AIDS TREATMENT NEWS Issue #211, November 18,1994
John S. James

We do not share the pessimism, because there are also excellent opportunities to move forward, given the will and the organization to do so. The potential good news is largely unreported in the media, and missing in the ongoing public conversation which largely determines peoples' views. But new developments are starting to save lives now, and could save many more lives in the near future. How many lives will depend on whether people pay attention, understand what is happening, and effectively support its development.

Recently AIDS TREATMENT NEWS has published a series of articles with a common focus: developing certain emerging opportunities into a strategy for moving forward, a strategy we can apply today, a strategy which will pay off now and in the near future, as well as the distant future. This is our tenth article this year in this series; for a list of the earlier ones, see below.

Last week, at the New Directions in Antiviral Chemotherapy conference (November 10-12 in San Francisco), both the despair and the grounds for hope were evident. After Friday's sessions, what stood out most was the lack of new information. Earlier that day, while one of the speakers droned on, a prominent physician in the audience commented to us that the leading researchers (with most of the medical profession following) were going to continue treating AIDS like hepatitis, and continue to accept the death of all of their patients.

But those who showed up early Saturday morning heard Douglas Richman, M.D., one of the leading AIDS researchers, in an aside from his talk on antiviral drug resistance, cite studies from around the world showing that, "In a two-week study, you can show whether a drug works or doesn't work, and you can do a dose-response curve. Now it doesn't tell you what's going to be a useful drug, because it's a chronic disease, so it doesn't tell you what's going to happen long term... In terms of being a useful drug, we need longer studies. But in phase I studies to ascertain whether you've got a drug that works or not, you only need a two-week study." (For more of this transcript, see "Viral Load, Small Trials, and Immune Recovery," below.)

What is important in Dr. Richman's talk is:

* The concept of small, rapid trials to look for antiviral activity in people;

* Evidence that if viral load, as measured by plasma HIV RNA, could be kept down, the immune system could recover spontaneously (see transcript below); and

* The rapidly increasing momentum these ideas are getting in the professional community.

The ideas are not new. But Dr. Richman's discussion -- a 5- minute aside in a longer talk on resistance to antiviral drugs -- brings together strong evidence in their favor, a coherent interpretation of the evidence, and a clear path for moving forward.

Some other researchers have shown a mental split on this issue. On one hand, they say it is unproven that reducing the plasma HIV RNA and keeping it down will benefit the patient, that this must be proven by prospective studies (which in practice will take years to design, conduct, analyze, and publish). But on the other hand, the same people can be seen to be basing their own thoughts and plans on the working assumption that lowering this viral load is the central goal. Many researchers do agree that trials to learn how to lower the HIV RNA is what we should be doing now -- although everyone also knows that we also need more studies on what this marker means for clinical practice. And pharmaceutical companies, which bet money on drug-development strategies, are now including HIV RNA in almost all their trials of new antivirals, providing de facto acceptance of viral load measurement in early human trials to screen new drugs.

But in Dr. Richman's talk, as in almost all talks by professional researchers, the only drugs mentioned are those being developed by pharmaceutical companies. If these were the best candidate drugs -- if pharmaceutical companies were efficient in selecting what to develop -- then this limitation might not make much difference. But the industry's selection process is not efficient, because it only looks in certain places; it only considers drugs where the company has, or can readily acquire, exclusive proprietary rights. Usually this means new chemicals, which will take years to develop because they have to go through laboratory testing, animal tests in different species, pharmacodynamic tests in people, phase I dosage tests in people, etc., all the time with many committees and reviews. Another problem is that it usually takes so long to build management and financial momentum for a new product idea, that years are likely to pass between the time a few scientists realize that a new approach is important, and the time that management decides to go ahead and develop an innovative drug. And during this time the data, and often even the existence of the project, are generally secret. This means that innovations are routinely delayed for years, for no scientific or medical reason -- not only delaying the drug in question, but often impeding other projects which could benefit from the information. Industry is usually fixated on getting individual proprietary drugs through the FDA -- which is only part of the job of giving doctors the tools they need to be effective.

Meanwhile, natural products, traditional medicines used in cultures around the world, and readily available prescription drugs approved for other uses and often long off patent, are not considered as potential HIV treatments, even when there are excellent reasons to study them. Yet if any one of these were found to be useful in treating HIV disease, that finding would have great public-health importance, since these drugs are readily available, usually inexpensive, and well known in human use. Basic information on dosage, risks, precautions, etc. is already there; the financing of a major development project, the convincing of management, the laboratory and animal tests, etc. are not necessary. There are seldom any supply or manufacturing issues, nor need to fight with companies or the FDA over expanded-access programs.

What is needed instead is (1) to find out if there is scientific evidence that an available drug shows antiviral or other potentially beneficial activity in people, and if so, (2) to learn how to use the treatment most effectively -- for example, learning which patients may benefit, what doses are best for HIV treatment, and what additional safety precautions may be required for persons with HIV. While this work is proceeding, the drug can also be tried as an element in combinations, which can include existing approved HIV treatments, experimental drugs under development, and other already-available drugs which have shown promise. The first test for scientific rationale may look for reduction in HIV RNA; or other tests could measure markers of immune function, for example.

These other tests may be equally important; we have emphasized HIV RNA because it has several advantages at this time. It has a central rationale in HIV disease, since it directly measures the amount of virus in the blood -- which also appears to be a good indicator of the activity (although not the amount) of the virus in lymph nodes and throughout the body. Tests for HIV RNA have been well standardized, and are known to be highly reproducible from sample to sample; also, early data on average day-to-day variation in patients has been published. The test is commercially available, meaning that researchers and physicians can order it when they need it, instead of spending months in negotiations or years in assay development and standardization, which is often necessary for research tests.

Overcoming Drug Resistance

HIV resistance to antiviral drugs is a major and growing problem. The conventional approach to overcoming resistance is to combine drugs, either targeted against the same viral protein (for example, AZT plus ddI plus a non-nucleoside reverse transcriptase inhibitor such as nevirapine), or against different proteins (for example, AZT combined with a protease inhibitor). This approach is important, but it is too early to know how successful it will be.

There is another approach which may be more successful in overcoming resistance, but which unfortunately is largely being ignored. This is to combine drugs like AZT or protease inhibitors, with different kinds of drugs which inhibit HIV without targeting viral proteins at all. There are many different kinds of such potential drugs, many different mechanism of action. Here are four of them:

* Immune-based therapies. An ideal treatment would be a way to restore the body's ability to keep HIV under control. This is because the immune system can control HIV much better than any known drug. Eventually, in most people, it loses this ability, for reasons which are unknown, but which are probably related to some injury to the immune system caused by the virus -- an injury which appears to be reversible, at least in large part, if the virus can be stopped (see "Viral Load, Small Trials, and Immune Recovery," below). If we knew specifically what caused this loss of immune function, it would probably be possible to intervene pharmaceutically, creating a new HIV treatment entirely separate from antiviral drugs -- which could still be used in addition, if necessary.

* Hydroxyurea, etc. Another approach is to reduce the level of substances which HIV needs, but which are produced by human cells, not by the virus. Viruses always rely on many substances which they cannot produce themselves. Of course it is necessary to find a drug which can inhibit the virus without harming the human cells, which often need the same substances. But once such a drug is found, it will probably be difficult for the virus to work around it, as there is no viral protein which is being directly targeted and can evade the drug through mutations.

One such drug now in the news is hydroxyurea, which has been used for decades in treating certain cancers (see "Hydroxyurea -- Call for Information," below.) In laboratory tests, it greatly inhibits HIV at concentrations which are easily achievable in the blood. Laboratory tests also indicate that it might work especially well when combined with ddI. So far only a handful of people have tried hydroxyurea as a treatment for HIV, apparently with quite promising results; because of safety concerns, however, most physicians understandably want trials to be run first, before they prescribe the drug for their patients. But, in a tragedy which would also be a scandal if it were not so common, no trials have been run (except for a small study recently started in France), despite great efforts by researchers to get a trial going. The problem seems to be that the clinical- research system is built around the assumption that drugs will be developed by well-financed pharmaceutical companies; and in this case, no company has an incentive, since the drug is off patent. The critical need is for the first, small study, to get credible data which will provide momentum for further research, as well as data about safety and side effects in persons with HIV. Such a trial would not need to be very expensive. But neither government nor private research organizations have succeeded in getting a study going, and activists have not followed the situation or raised an alarm about the lack of research.

* LTR inhibitors. A third approach is to reduce viral activation of the LTR (long terminal repeat) of HIV, which acts as a master switch which makes the virus more active. AIDS TREATMENT NEWS has reported on this mechanism of action, which has been largely ignored in conventional drug development. Some treatments which work this way will probably be susceptible to HIV drug resistance, but might still be useful in combinations with other classes of drugs. Other approaches, less susceptible to resistance, may slow HIV progression by reducing abnormally high levels of certain substances, such as TNF (tumor necrosis factor), which are naturally present in the body and known to stimulate HIV.

* It appears to be possible to slow HIV progression by aggressive diagnosis and treatment, suppression, or prophylaxis of certain opportunistic infections, which may stimulate HIV. If it is true that continuous acyclovir use can extend average survival in persons with AIDS, as some evidence suggests, it may be working indirectly by suppressing certain herpes viruses which may activate HIV.

Drug Mechanism of Action, and Viral Load

With small, rapid trials, many leads can be followed up quickly, and new combinations can be rapidly developed. Whenever a treatment does look promising, the trials set up to test it should, of course, be followed indefinitely. The first challenge is to reduce the viral load; but the most difficult challenge will be to keep it down.

Testing for viral load (usually by measuring plasma HIV RNA, which is the most feasible viral-load test today) is clearly useful for trials of antivirals which directly target viral proteins; in this case, we know what to expect if the drug works (see "Viral Load, Small Trials, and Immune Recovery," below). It now seems clear that hydroxyurea greatly reduces the level of HIV RNA in people, so the same test should be able to measure its activity -- although less is known about this drug, since no trials have been done.

For drugs with other mechanisms of action, however, viral load tests will need to be used with care, sometimes in an exploratory mode where researchers are looking to see what happens, rather than trying to confirm or deny a pre-existing hypothesis. For example, an immune-based therapy may reduce viral load indirectly, by helping the body control the virus. But at first, certain immune-based therapies may actually increase viral load temporarily, by causing immune stimulation which can activate HIV.

There might also be treatments which reduce the damage that HIV causes to cells, but do not reduce the level of virus. In this case the treatment could be beneficial, even if nothing at all is seen on the viral-load tests.

Or consider the case of acyclovir, which does not have any direct effect against HIV. If this drug does improve average survival of persons with late-stage HIV disease -- and the evidence which suggests it does is controversial -- it is probably doing that by suppressing other viruses which activate HIV. If so, then it is possible that some patients might be getting a large benefit, while others who do not have those viruses might be getting none at all. Viral-load and other blood tests could be used to explore this hypothesis. For example, a controlled trial could assign one group of patients to use acyclovir continuously, while others used it only when necessary for suppression of herpes; the latter group would have HIV viral load measured whenever a herpes recurrence occurred but before acyclovir treatment was started, and then have repeated viral-load measurements while the acyclovir treatment continued. Such a trial might help researchers understand the mechanism of action (if any) of acyclovir in improving AIDS survival, and perhaps make it possible to identify groups of patients most likely to benefit.

Some Drugs to Test

One cause of the prevailing pessimism about AIDS treatments is the sense that there are no drugs to test. So we started a list of candidate drugs which are already in use in people, and have some rationale suggesting that they should be tested for possible use in treatment of HIV disease.

The list of 27 potential treatments below is just a beginning. We only included drugs, nutrients, etc. which are already in human use for other purposes. And we only included the drugs which came to mind in the last two weeks; we have not yet done literature searches, nor talked to experts in micronutrients, or in Chinese or other systems of traditional medicine, etc. As we do these things, the list below will certainly grow longer. (Also, this list only includes potential treatments for HIV disease, not for opportunistic infections.)

Note that most of these drugs are not antivirals; in some cases, the mechanism of action, if any, is unknown. For such drugs, results of viral load and other tests will have to be interpreted especially carefully.

We will add to this list in the future. You can help by suggesting other treatments which should be considered. For this particular list, we are interested in treatments which are already in human use for some purpose, so that they can be tested quickly for possible use in HIV, without the need to go through animal studies, etc. Also, we have not included drugs which are already in major development projects, since in that case the testing which we are proposing is already being done.

Note that this is a list of research possibilities, not treatment options. Some of these drugs can be quite dangerous; and while there is a rationale for further research, the evidence in hand showing actual benefit to patients is usually slim to non-existent. We were reluctant to publish the list, at least without first completing the library and phone-interview research on each of the drugs, to gather the information which is already known. But that process would take months or years, and by then there would be new drugs to list anyway. So we expect to keep an ongoing list of drugs needing research as possible treatments for HIV disease, and publish it from time to time. We hope this will encourage public interest and advocacy, to get the necessary research done. If even one of these 27 drugs is found to be useful in HIV treatment, that finding would be immensely important. (Our guess is that several will be found useful -- if the studies are done.)

Initial list of drugs already in human use which need small, rapid trials to look for possible activity as HIV treatments (in alphabetical order):

Acyclovir (indirect effect); aspirin; cimetidine; co-enzyme Q; curcumin; DHEA; doxycycline; DNCB; glycyrrhizin; HCG; hydroxyurea; hypericin; isoprinosine; NAC; papaverine; pentoxifylline; peptide T; ranitidine; ribavirin; sulfasalazine; thalidomide; thymomodulin, etc.; topotecan; tricyclic antidepresants; vitamin B6; vitamin C; warfarin.

Strategy of Hope: Previous Articles in AIDS TREATMENT NEWS

Our most important previous articles on the AIDS treatment development strategy discussed here are:

* Research Strategy Proposal: High-Tech Exploitation of the Unexpected, issue #190, January 7, 1994;

* Antivirals and Immune Recovery: Interview with Michael S. Saag, M.D., issue #200, June 3, 1994;

* AIDS Research Strategy: Rapid, Small Trials for Promising Treatment Leads, issue #201, June 17, 1994;

* HIV RNA: New Blood Test for Individualized Therapy and Faster Trials, issue #204, August 5, 1994;

* AIDS Pathogenesis: New Understanding, issue #206, September 2, 1994;

* Why AIDS Drug Development Has Failed, issue #206, September 2, 1994;

* "Surrogate Markers": Current Status, Future Directions (Part I), issue #209, October 21, 1994;

* Maternal Transmission and Viral Load, issue #209, October 21, 1994; and

* HIV RNA -- Time to Wake Up and Save Lives, issue #210, November 4, 1994.]

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