As CROI 2008 in Boston drew to a close, I found a chance to talk to Robert Schooley, M.D., professor and head of the Division of Infectious Diseases of the University of California, San Diego. Dr. Schooley is a leading clinical investigator who led the National Institute of Allergy and Infectious Diseases' AIDS Clinical Trials Group [ACTG] from 1995 to 2002. Dr. Schooley has been caring for HIV-infected patients since the beginning of the pandemic. I asked him to discuss what he felt was the most significant research presented at CROI 2008.

Dr. Schooley, I was wondering if you could tell me some of the highlights of CROI 2008?

I think, from the therapeutic standpoint, there were not a lot of new blockbuster drugs, but the good news is that the new classes of drugs we saw last year continue to look pretty durable in terms of their effects, and no surprises have come up in terms of new toxicities. So it's reassuring that a lot of the hope that we had last year has been reaffirmed this year, about new agents initially, particularly for people with more advanced disease and drug-resistant virus. But, as we learn more about the safety of these agents, we're seeing them move up into patients with less treatment experience, and these treatment options are good.

There were a couple of studies that have been talked about a lot. Could you comment on the abacavir [ABC, Ziagen] results from the D:A:D study?¹

I can't, because I don't really understand them. It's hard sometimes to interpret large cohort studies, because there are a lot of things going on. The people doing the studies can, in all good faith, try to control for all the variables, but there are often variables that you don't know about, or can't control adequately for. I don't completely understand the mechanism for this, or a reason for why this happens.

Now, that doesn't mean that it's not real. It means that we need to look to see if we can understand it and see if it's replicated in other cohorts -- see if, when GlaxoSmithKline puts together all of their abacavir experience, they see the same signal in control studies.

There are a lot of things that this observation should trigger, and I'm sure is triggering. But you have to be careful about jumping on the first signal and assuming that what you see is what you've got.

So you don't think that anything needs to be changed in clinical practice, because of these results, at this point?

I don't think we know enough to change clinical practice over this right now. I'm sure that -- as with many things in medicine -- what will happen is, if there is a patient who's got several cardiovascular risk factors and you're trying to decide what drug therapy to use, and you have other options that are just as good, you might decide in this instance to use another option until you get additional data.

But you wouldn't want to compromise your treatment options, in terms of suppressing the virus -- which is what kills people -- by choosing drugs that are virologically less active over a study in which, although the study is large, the number of cardiovascular events themselves are very few and far between. The risk rate seems high, but the actual risk, the real number of people having heart attacks, is low. Compromising your antiviral therapy because of the perceived cardiovascular risk is something that people have to be very careful about doing. We need to understand it. I think we will understand it soon.

In some ways, it's a microcosm of the discussions we had several years ago, when we began to see lipodystrophy and some of the concerns about antiretroviral therapy. We understand body shape changes better; we know which drugs cause them, and how to avoid them in most patients.

But at the time those came up, there were people who had forgotten about how bad things were before we had the drugs, when we had people dying at six-month survivals after pneumocystis.

We are going to continue to have signals in which new things come up. We need to understand them, and we need to move on. But this one is a single observation in a large cohort study that needs to be replicated in other cohort studies, understood mechanistically, and examined in rigorous structured trials.

So no rush to judgment right now.

I think there shouldn't be a rush to judgment right now.

Related to that study are the general studies being presented on HIV and aging, and non-AIDS-related infections and malignancies. Can you comment about that?

I think that, as someone getting older myself, I'm at increasing risk for cardiovascular disease. I could increase that further if I could find some cigarettes I liked and would stop exercising, and eat more. As any population ages, cardiovascular risk factors become more important, in terms of th population's overall morbidity and mortality. All of us need to work on it.

The good news is that we have this problem. I mean, who would have thought in 1986 -- with the initial AZT [zidovudine, Retrovir] study, which was a nice signal that there ultimately would be a way to treat the virus -- that we'd be worried about HIV-infected people in their 70s having problems with cholesterol?

We have approaches to cardiovascular risk that we've been working on in the non-HIV-infected population for years. It just makes us have to be better internists, and I relish the challenge. It's nice to have other problems to work on in HIV-infected patients. Previously, we could do so little about their underlying disease, that these kinds of problems were irrelevant.

How do you deal with a 22-year-old patient who hears the news coming out of this conference about HIV and aging, and malignancies, and heart disease, and is scared by it? Who is thinking, "Oh, my God. Should I take HIV treatment?"

I think that the take-home message is that we know about the natural history of HIV untreated when you're 20, from what happened in 1986. We know what the natural history is. Survival rates are much shorter than they are when the virus is treated. We know from the data from the SMART study that there are inflammatory markers that have an impact on heart disease if you don't treat the HIV.²

Treating the HIV may well lower your cardiac risk, rather than raise your cardiac risk. You want to think about drugs that are less likely to cause cardiovascular risk, which is how many of the current regimens are chosen.

What you tell a 22-year-old is, the SMART study says that there is more cardiovascular risk if you're not treated than if you are treated. Being treated is a good thing to do from a lot of standpoints. Being 22 is also a good time to think about stopping smoking, if you're smoking.

Do you think that the clinicians right now are asking people to make lifestyle changes to reduce these kinds of risks?

We should be doing that with every patient.

Can you comment on the news about the growing rate of hepatitis C [HCV] transmission in gay men, both in the United States and in Europe?³

HIV and HCV have a lot of parallels. We have known for a long time that each of the viruses is found in the bloodstream. We have known for a long time that each of the viruses can be transmitted sexually, although at different rates. HIV is easier to transmit than HCV. But what we're seeing in the HCV studies now is that the same people that were at the greatest risk for HIV transmission early in the epidemic, those with larger numbers of sexual partners, those with sexual practices that lead to mucosal surface damage, are the ones who are more likely to be at risk for HCV transmission. It's another reason why just knowing someone's HIV status is not enough when you think about whether to have protected or unprotected sex. There are a lot of pathogens that are transmitted sexually, including HSV [herpes simplex virus], CMV [cytomegalovirus], HHV-8 [human herpesvirus 8], syphilis and chancroid. You can go down a long list. This is just another example of something that has to be on that list, when you consider the risk of having unprotected sex.

Do you think clinicians in the United States are thinking about hepatitis C as a possible coinfection in their HIV-infected patients? Are they looking at ALT [alanine aminotransferase] levels and saying, "Oh, that could be HCV?"

They should be, because about 20% of the HIV-infected population in the U.S., and more in populations that acquired the virus by injection drug use, are HCV seropositive. So it should be a part of the routine care of an HIV-infected person to look for hepatitis B and C.

Right. Wasn't it once considered rare for HCV to be transmitted sexually?

It still is rare for it to be transmitted sexually in HIV-uninfected heterosexual couples. We don't understand all of the reasons for that, but one of the reasons may be that we know that HIV infection leads to an increase in the amount of HCV replication, or levels in the bloodstream, that may make people more infectious.

But the baseline rate in heterosexual couples has been low in the past, and reflects the fact that HCV, as I said earlier, is a bit more difficult to transmit than HIV is.

There is some connection, it seems, between the sexual transmission of hepatitis C and methamphetamine addiction in the United States. Have you seen that kind of connection?

I haven't seen it in individual patients. But the behaviors that can be unmasked with methamphetamine use are the types of behaviors that can put you at more risk for mucosal damage, and for the sorts of things that are being associated with HCV transmission. So I'm not surprised by those things.

There was a presentation⁴ suggesting that maybe HIV treatment should be initiated at even higher CD4+ cell counts than 350. Even though the U.S. DHHS [Department of Health and Human Services] guidelines just noted in January⁵ that initiation should be at 350, this new study hints that maybe 500 might be the new interesting number. What are your thoughts?

The when-to-start-therapy question is one that has been going on for two decades already and will continue. I have a slide that I made back when we were using 35-mm slides that showed the considerations in earlier and later therapy. The point of the slide was that what we're thinking now is going to change over time -- that as we develop drugs that are safer over the long-term, as we develop more treatment options, as we understand better the natural history of the disease, there will be more reason to start early.

If it turns out that drug development stalls and we become more worried about long-term toxicities, then treatment initiation will be later. What's happening now is, we're realizing that many of the drugs we have are quite safe over the long term. HIV has its own risks, in terms of morbidity beyond the easily recognized bouts of pneumocystis that brought HIV to our attention to begin with. With two new classes of drugs last year, the concern about running out of drugs in two years is not the kind of concern we had several years back.

The question about how to decide when to start therapy I think will almost always remain one that is based on consensus, as opposed to a rigorous clinical trial, and the preference of the individual patient. The attempts to do when-to-start-studies in the past have all failed because, at the end of the day, when a potential study participant is sitting down in a room to discuss the study, they say they would like to know when to start therapy, but they don't want to have themselves be randomized to figure it out. So attempts to fill large studies with people in randomized clinical trials about when to start have not been successful. There's no reason to think they'd be successful now.

I think the other issue, and I think what is increasingly going to happen, is as we understand more and more about what the individualized risks are, decisions will be made on an individualized basis. As we learned from this year's CROI meeting, a smoker with risk for cardiovascular disease -- these are the folks who are at most risk with unbridled HIV replication -- might be somebody you'd start earlier, based on the SMART study analysis.⁶

In the old days, you might think, I'll wait to initiate therapy in that patient, because I don't want to put them at cardiovascular risk. But as we understand more about the individual issues related to the disease, we can make individual decisions that are tailored to that individual patient.

We have to get away from the concept that there is an average patient living somewhere in the geographic center of the HIV universe that should represent the decisions made for everyone.

In resource-limited settings, we've often started HIV therapy later because the argument has been we don't have the resources to treat everybody. But in resource-limited settings, where tuberculosis brings people to medical care earlier, we probably should be thinking about starting there earlier than in Los Angeles or in Boston.

I think we need to keep thinking about this question in a less average patient/global way, and think more about the individual considerations, in individual patients, based on rigorous data gained from a number of clinical trials.

What that means is that HIV medicine -- like many other areas of medicine -- is going to be best practiced by people who are knowledgeable about the data, thoughtful about individual patients, attentive to the patient and able to make joint decisions with the patient based on individualized risks.

In fact, isn't that what the guidelines say: That there's no upper limit anymore? It used to be: Do not start over a certain CD4+ cell count. Now the guidelines say treatment is recommended at 350.

Right. That again, I think, reflects a little more humility. Because in the earlier days, we'd ramp down the guidelines for therapy based on randomized clinical trials with regimens that weren't as good as the regimens are now. At the time, we had cohort studies that initially said, we can't show an improvement starting patients at a CD4+ count of 350 over starting them at 200, so you can wait till the patient has a CD4+ count of 200.

But those were cohort studies that were done in a time when we didn't have a long-term follow-up. As you might imagine, the people who had higher CD4+ cell counts, when they entered in such a cohort were going to take longer to have events accumulate. So in a lot of ways, making a decision early on in a cohort that the people who are least likely to have events are fine is like watching somebody jump out of a 10-story building, and as they go by the fifth floor, say they're fine ... so far.

What we're seeing now with 500 is, as the 350 CD4+ cell initiators have been followed longer, you begin to see a signal that people who started earlier are doing better. It's not rocket science to understand why you're seeing that happen from the cohort studies. They're maturing.

Interesting. Just a few more questions. Did you see the vaccine results?⁷ Do you think this was expected? Is this making everyone feel depressed about the hope for a vaccine in the near future?

For a long time a lot of us have been depressed about being able to have a vaccine in the near future. We need to keep working on vaccines. It's an important goal. But we should stop planning as if we're going to have an effective vaccine. The reason I say that is, there have been a lot of plans made in public sectors about the need for care, and in care and prevention, based on the premise that we'll have a vaccine soon.

If you use that as a rationale for not thinking about the fact that HIV is going to be here to stay for a while, you have a lot of people who should be treated that don't get treated. You have a lot of people who might have come out to be tested for HIV if they knew they could be treated. You have a lot of people who, after being treated, might be less infectious.

There are a lot of things we were not doing for prevention because of this false hope that there was going to be a vaccine within 24 months or 36 months.

I think we should work assiduously on vaccine development, but we should plan public health interventions based on the premise that we are not going to have a safe and effective vaccine for decades to come. If we get one, we'll all be delighted and we can go to Plan B, which is: Now we have a vaccine. That's, I think, a much more prudent way to plan than to plan as if we have one just around the corner.

Compared to vaccines, microbicides are looking a lot more hopeful than ever before.

I wish I could agree with you. I think there are a lot of agents that you can inactivate virus with. That's been true for a long time. But going from being able to inactivate virus to being able to have an effective microbicide in the clinical setting is a big leap. Again, the research needs to continue. We don't have a microbicide around the corner, either. We have to be careful not to fall into the same trap we fell into with the vaccine studies.

In fact, every microbicide trial that's been done either shows that people didn't do any better, or did worse. I don't see where the positive signal is coming from about microbicide hopefulness. Yes, we have a lot that should be studied. But no, we don't have any clinical trials that indicate that we're any closer to an effective microbicide than we did 10 years ago, that I'm aware of. Can you think of any?

There's data about maraviroc [MVC, Selzentry, Celsentri] that might be interesting.⁸

It's an interesting premise to study, and I support science in doing studies. But premises and a positive study have one thing in between, and that's the study itself. Right now, although maraviroc is very well tolerated and may not cause the problems that some of the gels that were used caused, that may have enhanced infection, we have no more reason to think that maraviroc will work than nonoxynol-9 will work until a study is done. And so I support doing the studies, but don't start planning national policy on a microbicide being around the corner.

One other track that you may not have followed was immune-based therapies: IL-2 [interleukin-2, aldesleukin, Proleukin], IL-7 [interleukin-7]. I know there are going to be big IL-2 trials presented next year. Is there any hope for therapeutic vaccines or immune-based therapies?

I think that right now they are more probes of pathogenesis than they are realistic therapies. The ACTG presented a study with a therapeutic vaccine yesterday.⁹ What we saw in that study was a modest -- a very modest -- transient viral signal, and a very modest immune response that correlated with people who better controlled their virus. We may learn from that what types of immunity we should be trying to enhance in the future using immune-based therapeutic interventions. But when you compare the virologic benefit in the vaccine study we presented to the virologic benefit from taking three antiretroviral drugs, you're talking about the difference between walking and getting in a space ship.

We, I think, learned that virus-specific CD4+ cells are an important marker of immunity that helps you control the virus, and may be a very important marker to follow as better vaccines come along. But therapeutic vaccines are not around the corner either, in terms of replacing antiretroviral drugs. IL-2 will increase your CD4+ cells. We've known that since 1985. Are you going to want to take cyclical IL-2, with the attendant cost and toxicity, compared to antiretroviral drugs that the guidelines panels are now saying do not necessarily have any upper limit as to when you should start? A lot of the premise about IL-2 has been, if you start with IL-2, you can delay the time until you take these "toxic drugs."

But the previous concerns about a lot of the toxicities that we were talking about at the time the IL-2 studies started -- we're learning more about the contexts of those concerns, and the risk/benefit ratio comparing the two interventions is changing. I would not be at all surprised to see that people who had cyclical IL-2 therapy could wait longer to start their therapy, based on a CD4+ cell guided treatment intervention, or initiation.

But if you're sitting in Omaha, and you're trying to decide whether to start tenofovir/FTC [Truvada] and efavirenz [EFV, Sustiva, Stocrin], or AZT/3TC [zidovudine/lamivudine, Combivir] and atazanavir [ATV, Reyataz], or intravenous cyclical IL-2, followed by subcutaneous IL-2, I think the patients will vote with their feet and will say it's a lot easier to take a pill once a day than to take a parenteral medication.

I was thinking more of strategies for patients who are immune discordant. They might be suppressed and they just can't get their CD4+ count to rise.

But in IL-2, those aren't the patients being studied. The other thing to keep in mind, which I think is a very important message, is that the risk for opportunistic infections is much lower when your virus is suppressed at a given CD4+ cell count than when it's not. A lot of the risk stratification for which infections happen at what stage of HIV disease happened when we didn't have any viral drugs that worked.

Why that makes a difference is this: Suppose I'm sitting here with a CD4+ cell count of 175. I've got pneumocystis on board and I'm not on antiviral drugs. The pneumocystis reactivates. I try to respond to it. The virus jumps on my T cells, and pneumocystis causes trouble. If I have the same CD4+ cell count and my viral replication is suppressed, the pneumocystis tries to reactivate and my T cells are protected in response. The absolute risk of infection is lower than people thought it was several years ago at the same CD4+ cell count.

Although having a CD4+ count rise decreases your risk of opportunistic infection, you're still better off on antiviral drugs with no virus than on antiviral drugs with virus, and we don't know whether putting someone on IL-2 will decrease the risk of infection.

IL-7 is interesting, because there are some things that IL-7 is doing that IL-2 isn't doing. Whether that will translate from a probe of HIV pathogenesis and immunologic restoration to a practical therapy is something that still needs to be determined. I'm a big supporter of studies looking at that because we need to understand the virus-host interaction.

From the standpoint of patients out there today thinking about whether next year they'll be coming in for their IL-7 shot, I don't think we're there with that, either. Important studies, but not, from the clinical intervention standpoint, ready for primetime.

Are there any studies at this conference exploring what to do with patients who have immune discordance? I am asking the question because of the association between being immune suppressed and malignancies, and clinicians trying to figure out how to change that risk.

The problem is that it's difficult to know how to study this. The event rate is low. In other words, yes; people are at greater risk for malignancy with a lower CD4+ cell count. But the number of people who develop Kaposi's sarcoma or lymphoma is low, and you'd have to find a lot of people who are at risk for these tumors, and then do something to some of them but not to others to show the event rate change. That involves a very big study, with interventions that we don't completely understand how to use yet.

I think that the risk is there, but how to translate reduction of that risk to clinical practice with the immune agents we currently have, is a bigger goal than people understand. Because at the end of the day, if your CD4+ cell count is 140, and you raise it to 270 with IL-2, you don't know whether your risk for lymphoma goes down to what it would have been at 270 if you'd raised your cells yourself, compared to raising them with IL-2. The only way you can know that is to do a clinical trial and compare the people who raise their CD4+ cells to 270 to those who don't get the IL-2, and that's a big study.

Is no one thinking about it right now?

I think we think about a lot of things, and you have to end up prioritizing where you think you have the best chance of success, and where success will affect the most people in the most positive way. I think most people understand there are a lot of unanswered questions. We all want to ask those questions. We have to make sure the AIDS research effort is not dismantled in the current federal budget debacle. There are a lot of pressures on the NIH's [National Institutes of Health] budget -- not just the AIDS budget, but the entire NIH budget. The progress we've made has been dependent on rigorous and ongoing investigation. For people to say, "Everyone with HIV is doing fine. We don't need to spend time worrying about that anymore," I think is a big mistake at this point. I think what you've seen at this conference indicates that progress is being made and there are a lot of questions we still have.

You have asked some good questions today, and unless we have the tools to keep asking the questions, we're going to be, in 2012, where we are in 2008, and I'm still looking for the upside.

What can people who are reading this do to change that situation? Could they write to the NIH? Could they write to their senator?

They can vote. We're all for voting. They can read the platforms of people running for office, both locally and nationally, and look at who thinks health care and medical research are important.

There are a lot of issues that challenge our country today, and health care and health research is only one of them. But it is one that's very important to all of us, and people for whom it's an issue should think about which candidates are most likely to push that forward as a national issue. We have to work together here. I think that I voted with my feet and went into health care years ago, because I think it's nice to see people healthy, and we have a great country that can do that. We need to elect leaders who share that vision, in my view.

Great advice! If people reading want to go to AIDSvote.org, there are a bunch of things there about different candidates, and what their platforms are.

I've not been there and have no idea, but I would just encourage people to get the information and go out and vote.

Great. Well, thank you very much, Dr. Schooley.

For more information on the 2008 U.S. presidential election, browse through our collection of articles.

This transcript has been lightly edited for clarity.

Footnotes

1. Sabin C, Worm S, Weber R, et al, and the D:A:D Study Group. Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction? The D:A:D study. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 957c.
   View poster: Download PDF
2. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296.
3. Fisher M, Richardson D, Sabin C. Acute hepatitis C in men who have sex with men is not confined to those infected with HIV, and their number continues to increase. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 130.
4. Phillips A. Morbidity and mortality in the HAART era. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 8.
5. The DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Office of AIDS Research Advisory Council, US Dept of Health and Human Services; January 29, 2008.
6. El-Sadr W and SMART Study Group. Re-initiation of ART in the CD4-guided ART interruption group in the SMART study lowers risk of opportunistic disease or death. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 36.
7. Robertson M, Mehrotra D, Fitzgerald D, et al. Efficacy results from the STEP Study (Merck V520 Protocol 023/HVTN 502): a phase II test-of-concept trial of the MRKAd5 HIV-1 gag/pol/nef trivalent vaccine. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 88LB.
8. Dumond J, Patterson K, Pecha A, et al. Maraviroc (MVC) pharmacokinetics (PK) in blood plasma (BP), genital tract (GT) fluid and tissue in healthy female volunteers. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 135LB.
   View slides: Download PDF
9. Schooley R, Wang H, Spritzler J, et al, and AIDS Clinical Trials Group. Therapeutic vaccination with a replication defective adenovirus type 5 HIV-1 gag vaccine in a prospective, double-blinded, placebo-controlled trial (ACTG 5197). In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 87.