Gay Men's Health Crisis: Treatment Issues - Volume 5 no. 4, May 15, 1991
Kevin Armington

KA: Your research has shown that people have extremely high levels of virus in their blood soon after infection, but that those levels drop after the body mounts an immune response. Any theories as to why the immune system is able to control HIV early on?

DH: First of all, we should not be surprised that the immune system is able to reponse like that. With every viral infection that has been studied in detail, for example, CMV (cytomegalovirus) and influenza virus, there is a burst of virus replication and a rapid control by the immune system after initial infection. We have not formally documented the immune parameter responsible for this, but we suspect that it is likely to involve a combination of killer T cells and antibodies. What is different with HIV is that this virus, in time, escapes from the immune response, and we don't understand why. Perhaps it is because of HIV's rapid production and variance.

KA: Do you think in general there has been too much emphasis on drugs like AZT, ddI and ddC (nucleoside-analogue reverse transcriptase (RT) inhibitors)?

DH: Well, that's all we had to talk about for a while. But now I think a lot of people are focusing on non-nucleoside anti-HIV drugs. Now, there are several non-nucleoside reverse transcriptase inhibitors like BIRG, TIBO derivatives, etc. And you also know there are several candidate drugs that inhibit other HIV enzymes, like protease. These things are all non-nucloesides.

KA: But it seems that these drugs entered clinical trials only recently and anti-HIV research has been going on for seven or eight years now.

DH: But the technology for some of those approaches was rather limited. If you consider protease (an enzyme on HIV), the crystal structure only became available about two years ago. So the technology was limited until 1987 or 1988. Now they can move ahead quickly. Lots of attention was focused on RT early on because it was the only enzyme we could test for. The RT test was available back when HIV was known as HTLV, or even before.

KA: What do you think are some of the most hopeful targets?

DH: Tat (a gene on HIV) and protease. I still think you need to combine them with drugs that target RT. They are different from the RT inhibitors in that they can have an effect on infected cells. AZT is not going to do anything to chronically-infected cells; those cells will make copies of HIV happily even in the presence of antibodies or AZT. Protease and tat inhbitors, however, could have an antiviral effect on these cells. That's their conceptual advantage. Also, the technology around protease inhibitors is fairly advanced because the protease for HIV belongs to a family which includes enzymes that control blood pressure -- renins, specifically. Research has been done for many years with renin inhibitors to treat hypertension and that research will be somewhat applicable to the development of protease inhibitors for HIV. And there are lots of candidate drugs to take off the shelf to screen for anti-HIV activity. I think people are going to be coming out with more and more protease inhibitors.

KA: Work done in your lab has shown some important shortcomings with the antiviral drug CD4. Do you think further research with this drug is warranted?

DH: CD4 looked very exciting in the beginning but we quickly realized that it wasn't working as well as we thought it would. Now we have the opposite situation; people have abandoned the drug. CD4 will never be a cure, but it still may be an important adjunct. In its current form, however, it won't go very far.

KA: Do you think your talk in San Francisco at the Sixth International AIDS Conference dampened enthusiasm for CD4?

DH: I believe so. Unfortunately, the pendulum has swung to the other extreme. We've always been "middle of the road" with CD4. I don't think we should abandon the concept of blocking entry of the virus into cells. But I would focus on the second generation of CD4 drugs rather than the original formulation.

KA: Do you think that one of the reasons interest is being kept alive in CD4 is its potential role in protecting health care workers exposed to HIV through needle sticks?

DH: That is one setting where the drug might be useful. But I know the producers (Genentech) of the drug and they're not really targeting that population. If they think there's a place for CD4 it is in preventing transmission from mother to fetus.

KA: Do you see a role for immunomodulatory therapy?

DH: I have mixed feelings about that. I certainly would be in favor of rejuvenating the immune system but not at the risk of turning on the virus even more. We know that many of the immunoenhancing agents also stimulate HIV in the test tube. There's no question that IL-2 does; we use it in the lab to grow HIV efficiently. There's some debate about tumor necrosis factor: some say it stimulates HIV; some say it doesn't.

KA: Some of the community-based groups are looking at drugs that might have an immunomodulatory effect. What do you think of this?

DH: I think I would caution against haphazard studies. I think immunomodulators are worth looking at, but you should look at them in a setting where you can get some meaningful information about them by careful monitoring of patients who go on them.

KA: There's not much out there for people who've developed AZT resistance, and who can't or won't take ddI or ddC. Unless they want to go into a trial of some new antiviral (and they happen to fit the eligibility criteria), their options are limited. A lot of people in that situation are willing to experiment with various drugs available through the underground network. What do you think of that sort of experimentation outside of clinical trials?

DH: Well, I think once you get to a more desperate situation, logic and rational approaches don't hold much water. You try whatever you can get your hands on. A last attempt to take something may be useful -- who knows? I certainly understand that. The patients I cared for in Los Angeles all did that when they ran out of options. I don't have any specifics to recommend. Some would try meditation, various herbs, acupuncture. I would keep an open mind. We have screened some herbs in the lab and some of them have pretty good anti-HIV activity. We need to systematically characterize these compounds and their mechanisms. Some useful agents may come out of this approach.

KA: Will some of these alternative compounds be screened at this lab?

DH: We're already doing it. We're taking natural products from Asia and screening them the way many scientists would study a compound off the shelf. So we want to do it in a way that will convince other investigators in this country.

KA: What about trichosanthin (Compound Q)? Are you working with that drug at all?

DH: We have in the past. It's not one of the natural products we have found to have good activity against HIV. We have not looked at the preparation that Geneslab is producing; we used trichonsanthin from China. It was not one of the compounds we selected.

KA: What do you think about using unproven approaches to prevent opportunistic infections (OIs), like MAI or CMV?

DH: There are already some trials for prevention of various OIs like toxoplasmosis. There's talk of using high-dose acyclovir for CMV. These things should be addressed; especially within the AIDS Clinical Trials Group (ACTG) system. The ACTG network is massive and consumes so much federal money, yet how many new anti-HIV drugs do we have to look at? If the ACTG is going to continue to be supported, at least for the short run, more attention should be focused on OIs. It might be different three years down the line when there are more anti-HIV drugs to be tested, but right now there are only a handful.

Why aren't people working harder to look at OIs? I think, to a large extent, those studies are not as sexy.

Investigators are all human beings; they all want to do the most exciting studies. But they're using massive amounts of federal funds and they must do what is in the patients' best interests. To some extent, Dr. Fauci and others are trying to get the system to be more responsive in those areas.

KA: Do you think it makes sense for clinicians to experiment with prophylaxis before trials are done?

DH: Once again, I think any time a practitioner wants to experiment, it should be done in a way that useful information can come out of it. Otherwise, I'm not sure the whole thing is worth it.

KA: What do you think about the role of underground buyers' clubs that help people import drugs approved abroad but not available here, for example, clarithromycin?

DH: I think if you know a drug is of a specific use, and it's not available it seems very reasonable to go through whatever channels necessary to get it. Now what I sometimes fail to understand is why a lot of people go through these clubs to buy things that have no proven efficacy.

KA: For example?

DH: Well, Compound Q, for one. Many people have made lots of efforts to obtain this drug.

KA: What do think about the potential role of co-factors in the development of HIV disease? Specifically, do you have any comments about Dr. Montagnier's claims that mycoplasma is an important co-factor?

DH: I'm a strong believer in co-factors. Based on everything we know about the virus, co-factors could play an important role in HIV pathogenesis. But I'm sure I'm not prepared to say that mycoplasma is the co-factor. It may be one important co-factor, but there are probably many others.

I'm not sure Montagnier is saying that, but because it's Luc Montagnier making the statement, it's being portrayed as the major development in the field of co-factors. I think it is just one aspect. I'm not sure it is justified to make a big deal out of it; mycoplasma is everywhere. It is a common contaminant in laboratories, particularly AIDS laboratories.

KA: Some clinicians are treating mycoplasma in their patients with HIV infection, using antibiotics such as doxycycline. Do you think it is too early to do that?

DH: Not if mycoplasma is found. But if there's no documentation, it might not be justified to treat it.

KA: But the more sensitive tests are not easily available to clinicians, so cases of mycoplasma might be missed.

DH: Right, so many clinicians must rely on the routine clinical lab. But the more obvious cases of mycoplasma won't be missed. I don't know about treating mycoplasma without looking for it. Clinicians who are doing that should keep track of their data and write it up so people can learn about their experience. If people are going to be subjected to novel approaches, the data should be gathered in a useful way.

KA: Unfortunately, most clinicians who are trying novel approaches have extremely busy practices and they don't have much time to write up results. So there are obstacles to compiling these data.

DH: I don't know if these clinicians need to do everything themselves, but if they are going to build novel approaches into their practice, they almost owe it to their patients to get useful information out of new treatment approaches. They may be able to get some assistance from nurses, for instance, to compile the data in a simple way. I'm not talking about constructing a complex clinical trial; just compare treated versus untreated patients.

KA: Do you expect any big stories to emerge from Florence?

DH: Perhaps, but I'm not expecting half a dozen major breakthroughs. I am expecting significant developments on selected topics. If you ask me how many of those will translate into direct patient care in 1991, I'd say ... maybe one? But usually if there's a major breakthrough in someone's lab, word gets around, and we haven't heard anything yet.

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