the side effects of HIV medicines, particularly the cardiovascular effects. There was a really important paper published in the New England Journal of Medicine by the D:A:D group.15 The D:A:D study is a large, metacohort study, meaning that it’s a collection of different large studies all pooled together. It’s pretty powerful; over 30,000 people are enrolled in this study currently. What the researchers are able to do with that kind of data is look for trends that occur during HIV therapy. One thing they’ve been able to do is look at the risk of heart attack, and the rates of heart attack.
In this analysis, which was published at the end of 2007, what the researchers found was that there were about 350 or so heart attacks in the group of patients that they had — about 23,000 at the time of this analysis. They were looking at what the risk factors were that led to individuals having a heart attack. One of the things they looked at was a patient’s exposure to HIV therapy. They’ve shown that over time, as you’re on combination HIV therapy, your risk of heart attack increases incrementally.
What the researchers were able to also do is tease out which type of HIV therapy might have this effect, and they found that protease inhibitor therapy was associated with this increased risk of myocardial infarction. Whereas the non-nucleosides, like Sustiva and Viramune, were not.
This is kind of controversial and we’ll have to think more about this over time as more data come in. But what they were able to show is a pretty clear signal for protease inhibitors.
The non-nucleosides, like Sustiva and Viramune, did not have as clear a signal. It was a little bit of a wiggle line; it went up and then it went down a little bit. So, it was not as clear. Part of the reason for that is that there are not as many people on those drugs in this cohort — this cohort is mostly European, with some North American patients included. For protease inhibitors, which were much more popular in this group of people, there was a clear trend that was significant.
The bad news is that protease inhibitors seem to increase your risk of heart attack. The good news is that the risk of heart attack in this study was really low. As I said, we’re talking about 350 heart attacks among 23,000 people. Not tremendous numbers, and it’s important to remember that not every single one of those heart attacks was due to medicines. If you followed 23,000 people without HIV, there would be some number of heart attacks. Some of these were inevitable; some were influenced by HIV; some were influenced by HIV medicines.
Other important data have shown us that if you’re not on HIV medicines — for example, if you are someone who started on HIV medicines and then stopped taking them — your risk of cardiovascular disease goes up.16
That is, stopping HIV medicine, allowing your virus to go kablooey, and all the subsequent inflammatory changes and things your body has to do to deal with the virus are really bad for your heart.
Overall, protease inhibitors probably increase the risk somewhat of a heart attack, but it’s better than being off HIV medicines. I think this is an important study that helps us quantify the risk, but also reassures us, because at least during the time period of the study (about seven years) heart attacks were fairly rare.
The researchers never did tease out how many of the people in this study were smoking cigarettes, for instance.
We know that uncontrolled virus puts a strain on the body in many ways, leading to more problems with liver disease, leading to more problems with heart attacks, and leading to more problems with kidney disease. The virus itself is probably worse than anything else.
Right. So there are other risk factors, and they try to correct for them. The other thing that they don’t really do a great job of is telling us, in the people who got heart attacks and were on protease inhibitors, were the protease inhibitors working? Did the people have uncontrolled virus [i.e., a high viral load]? We know that uncontrolled virus puts a strain on the body in many ways, leading to more problems with liver disease, leading to more problems with heart attacks, and leading to more problems with kidney disease. The virus itself is probably worse than anything else. Protease inhibitors are making a rare event a little bit less rare, but that is better than not being on protease inhibitors.
What would you say to a 25-year-old person living with HIV, who’s worried by this kind of study and who’s on a protease inhibitor? What can he or she do?
I think the most important thing is to understand that the magnitude of the change of risk in heart attacks with protease inhibitors was a fraction, really, of what you get with smoking or with uncontrolled high blood pressure — those are the things that we can change.
In this group of patients, about 60 percent smoke.17 That’s an incredible amount — and we see this consistently in HIV-positive people!
When you look at Americans and Europeans with HIV infection, the Americans smoke like Europeans. It’s incredible! HIV-infected people smoke like French people do.
In comparison, in the general population of the United States, only 21 percent of people smoke,18 so we see that smoking is very prevalent in patients with HIV.
What we should do, rather than mess with their HIV medicines, is:
* Get people to stop smoking.
* Get them to control their blood pressure.
* Get them to exercise more.
We need to take care of the usual, traditional things when we think about risk for cardiovascular disease. I think HIV medicines are secondary in that respect.
These are things people should be motivated to do if they want to survive. I think this is important, but it really puts this into perspective. We need to take care of the usual, traditional things when we think about risk for cardiovascular disease. I think HIV medicines are secondary in that respect. So I’d tell that young person, “Your risk is pretty darned low because you’re young. You’ve got to stop smoking because you’re aggravating your risk and we want to see you be here for a really long time. I wouldn’t worry so much about your medicines; we can handle it.”
Would you say something similar to someone who’s 45, doesn’t smoke, and doesn’t have genetic risk factors, but is on a protease inhibitor? Is there a greater worry for that person?
I think there is greater worry the more risk factors someone has that you can’t control — such as a family history of early heart attacks, under 55 for a close male relative and under 65 for a close female relative; a history of blood pressure problems, even though it’s controlled right now; and diabetes.
People who’ve done everything they can to control their risk factors, but have these immutable, unchangeable risk factors, including genetics, are the people for whom you really try not to put another straw on the camel’s back. It’s one of the factors that you have to weigh when deciding what HIV medicines to be on.
In this particular study, it looks like protease inhibitors are worse than non-nucleosides, but it’s going to take a little bit more time to make sure that’s actually so. If it is, then yes, given the data we have now — yes, that may gravitate the clinician and the patient to think, let’s stay away from protease inhibitors.
When we look at lipids, there’s not as much of a difference between protease inhibitors and Sustiva as we once thought there was. It’s not all about cholesterol; there’s something else going on here. So yes: It’s one important factor. For someone with very few risk factors, for me, it’s not a big deal; it’s not a big factor.
So really, the answer is that it depends on who you are, and what your story is.
I think these data are important in light of recent data from the same study group, looking at Ziagen [abacavir; this drug is also contained in Epzicom (abacavir/3TC, Kivexa)]. The data suggested that Ziagen — and Videx [didanosine, ddI] — also increased the risk of heart attack.19 It’s the same sort of story. I think we have to look closely at the patients we’re seeing, their risk for cardiovascular disease, and weigh the benefits from this particular study of giving a drug or not giving a drug.
Defying Expectations: Kaletra, Sustiva and Body Fat
On to number four.
Number four follows a similar vein; it looks at a different metabolic complication of HIV medication, and that’s body shape, with some hint of lipids here, too. It was a really, really important HIV study that we in the HIV field got very excited about, because it was done not by a drug company; it was done by the federal government here in the United States, and it was done across the country.19
It really was a nice representative study of treatment for people who’d never been on HIV therapy before. The study was done by the ACTG, and that stands for AIDS Clinical Trials Group. AIDS Clinical Trials Group is a federally-funded network of study centers across the country. This study is called ACTG 5142. The ACTG numbers their studies; they don’t have cute little acronyms or abbreviations.
This study pitted Kaletra [lopinavir/ritonavir], a protease inhibitor that’s very popular for initial therapy, against Sustiva. People could take either one of these drugs plus two nukes [nucleoside reverse transcriptase inhibitors], like Retrovir [zidovudine, AZT; this drug is also part of Combivir (AZT/3TC)], Epivir [lamivudine, 3TC; this drug is also a part of Combivir], Zerit [stavudine, d4T] or Viread [tenofovir; this drug is also a part of Truvada (tenofovir/FTC)] — commonly used drugs. There was a third arm in which people didn’t use any of those nukes, but just took Kaletra and Sustiva together.
The real important data, for our purposes, was the comparison of the people who took Kaletra with two nukes with the people who took Sustiva with two nukes. We had assumed that the Kaletra was going to lead to more body shape changes and higher cholesterol and all that stuff. But that turned out not to be the case.
In a rigorous study of a large number of people — 700 people — what we found was that the differences between these two drugs was not that stark when it came to big bellies. Both drugs made people’s bellies increase in size. Both drugs led to increases in cholesterol — not only the good cholesterol (HDL cholesterol), but also the bad cholesterol (LDL cholesterol).
Importantly, triglycerides were a little bit higher with the Kaletra than the Sustiva, and that’s been shown in other types of studies as well. Not a big surprise there. The surprise was that cholesterol was not a big deal; also, bellies were not a big deal.
What also was a big surprise was, when we looked at limb fat — that’s fat on the arms and legs — that’s where we saw a difference. Surprisingly, it was against the Sustiva. People who took Sustiva, regardless of what other medicines they were taking in their HIV regimens, had more wasting of fat in their arms and legs than people on the Kaletra.
These results totally blew people away. … It opened up our eyes that we have to think anew about body shape changes, that it’s not a protease inhibitor thing. In fact, if anything, the protease inhibitor was associated with protection against fat wasting of the arms and legs.
These results totally blew people away; these were completely unexpected results for most people in the know, who are really interested in this. It opened up our eyes that we have to think anew about body shape changes, that it’s not a protease inhibitor thing. In fact, if anything, the protease inhibitor was associated with protection against fat wasting of the arms and legs.
There was no data about fat wasting of the face included in the study. These were all objective measures using scans of the body, so we don’t have any important data yet about facial fat wasting. What we do see is that fat wasting of the arms and legs, which generally correlates with fat loss elsewhere, was worse with Sustiva.
With Truvada and Sustiva [this is the combination of drugs in Atripla], the risk was pretty darn low. It was higher than if you took those two nucleosides with Kaletra, but the good news is for people who are on Atripla, the risk of having significant wasting of fat in the arms and legs was fairly low and uncommon. I feel somewhat reassured in giving people that combination. The problem was more when you took Retrovir or Zerit along with Sustiva; then you saw unacceptable rates of fat wasting.
It was a really important study that helped debunk some of the myths we’ve had even in the absence of data about what these medications do to body shape and to lipids. I think that’s important and that’s what research is about.
But this is just a clue about some of the body shape changes that happen with these drugs. Isn’t it true that we still don’t know how to treat those problems and we don’t completely understand them?
No, in fact, a lot of people after this felt like we had to just throw away everything we understood about fat wasting. If anything, people are thinking that maybe it’s not so much that the Sustiva causes fat wasting, but that the Kaletra protected against fat wasting. There may be suggestions from other studies that that may be the case — that there’s something with protease inhibitors, ironically, that protects against fat wasting.
I think you’re right that this really makes us have to think outside the box about this. It says nothing about treatment, but it may say something about prevention.
It may be that we’re understanding that, if you want to avoid fat wasting, you shouldn’t use Retrovir; that Viread would be a better drug than Retrovir. That’s important information for people to think about when starting medicines. It depends how big a deal this is to you. There are people I see who say, “I’ll take anything, but I don’t want to look bad.” I steer them away from those regimens that were associated with fat wasting in this particular study.
Which would be?
Sustiva with Retrovir and Epivir. Certainly Zerit, which we don’t use anymore. I wouldn’t even use Combivir with Kaletra.
I would prefer to use alternative nucleosides. In this case, Viread looked really good. Ziagen was not studied in this study, and there are other issues with Ziagen that are emerging.19,20 Right now, there’s a limited choice as far as nucleosides for people who are concerned about this complication, so you just have to pick from that short list. When body shape is a major issue, we’ve got to look at the data and we shouldn’t just rely upon assumptions or perceptions.
Sperm Washing Effective for HIV-Positive Men Who Want Children
On to the next one, number five.
Number five is something completely different. It looks at an issue that’s incredibly important to a lot of people in our clinics, and that issue is whether they can have a baby even though they are HIV positive.
This is a really important and interesting study that was able to quantify some of the experiences that individual providers have been able to offer us. The bottom line is that we know that among women who are HIV infected and who get medications, we can reduce their risk of transmitting the virus to their babies by almost 99 percent. Maybe 95 percent of children born to HIV-positive women will be uninfected, with the proper interventions — HIV medicines — to mom and baby.21
What’s a little bit less clear is what to do about HIV-infected men who are in a discordant relationship — meaning they’re in a relationship with a woman who is HIV negative. Can they produce a child? We shouldn’t underestimate the drive of our species to reproduce, and how much joy people get from that. It’s hard to deny people with HIV that, and this has become an ethical issue as well as a scientific issue and a medical issue.
This study addressed the biological issue.22 The researchers looked at sperm washing, which is a technique where the sperm, which are not infected with HIV, are separated from the semen and surrounding cells that are infected with HIV. That sperm is used to artificially inseminate the woman, either directly or in vitro, to create a baby. This is a technique that is offered at clinics across the world, and the idea here in this study was to report on that experience.
What the researchers found was that among the over 1,000 couples who underwent the procedure, pregnancy was the result in 51 percent of these cases. There were 410 deliveries. Things looked great, and six months after the procedure, almost 1,000 women had negative HIV antibody tests. There was no known female seroconversion after this procedure.
I think that is really important information that doesn’t say that it’s impossible or that this is 100 percent completely safe. It says that the HIV risk is extremely low for an HIV-negative woman when this procedure is used. This is good news and this is something people are very interested in.
Unfortunately, the price really precludes a lot of people from using this procedure. But at least it’s an option and it’s something people can have a little more faith in if it’s something they want to pursue.
It’s interesting that this was a European study. Why aren’t these studies done in the United States?
I think you’re right. This could have been done in the United States if the different clinics that perform this procedure were able to pool their data. I think sometimes the Europeans do a great job of creating networks across countries, as we saw with the D:A:D study. One thing I’d like to mention, though, is that with any assisted reproductive technique that involves trying to increase fertility or the insemination of more than one embryo, there is a risk of twins. That was something that was seen here among the women who had that type of procedure. You may get more than you bargained for.
Dr. Wohl, wasn’t the risk of twins due to the fact that these women were also receiving fertility drugs after their partners underwent the sperm washing procedure?
It seems that in Europe they are very friendly towards HIV-positive people who want to have children. There’s not a lot of encouragement here, in the United States. There isn’t a lot of fertility treatment available for people who are living with HIV.
Yes, I think that’s right. That may have something to do with the epidemiology of the epidemic here, versus in Europe. Also remember, this is a study of a procedure wherein we’re talking about HIV-negative women. It’s the guys who are the positive ones.
I think you’re right that for HIV-infected women, there has been this view that their having babies carries a risk, and there is the question of whether it is really a good idea or not. I do think that’s evolving and moving in a direction of being more supportive of HIV-positive women giving birth, because the intervention is so good.
In this case, we’re looking at men who are positive, and their discordant relationships. I think this is interesting and novel. What most of us can understand, now that HIV-positive people are living for so long, is how one of the things that separates HIV-positive people from people who are uninfected is the ability to have a child. Now we’re finding that that probably doesn’t have to be the case any longer.
Genetic Screening for Hypersensitivity to Ziagen
On to number six!
Number six involves a drug we’ve previously talked about indirectly, and that’s Ziagen. I think one of the positive aspects about Ziagen over the last year has been our ability to neutralize one of the biggest obstacles to using this drug.
Ziagen is a drug that’s in the nucleoside class; it’s one of those nukes like Retrovir, Viread and Videx. The problem with this drug is that about 5 to 10 percent of people who use it will develop what’s called a hypersensitivity reaction.23
Anyone who’s ever been prescribed this drug knows all about this because, when they go to the pharmacy, there’s a big warning that they’re given, that when they take this drug, they can get this hypersensitivity reaction, which is almost like an allergic reaction. If they experience this reaction, they’re to stop the drug and not retake it.
Years ago there were instances where people developed this reaction, stopped taking the drug, and then started again against medical advice, and died. The possibility of death being associated with an HIV drug is really horrible, so there was a lot of concern about this medication and counseling that had to go with it.
A significant contribution to science in general has come from a couple of different studies that have looked at trying to understand who develops this hypersensitivity reaction and who doesn’t.24,25
Work that has been done by a couple of different groups has linked the risk of this reaction to the type of genes a person has. Not the virus’s genetics, but individual people and their genetics. There is a genetic predisposition towards this reaction in some people. The gene that’s associated with this reaction is much more common in white people than it is in African Americans; and it’s even rarer in many Asian groups.
People have thought hard about how to use this information. There was a very nice presentation,24 which is now published,26 looking at using this as a strategy to screen people for this gene. Those who have the gene were not given Ziagen.
The bottom line is that that strategy works really well, such that there’s been almost no case of anyone developing a hypersensitivity reaction who does not have this offending gene. Screening for this gene has become clinically adopted already. It’s called HLA-B*5701. We call it 5701 for short. What we’re doing in clinics is screening people who we’re thinking of giving Ziagen; if they have the gene, we don’t give Ziagen to them. For people who don’t have the gene, we feel much safer about giving them the drug.
This is one of those examples where HIV is a leader in the medical field. In a short period of time, we’ve identified the gene and made it clinically relevant. … As we speak, a clinician is ordering this test to determine whether or not they should give Ziagen to someone.
That opens up a whole new opportunity to use this medication, whereas before we might have been reluctant to do so. So I think that’s good news for this medication.
Is this test expensive?
Initially it was, and I think it varies from lab to lab, but most clinics now are able to get this test done for about $50 to $150. You can think about in the scheme of things how expensive that is. It’s good because it’s a one-time test; there’s nothing that changes. Your genes don’t change.
Are genetic tests commonly used before prescribing medication in the United States?
No, and that’s one of the things that really excites me about this research. For years, we’ve been talking about this wonderful science of using a patient’s genes to tailor their medical therapy, but it’s all been talk. We really haven’t been able to use genetic analysis to help craft medical therapy for an individual.
This is one of those examples where HIV is a leader in the medical field. In a short period of time, we’ve identified the gene and made it clinically relevant such that right now, as we speak, a clinician is ordering this test to determine whether or not they should give Ziagen to someone. That’s just fantastic! I think that’s great.
So this is a real first for medicine in general?
That’s right.Back to the Drawing Board for HIV Vaccines
Wow. That’s great. OK, on to number seven.
Number seven is a downer, and that has to do not so much with hope, but with defeat. What we’re talking about here is an HIV vaccine. It’s been pretty clear that condoms are great, but we’re not going to be able to use condoms to get rid of this epidemic.
We’re not going to have people adopt safe sex practices or do any of these other prevention things people have talked about to stop this epidemic in its tracks, except for a vaccine. There’s been a lot of money put in by various private and public organizations to try to develop a vaccine.
One of the most promising vaccines was the Merck vaccine. It uses a virus called adenovirus — which normally causes a cold — to try and stimulate the immune system. The vaccine also contains viral proteins from the HIV virus that are dead, but that can be used to stimulate a really nice immune response against the virus such that when the person actually encounters HIV, they would already have really good immunity and could fight it off and prevent HIV infection. Well, that was the idea.
The reality was that the data from a trial of this vaccine that was done among 3,000 people across the planet showed that the vaccine didn’t work.27 Not only did the vaccine not work but, very sadly, people who had a strong immune response to the adenovirus at baseline — meaning before they got the vaccine — actually seemed to be more susceptible to HIV. There weren’t very many infections during the study, there were about 44, but they were concentrated and more likely in the people who had this adenovirus immunity before they got the vaccine.
The bottom line is:
1. The vaccine didn’t work; it did not protect people compared to people who got placebo vaccine.
2. In a subset of people with an immune response to the vector — the thing that’s included in the virus vaccine — there even seemed to be a hint that these people were hyper-susceptible to HIV.
Is this the end of all HIV vaccines? Are there others in development?
This is the end for this vaccine. There are similar vaccines that are going to be tested, and I think what you’ll see is wider use of these vaccines in people who do not have immunity, or an immune response, to the adenovirus vector.
I think there’s going to need to be much further work. There’s a strong and vocal group that feels that vaccines are nowhere near ready for testing in humans and that we really should go back to the drawing board. There are others who feel an urgent need to start clinical vaccine trials in people.
I think this, at the very least, puts a big chill on HIV vaccines in general. Many vaccine trials were either underway and had to be stopped, or were about to start and had to be stopped. We’re going to have to try to understand what it is that’s going to make the immune system develop a protective response against HIV.
The fact that people can get superinfected with virus (i.e., people can be HIV infected and still acquire a new strain of HIV), bodes very poorly for us being able to figure out how to trick the immune system to have a great response.
If natural infection with virus doesn’t protect you, that means we have to do even better than Mother Nature and produce a super response. I think that’s going to be extremely daunting and very difficult. Sadly, that’s what we learned with this vaccine trial.
One interesting thing about this vaccine trial that came out recently was that, among men who were circumcised, there was much less risk of HIV infection — such that it partially neutralized the increased risk that occurred by having that adenovirus immunity at baseline.28 I think that’s really interesting, and again, shows that there is a role for circumcision in HIV prevention. It’s not going to be the cure-all, it’s not going to be the magic bullet, but it certainly can be very powerful.
Crystal Meth and HIV
On to number eight.
Number eight, basically, is just trying to understand where methamphetamine [meth] use fits into the HIV epidemic. We’re learning and understanding that the number of people with HIV infection in our country is increasing, it’s not decreasing,29,30 and that transmission of the virus among men who have sex with men also seems to be increasing. I’m interested, and I think others are also, in understanding how much meth use contributes to this.
What I wanted to highlight here was not a news story; there are people who work in big cities that have seen meth for years now. I think what we’re understanding is that there’s just not as much information as we need. There certainly isn’t a good understanding of what the contribution of meth is to some of the statistics we’re getting from the CDC and elsewhere. I think that’s one thing.
The second thing is just how much meth use impacts what happens to people with HIV infection. I think meth use is probably going to be found, conclusively, to be associated with poorer outcomes. We’re seeing some evidence that it could be associated with HIV drug resistance, and acquiring HIV drug resistant virus.31
We’re seeing also that treatment for methamphetamine is dismal, and that the prognosis of people who are meth users is not very good.32 We see this in people; in their testimonials, they indicated that getting off this particular drug is extremely difficult.
I think that there is a story here. I think it’s one that’s going to persist. I think that all we need to do is not lose track of how methamphetamine is probably responsible for more than we realize when it comes to the expanding HIV epidemic here in our country.33 It’s not only on the West Coast; it’s not only on the East Coast; it’s in the interior. I work in North Carolina, and we’re seeing this in rural dwellers; we’re seeing this in the Midwest. I think this is a big story, and we’re only seeing the tip of the iceberg, here.
It’s about the present as well as the future, then?
It totally is. The best prediction of the future can be examining the past, and we’ve seen what happened with crack cocaine. I think we’re starting to see the signal from methamphetamine. Methamphetamine use in one of the studies that I cite from San Francisco has increased dramatically among homeless and near-homeless people — from 5 to 15 percent.34 We’re seeing the use among men who have sex with men increase dramatically.
The characteristics of this drug are like nothing we’ve ever seen before. People become hypersexual; people become wide awake and have sex for hours and days at a time. People are not using meth and then putting on a condom.35 It causes impotence so that some men who are normally on top become bottoms, leaving them more susceptible to HIV infection.
It’s just incredibly devious and evil, and it’s the kind of thing we don’t need right now. I think it’s erasing some of the benefits and some of the advances we had in trying to control this infection and the spread of this infection. I think this is a huge concern. Maybe I’m being Chicken Little and saying the sky is falling, but from all the data I’m seeing, I think that methamphetamine use is one of the biggest threats we’re going to face in this country when it comes to containing HIV infection.
Survival With HIV: Great Expectations
Number nine has some good news!
Number nine is good news, and that has to do with survival with HIV infection. One of the questions I’m often asked after a person learns that he or she is HIV infected is, “How long do I have to live?” The good news is that we know it’s on the order of decades. In a really, very well done study that came out of Denmark, we see a really nice estimation of how long people can expect to live using modeling. The researchers were able to accomplish this, because they keep track of every single person with HIV infection in Denmark, and they also have great data on the population as a whole.36
What they were able to show us was that someone who’s age 25, the hypothetical 25-year-old you mentioned before, who’s HIV infected, can expect to live on the order of 20 or more years with their HIV infection. Now, that is less than for the general population, but I think it’s really very encouraging.
When you look at survival for people with HIV infection who were diagnosed more recently, that number goes up to 32 years, and that reflects the use of potent HIV therapy. Just looking at the aggregate over a time period of a decade or two, we see that there are already indications that the longevity number is just going to keep getting bigger and bigger.
What I tell people is, if we say that you have 20 to 30 years of life expectancy from now, just imagine what’s going to happen in the next 10, 20, or 30 years — imagine the advances we’re going to see realized, and how that’s going to extend your life even further.
I think this is great news. It’s encouraging and also, importantly, it puts forth a fixed number that people sometimes just need to be able to grab on to. So if I say to this 25-year-old, we’re looking at 32.5 more years of your life, in general, and that things are going to happen that’ll be amazing during that time period that’ll extend it even further, I hope that’s reassuring to that person, that they’ll be around for a long time and that they will probably succumb to something other than HIV infection.
So they shouldn’t get stuck on the numbers — shouldn’t say 25 plus 32 equals 57. I’m going to be dead at 57 and I should plan for my funeral that year.
I think that’s important. [If they did get stuck on the numbers,] I think that would be understandable, but naive [of them]. Remember, these are aggregate numbers that come from thousands of people — this is not individual. I think we have to understand that for all the research we’re talking about.
When we look at studies, they don’t tell us what’s going to happen to the individual patient, they tell us what’ll happen to a group of people. Any individual person has to decide for themselves, is this study a good study? Do I look like the people who were studied? Do I live in Denmark? Do I have a system like they have in Denmark, where there’s universal health care?
You can’t necessarily apply everything you read from one study to yourself, but this gives us sort of a ballpark figure we can use when thinking about this. We certainly know that it’s obsolete to say you have 10 more years to live after you get HIV diagnosed, data we had generated from 15 to 20 years ago in a different world.
I tell people, ‘Chances are that if you do most of what we talk about and take care of yourself, you can get old.’
I find this reassuring; it kind of does tag that number on along with our perceptions. I tell people, “Chances are that if you do most of what we talk about and take care of yourself, you can get old.” I think that this study shows that.
One thing the study also showed, though, and about which we have to be very careful, was that this longevity was truncated, limited, among people who have hepatitis C. We really should try hard to make sure that people understand that and do not become infected with hepatitis C if they don’t have hepatitis C right now. It also means that, for people with hepatitis C, we have to really take care to neutralize that problem the best we can by offering them treatment.
Immune Function and the Risk of Cancer
On to number 10.
Number 10. This follows a similar sort of line, and that’s trying to understand what are the risks as people live longer with HIV infection. We’ve talked a little already about cardiovascular disease, and it makes sense that, as people live longer with their HIV infection and do not succumb to HIV-related diseases, well … everyone’s gotta die of something. None of us are immortal. If you’re an HIV-negative person living in the United States or Europe, you’re probably going to die of cardiovascular disease or cancer. What we really want to understand is whether there is a greater risk of cancer due to the HIV infection. Is there a greater risk of cardiovascular disease due to the HIV infection itself? We want to know whether this is not just a normal process.
There was a very nice and interesting study published in The Lancet that looked at this in a very creative way.37 What they were able to do was look at different published studies of cancer rates among people with HIV infection, and they compared it to another group of people who also suffer from problems with their immune system, and that’s organ transplant recipients. These are people who take medicines that reduce their immune system function so that their body doesn’t reject that organ.
Looking at these two groups, the investigators were able to understand the patterns of cancer, and how much this might be related to immunosuppression.
Most of us think of the immune system as protecting us against germs. The immune system also protects us against cancers. We’re just starting to understand that over the last several years. When a cell becomes cancerous, the body responds to it by saying, “You don’t look like me, you look foreign.” That’s the same response the body has when a germ comes into it. It says, “You don’t belong here, and we’re going to attack you.” A healthy immune system will take care of a cancer cell. People develop cancer cells all the time, and the immune system gets rid of them — you don’t even know it!
In people who have problems in their immune system, that protective mechanism is faulty. That’s why we do see cancers in people with HIV infection. Two of the first things we saw, Kaposi’s sarcoma and non-Hodgkin’s lymphoma, are cancers that people developed with HIV infection.
People with solid organ transplants also developed cancers. What the investigators found was that the patterns of increased cancer risk were actually not that dissimilar between HIV-positive patients and those who received transplants. The rates of cancers with an infectious cause — those are cancers we know are triggered by viruses, such as cancers related to human papillomavirus (HPV); Hodgkin’s lymphoma, which can be triggered by Epstein-Barr virus (EBV); or liver cancers caused by hepatitis C or hepatitis B. There were more of those cancers in both groups. The patterns were a little bit different, but not as different as you’d think, suggesting that the immunosuppression that occurs both with HIV and transplants leads to a development of malignancies.
This is important data because it really indicates to us that we cannot tolerate poor immune function among people with HIV infection. If we do, we risk the development of malignancies. This is not the focus of this paper; in fact, it wasn’t mentioned, but to me it brings up the issue of when do we treat HIV infection. Do we allow people’s T-cell counts to go down so low that we may be placing them at risk for these infections that could lead to cancers? I think this is part of that discussion, and it goes along with also the effect on the brain and central nervous system of having a lower CD4 cell count, and long-term exposure to virus.
Is there a risk of cardiovascular disease that occurs with uncontrolled HIV infection, and is there increased risk of cancer? Those are things we’re going to have to try to figure out over time.
I think this is a very important study that puts another dot on the paper; we just have to connect the dots and try to understand the data.
On to the runners up.
There were a few runners up.
HIV Among Street Youth in St. Petersburg
One of them was a nightmarish report from St. Petersburg.38 It looked at the HIV prevalence — how much HIV was present — in street youth in St. Petersburg, Russia.
For listeners and readers who are in the United States, you might say, “Oh, Russia, who cares?” But I think that this is important because there are some lessons for us as well here, including lessons about how society should take care of its people.
St. Petersburg is a big city, the second-biggest city in Russia. What the researchers found was an alarming amount of HIV among these kids. These are kids who have been basically abandoned; most of these kids are orphans.
The researchers looked at 313 street youth and found 37 percent were HIV infected. These are very young people between the ages of 15 and 19; these are people who are living on the streets, often drug addicted, and often abused. Forty-two percent of the male street youths were found to be HIV infected, and 29 percent of the females. Most didn’t know that they were HIV infected. It was just amazing. Two-thirds of those who were double orphans were HIV infected; so it’s a huge risk to be an orphan in St. Petersburg, especially a double orphan. Seventy percent of the teens who didn’t have a place to live or who had a sexually transmitted disease were HIV infected.
These are numbers that blow away seroprevalence studies of HIV in Africa.39 This is just amazing. This is in a country where there are hospitals, there’s medication, there are doctors, there are roads, there is electricity. This is just total neglect of a group of people within a society. There’s a cautionary tale here; for the people who live in Russia, this is a wake-up call. If these youths have such high rates — four out of 10 of these street youths are HIV infected — then you have to think about what’s going on in that society as a whole.
The rate of HIV infection is climbing so steeply in parts of the former Soviet Union that in a decade or two when we think about HIV, it’s going to be in that part of the world.
This is a shocking report; sometimes I just can’t stop thinking about these data. When I compare them to other parts of the world, it just blows me away. It’s just as important as the data we’ve gotten from parts of Africa, where we learned that one out of every 20 adults is HIV infected. It’s mind-numbing data that goes right along that same category.
Very few people think about Russia as similar to sub-Saharan African.
In 25 years, it’s going to be all different. Eastern Europe is going to be where people think about HIV. Right now we think about Africa, but the rate of HIV infection is climbing so steeply in parts of the former Soviet Union that in a decade or two when we think about HIV, it’s going to be in that part of the world.
Does HIV Accelerate Aging?
Another runner up you had was about aging and HIV.
This is an emerging story, and one I think physicians and clinicians are being led to by their patients.40 People are getting older with HIV infection, and there are questions about how to do that well. There are questions about how to grow older well in general, but especially with HIV infection vis-à-vis everything we’ve talked about with the increased possible risks of cancer, heart attacks and the like.
A number of studies have looked at this at the biological level, looking at cells and how cells age, and markers of aging and premature aging.39,41-43 The bottom line is that there is a picture emerging that HIV does seem to cause more advanced aging in many people. We have to understand more about this. We have to understand how we can counteract that. There may even be therapies we can develop to do this.
One thing that seems clear is that controlling HIV helps. Again, this is sort of a drumbeat from study to study. Getting control of your HIV — getting your viral load down and your immune system strong — that is one of the best things you can do.
Not smoking is another; smoking enhances the risk of many of the things that are associated with aging — the bad things: the cancers and the cardiovascular disease. People who smoke look older. It’s not new news; anyone can understand, you don’t have to be a scientist to see the deleterious effects of smoking on the body and how it can facilitate the problems that we think about as we get older.
I think there is something going on here. We’re just at the beginning of understanding what’s going on biologically. We do know that the immune system ages prematurely in people with HIV, so we should do everything we can to keep that immune system healthy and happy.
Underestimating HIV Rates in the United States
The final runner up was about underestimating HIV incidence in the United States. Can you talk a little about why you picked that?
Again, I think this goes along with a theme I tried to develop in picking the top 10 and the runners up, which is not so much trying to present studies that tell us what we already know, or confirm things we thought. I’m trying to look at things that help us understand what the future is going to be like. There’s no better way to do that than to look at how many cases of HIV are occurring every year.
The important part of the story is that while the world is reassessing how many people are HIV infected and downgrading their estimates, saying they overestimated,44 here in the United States, we’re finding we probably underestimate the number of people acquiring HIV infection.29 This is according to a leak from the CDC that has been reported in the Wall Street Journal about how the CDC is on the verge of adjusting their estimate of how many people are infected — and increasing it substantially, to indicate that maybe they were off by 10,000 to 15,000 people per year. That would be significant.
I think that this, if it pans out, will be important. It again refers back to some of the questions I had before about: Is this a phenomenon occurring among men who have sex with men? If so, why and what can we do about it? How much is meth use playing into this? How much of this is young men who have sex with men, who don’t have a historic memory of losing friends, who are not part of an active advocate community? What’s going on here?
There are more questions raised than answers, but most of the data suggest that the increases are going to be largely made up of men who have sex with men, and young ones at that.
I think this is where we have to focus more energy. We don’t have a vaccine; we’re not going to be able to prevent HIV that way. How do we work to have prevention happen, especially among those who are most likely to acquire the infection? I find this to be a very concerning development, despite all the millions of dollars and all the intelligence and the conferences that have been dedicated to HIV prevention. It’s a shame that we’re not seeing the decrease that we thought we should be seeing with all this effort. It really tells us that we have to go back to the drawing board and figure out what works, and how to get that to work in different populations.
Wow. Well, an amazing top 10, with runners up. I think I could have asked you questions all day about these studies. Many of them have so many implications. What a great job picking through all this research from 2007!
I hope people take from this mostly hopeful messages. I do think that there are tremendous advances that we’ve seen, and I do think we’ll see these kinds of things happen in the realm of prevention. I do. I think we’re at the beginning of that, despite the failures. There were lots of failures when it came to therapeutics, to treatment; we’re seeing treatment really mature here. We still have a ways to go; we don’t have a cure yet.
Thanks very much.
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