Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 9 - October 1994

Treatment Issues (TI): Given the substantial interest in HIV protease inhibitors, where do you think we are in the development of this class of compounds?

David Ho: It is nice to have so many compounds from different companies in clinical development. They all target the active sites of the protease. Many of them are really pretty potent against HIV in vitro [in the test tube] and there are several that are showing different levels of in vivo [in the body] efficacy. The thing that encourages me the most is the fact that we have inhibitors with different structures that bind differently to the active site, meaning that we might be able to combine some of these. And the in vitro observation so far is that you could have differences in the patterns of resistance, so that combining them might begin to make some sense. So I am encouraged by the number of inhibitors that are pretty potent, and the fact that the virus cannot make one mutation and resist all of them. At this point, looking at about ten inhibitors, there are at least two major patterns of resistance, and more likely three patterns.

TI: Researchers from Merck report that they have seen one patient who is resistant to all the protease inhibitors. Does this surprise you?

David Ho: When you are dealing with many different strains of HIV, given a particular background, and particular set of mutations, you can find viruses that become more and more resistant. But most of them do follow the patterns. Resistance to all compounds may occur in a particular case. But that may not be a general rule.

TI: Your lab is overseeing a clinical trial of the Abbott protease inhibitor. Can you tell us about it?

David Ho: We are doing a Phase I study of the compound in about two dozen patients and we are many months into it now. We would like to present our data on safety and antiviral efficacy at the ICAAC [Interscience Conference on Antimicrobial Agents and Chemotherapy] meeting. At this point, I have been instructed not to comment on the study. You could sort of guess that if we are eager to present at the October meeting as a late breaker report, we have some meaningful data, which would be of interest to the field.

Using Viral Load Measurements

TI: What standards should be used for determining whether the FDA should approve the protease inhibitors?

David Ho: It depends on your philosophy about this disease. My view is that we are dealing with a viral infection, a viral disease. I believe less in the autoimmune mechanism and such indirect pathways for pathogenesis. So for me, a very potent antiviral effect in vivo goes a long way. But that doesn't promise clinical benefit if the in vivo effect lasts only for a short period. So in the long run, we certainly need clinical endpoints to support the initial antiviral observations.

TI: If a drug is relatively safe and has reasonable antiviral activity, should it be considered for accelerated approval?

David Ho: Demonstrating the antiviral's effect is a very encouraging piece of data. I have mixed feelings about whether the approval should be made on that basis alone. I think there is not enough data to make a very conclusive statement on that issue [but] as we go through some of these, we may get better answers to that question.

TI: When will we be able to know whether and what kind of virus load changes are really significant?

David Ho: Over the years, many compounds were touted as antivirals, but when you measured viral load, no real changes were observed. For example, soluble CD4, compound Q, oral interferon and, perhaps, hypericin all had no antiviral effect in vivo even though they were developed as antiviral agents. This kind of data suggests that a drug should probably be dropped or at least modified.

But we now have some idea of the decreases one gets with compounds like AZT and ddI and other reverse transcriptase inhibitors, like nevirapine. And we have a pretty good idea from a couple of the protease inhibitors. With saquinavir [Roche's compound], by itself, and at doses tested, the antiviral effect is not dramatic. With the Merck compounds, the effect, at least short term, could be very dramatic. So you begin to get a feel for the magnitude of the antiviral effect in vivo. If we could correlate that with clinical endpoints, we would have learned quite a bit, which could be used in assessing future candidate drugs.

TI: Are you referring to a trial to study whether a specific drop in viral load correlates with improvement in people's symptoms?

David Ho: Well, a trial would be a more formal way, but I think we are getting the impression from these current studies that some compounds will be very useful.

TI: A couple of studies presented in Yokohama looked back to see whether reductions in viral load were associated with clinical improvement.

David Ho: Yes. The impression is that the antiviral benefit correlates with clinical data. The Walter Reed data[1] and the Coombs data[2] would be consistent with what we know about pathogenesis. The viral load and the biological properties of the virus all correlate with the disease progression. So, if we could bring viral load down to a level that we find in an asymptomatic individual, or better yet, the level in long- term survivors, we could conclude, based on the available evidence, that this would result in a significant clinical benefit. But that is putting a lot of different types of data together and making a link.

TI: Some physicians are using viral load measurements [Roche's PCR or Chiron's branched DNA tests] to get some idea about treatment strategies for their patients. Do you have any advice for physicians or patients who are spending significant amounts of money for these tests?

David Ho: I believe that viral load is a very useful parameter and that it is going to be the upcoming trend for clinical practice. These quantitative techniques have been available for several years in our labs, and I find them useful with the few patients that I see. We have a limited number of antivirals, but you could at least play with those using viral load as a guide. And the tests are becoming easier to do. They are pretty accurate. And now with these two companies [Roche and Chiron] making a major push, we hope the price will continue to drop so that it will be affordable. So I find these tests useful.

TI: In what ways?

David Ho: For example, if a patient starts on a new antiviral, fairly consistently we see a decrease in viral load. And if with time, say six months, three months, that creeps up or increases dramatically, assuming the patient is taking the drug, it says there is some evidence of virologic failure. You could think about adding or switching therapies. So I find it particularly useful, and have used that information to manipulate the antiviral agents, and try to keep it at a level that I am comfortable with. What I find is a lot of physicians in the New York area are using [the tests], yet they don't know what the values mean. Such as what does 25,000 [copies per ml] mean? Or 200,000 mean? The companies have not done a good job in educating the physicians who are likely to use this test.

TI: What does it really mean if you have an HIV RNA level of 200,000?

David Ho: Well, obviously, the lower the better. But let's say that it is on the order of 10,000 to 20,000. That is, relatively speaking, pretty low. Whereas if you begin to have levels of 100,000, that's pretty rampant viral replication, and I would do something to control that.

Initiating Antiviral Therapy

TI: What do you suggest to your patients about whether and when to begin antiretroviral therapy?

David Ho: I use the numbers to guide me. CD4 to some extent, usually in conjunction with viral load data. So if a patient's viral titer is, say, below 10,000, sometimes below 5,000 - and that is generally in conjunction with a pretty decent CD4 cell count - I say, that in most cases, we would shoot for levels like this, and you are already there. We don't know how low we could go, and the assays are not particularly good at monitoring the low levels in a reliable way at the present - although a year from now that might be different. So we would go through that discussion and probably not think about initiating therapy.

In addition to viral load levels, I also look at the CD4 trend. If a patient's CD4 count is 450 and if the viral load is pretty high, say 100,000 copies, I would be more comfortable in initiating something like AZT to bring that down to a level more consistent with asymptomatic carriers of the virus. So I do use viral load measurements to help me make decisions. But in practice today, I am not sure how many people have access to viral load tests to guide them.

TI: Let's say you personally were in a situation where you had been on AZT for six months to a year, and your viral load was going up again. Knowing everything that you know about the Roche or Merck protease inhibitors, would you try to get your hands on these drugs?

David Ho: Yes, I would. I know less about saquinavir by itself. But I have seen data presented by various investigators who are studying the Merck compound to know that the antiviral benefit is substantial over a course of a few months. And it is something that I would consider very, very seriously. I have been impressed by the initial viral effect of the Merck protease inhibitors.

TI: Do you think that the whole problem with new AIDS drugs is just viral resistance?

David Ho: Yes. Viral resistance and the magnitude of it. Protease inhibitors are going to have resistance too. But the level of resistance is more in the order of ten-fold, twenty-, fifty-fold, not a thousand-fold. So that poses a particular problem. Some suggest that there are different patterns of resistance in the non-nucleoside reverse transcriptase inhibitors. Certainly, Upjohn and Boehringer Ingelheim believe they have inhibitors with different resistance patterns. Perhaps in the future they could be combined.

TI: Could antivirals alone make HIV infection a chronic manageable infection or will we need some sort of immune therapy?

David Ho: Antivirals could go a long way for many of the infected. I really can't say that for the patients who are very, very advanced, whose immune system may be depleted. But for a lot of the patients we have been looking at, if you show me someone with a two log [100-fold] drop in viral load, I will show you consistently a very nice CD4 response. In fact, if you see virus go down like that, you almost always see CD4 go up [correspondingly]. With AZT and with protease inhibitor, we know that the decline [in HIV] is very quick. Even in patients with 50 CD4 cells, there could be a doubling or tripling of CD4 levels, sometimes higher. We have seen cases, this is perhaps unusual, that go up to 350 to 400. If you look at the production rate of virus, even though the patient may have steady viral load for the period preceding the treatment, a lot of production is going on. And then with the treatment, viral production declines and a new equilibrium occurs. And looking at the rapid CD4 cell increases, you realize that the regenerative capacity is still pretty good.

TI: Are these functional CD4s?

David Ho: We don't know. But it is telling that when you do this and you think about regeneration of CD4, you shift the equilibrium to a different level. And what happens is that when you go through this calculation, you realize that the production rates are actually pretty high. That says you haven't totally wiped out the bone marrow storage or whatever is responsible for making these cells. And it makes me think - this is where my bias comes in - that we have to deal with the virus first.

Long-Term Survivors

TI: You gave a talk in Yokohama about long-term survivors that caused a lot of discussion. And you suggested there may be something in CD8 cells that suppresses the virus in some patients. Does this represent a change in thinking for you?

David Ho: We looked closely at several different parameters in these long-term survivors. The virus in all of them is very well controlled. We went on to try to explain why that is and the conclusion we are left with today is that it is really not some sort of resistance of the host CD4 cell to infection, but rather a combination of immune responses to the virus and some evidence of attenuation of the virus. And the CD8 story is part of that. We found many more of the CD8 cells that are capable of suppressing virus replication. The mere finding of those CD8 cells was described by Jay Levy a long time ago. What we did was to quantify that response a little bit more, in greater detail, and show that numerically speaking, it takes a lot less CD8 cells for long-term survivors to see such inhibitory effect. At the same time, we also showed that the neutralizing antibody titers in long- term survivors are great. So that these individuals must be seeing the virus at least periodically. Maybe not fully infectious, aggressive forms, but at least seeing the viral antigen. So I think that information is useful to know as we design vaccine strategies and immunotherapeutic strategies. The CD8 story is very controversial. Jay Levy's contention is that they are not CTLs [cytotoxic lymphocytes]. Yet we know the CTLs in vitro could do exactly that. If you stimulate the CTLs, some CTLs will certainly kill the cell. Others will release various cytokines that are suppressive for virus replication. So one of the immediate questions that would help the field a lot is to resolve this issue. Are these CD8 cells simply HIV specific CTLs? And I haven't seen anybody doing experiments to answer that question in a more direct way. I have encouraged some in our lab to address that in a more direct way.

TI: So as far as the long-term survivors go, what would you say is a more significant immune response: antibodies or CTL?

David Ho: It would be hard for me to answer that question. In each case we have analyzed, we see great neutralizing antibody titers. We see, quantitatively speaking, a lot of these CD8 cells. And which is more important? I don't really know.

Acute HIV Infection

TI: Your group has done a lot of work on acute HIV infection. Should antiretroviral therapies be used in treating a patient with acute infection?

David Ho: A Swiss study suggests that treating reasonably early, in the first six months of infection, has some short-term benefit in terms of progression of various parameters. But theoretically it has always made sense that if you could control the virus really well, early on, with antivirals, you potentially could decrease the number of viral variants that first populate the patient. And you should have less problem in terms of variance and likelihood of developing drug resistance.

TI: If you were treating someone with acute infection what would you recommend?

David Ho: I personally believe that it makes sense to knock the virus down the best we can. If it were me, and I had all the currently available drugs in front of me, I would probably take multiple drugs over the short course. The ones that have been shown to have in vivo activity, say, the Merck protease inhibitor, AZT, and nevirapine. Put them all together. At least short-term, you know the major toxicity problem is not going to be a big issue, and resistance is not an issue. So if you could decrease virus very early on, there are a lot of theoretical advantages, but I have absolutely no empirical data.

Reinfection in HIV-Positive Individuals

TI: Couples who are both HIV-positive are told to use condoms because of the risk of "reinfection." Is the risk of "reinfection" real?

David Ho: There is little evidence to document that an additional "super" infection [or "reinfection"] with a second strain of HIV occurs at a period of time after initial infection. However, there is now plenty of evidence that you can have two strains circulating simultaneously. We just submitted a paper on an acute seroconverter who had multiple partners one night and got multiple strains of HIV. There is also a case where multiple units of blood were transfused into one person and coinfection occurred. So we know multiple strains can occur, at least simultaneously ["coinfection"]. Whether it can occur sequentially ["reinfection"], I don't know. But aside from HIV, you have to worry about other infectious agents and we know that other organisms can affect HIV activation and replication.

HIV Vaccines

TI: Is there any basis to believe that therapeutic vaccines will be a useful therapy for HIV.

David Ho: I still need to be convinced. If someone comes up with a very original idea to use various viral components to induce an immune response, I'm willing to listen. If it is suggested that giving the patient a gp120 or gp160 or one type of viral particle would stimulate a useful immune response, my response would be that the body sees more variants on a regular basis, compared to these proteins a few times a year. And the major problem seems to be, if you give the envelope protein, you are trying to induce primarily an antibody response. But that antibody response is very ineffective against circulating strains of HIV.

But I am still optimistic about developing a vaccine for HIV. We know vaccines are possible because Ron Derossier has an attenuated vaccine that works in animals. It would be nice to go and figure out in those monkeys what is mediating the protection.

TI: But they haven't been able to do that?

David Ho: They haven't done that yet. Superficially they have looked at neutralizing antibody titers in those protected monkeys versus monkeys that were not protected by other forms of vaccine. And, in fact, the neutralizing antibody response was lower in the protected animals. So, I am encouraged by the fact that protection is possible. We just don't know how to do it in ways that are more acceptable. So we have to be more creative.

TI: Do you think it was a mistake not to initiate a large trial of the gp120 vaccines?

David Ho: I was not in favor of pushing ahead, given the available information. I do not know whether that decision ultimately would be proven right or wrong. I just think that these vaccines will only induce an antibody response. So when antibodies have no activity against the viruses that are in the community, the rationale falls apart.

Beyond Protease Inhibitors

TI: Is there anything beyond the protease inhibitors that interests you and could be available within the next few years?

David Ho: This is something that we have talked about on the National Task Force on Drug Development. Many large pharmaceutical companies had some program on reverse transcriptase inhibitors and protease inhibitors. But there is precious little beyond those two targets, and that is a concern. How do you get the pharmaceutical companies to think about all the other targets that are out there? Such as tat, rev [HIV proteins needed for replication] and integrase [an HIV enzyme needed for infecting new cells]. But there are other targets that are less well known that are discussed in the basic literature. We know gag [HIV core protein] is a requirement for viral activity. And there are assays to screen for drugs that would block its interaction. Do you see a lot of companies thinking about that? Steve Garth's group shows that gag interacting with cyclophilin [a cellular transport protein] is a requirement for its activity. And there is a good assay that screens for cyclophilin inhibitors. Sandoz, because of its position in cyclophilin, has an interest in this area. But I see very little interest from others.

Similarly, you could go down the line: integrase - you could try to block protease dimerization [a step in constructing the HIV protease enzyme]. I see very little activity there. With protease, everybody is focusing on the catalytic side. But you could screen for inhibitors that would block the interactive surface. Nobody is working on that, as far as I know. And, there is evidence that the integrase must bind to a transcriptional factor. That sounds like a nice target. And there is a nice assay.

So we have to create a mechanism for the large pharmaceutical companies to use their chemical library on these targets using the assays. There is a real gap in anti-viral research, and we must try to fill it.

TI: What can government do to encourage companies to do this type of research?

David Ho: Government has got to provide incentives for the companies to do that. Because AIDS is such a difficult and controversial area, some companies just say it's not worth it. There is concern that there are too few companies that are truly devoted to finding something for AIDS. So, at the basic level, government must provide some incentive in terms of funding to get the companies with expertise into some of these new target areas. Exactly how, I think, is a difficult thing.

Government Sponsored AIDS Research

TI: Should the NIH be emphasizing targeted or investigator-initiated AIDS research?

David Ho: They are always trying to balance the two. The example I just gave you about providing incentives sounds like targeted research. And so there are situations where a targeted approach is useful. But in general, I favor what has accounted for most of the American success in science, and that is investigators pushing and developing their own ideas. A lot of the creativity is going to come from that. But if you have one obvious gap, where you see after extensive survey, almost nobody working on it, then in those situations, a targeted approach is required.

TI: You were one of the first well-known researchers to support the Office of AIDS Research [OAR] reforms at the NIH. Are you optimistic about these reforms?

David Ho: I like the new direction that has been taken. Of course, the new OAR really will only begin to have an impact on the '96 budget and thereafter. But some of the concepts that have been discussed by [OAR director] Bill Paul, I think, are right on. He's developed the plan after substantial input from many people outside NIH.

TI: What specifically do you like?

David Ho: For one, I like the idea of putting greater emphasis on basic research. In the therapeutic area, basic research will help generate a greater infusion of new targets and new drugs into the developmental pipeline. This pipeline goes from drug discovery all the way to clinical trials and so on. And the infrastructure needs to be reexamined each step of the way. That is what the OAR is doing. Does it make sense to have a huge infrastructure to test drugs, with very few promising drugs flowing through the developmental pipeline?

TI: How would you make the clinical trials program more efficient?

David Ho: In terms of the ACTG [NIH AIDS Clinical Trials Group], you have to look at what the accomplishments were over the years and what dollars have been consumed by that process. And almost go through it program by program.

TI: And how do you feel about the ACTG?

David Ho: This is a very controversial area. I think they have made contributions. There are a lot of groups out there that may be doing good work. The question is, does it apply to every single area? And that has to be evaluated.

TI: Can what has been done here at the Aaron Diamond Center be replicated on a government level?

David Ho: I think it is difficult. Here, they took a chance and committed the money and allowed us, with guidance from our boards, to go out and pick personnel first. That is not how government operates. With government you have to spell it out. It is better done as a private enterprise. In San Francisco, they have the Gladstone Institute which was founded, again, by a foundation. And they were able to go and pick people.

We were also able to do something very few places have been able to do - go and pick promising researchers with complementary skills and interests to form teams. A lot of institutions just put together their AIDS researchers whether they fit in with one another or not.

TI: Proposals for a "Manhattan Project for AIDS" focus on putting together people in different fields of AIDS. What do you think about such proposals?

David Ho: First of all, I would never call any project a Manhattan Project. I think teams along this line might be reasonable. Huge teams congregating at one site are probably not practical or even necessary given how easy it is to communicate. So I would not favor the type of arrangement that developed the atom bomb.

TI: In terms of the overall U.S. government AIDS research effort, what are we doing right and what could be done better?

David Ho: There is a large pool of very talented scientists working here. And the esprit de corps among scientists is much better now than before and there is a lot more positive interaction among scientists. In the journals, there is a lot of scientific development about HIV every month. So a good deal of incremental knowledge is being generated. Obviously we need more to get to a level where the clinical translation occurs in terms of therapy. We are fortunate in this country that the funding for AIDS research is quite large compared to funding in other countries and funding in other areas. So many of those things I am pleased with. And I think it is just a matter of juggling the priorities. If you say, what are we doing wrong, we need, as the OAR is doing, to look at the entire research portfolio and examine the priorities. Is it appropriate to put, you know, X amount on the front end, Y amount in the middle and Z in the back end? All of these need to be examined and some priority adjustments are required.

1 Mayers D et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; I(abstract 253B):75.

2 Kahn J. Tenth international conference on AIDS program book. Aug 7-12 1994; session RT-1:26.

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