AIDS TREATMENT NEWS Issue #141
John S. James

Our top-priority list of seven treatments and potential treatments appears below in order of importance (starting with the most important, the tat inhibitor). We also list two groups of treatments for AIDS-related conditions.

Tat inhibitor

Many leading AIDS researchers believe that blocking the "tat" gene of HIV may be the most promising approach to AIDS drug development. And new information presented at a recent conference but not yet widely known greatly strengthens the case for this kind of drug.

The HIV tat gene produces a protein which greatly increases the activity of the virus; without tat, the virus becomes inactive. Because this gene has long been recognized as a potential target for an antiviral, the U. S. National Institute of Allergy and Infectious Diseases (NIAID) has provided about $700,000 a year for tat research to a consortium headed by Hoffmann-La Roche, which developed a drug code-named Ro 24-7429, which is now being tested at Johns Hopkins University. No other tat drug is now ready for human testing.

Here is why this approach is important:

* A major advantage of a tat inhibitor over almost all other AIDS drugs is that it would probably be effective in chronically infected as well as acutely infected cells (as Ro 24-7429 has indeed been found to be). Other antivirals, such as AZT, ddI, ddC, and the non-nucleoside RT inhibitors, at best stop HIV from reproducing; they work after the virus has infected a cell, by preventing the genetic information of the virus from being inserted into the genes of the cell. But it seems increasingly likely that much of the damage of AIDS is caused by reservoirs of the virus in chronically infected cells (including macrophages, dendritic cells in the skin, and probably other kinds of cells also). HIV does not kill these cells, but it makes them behave abnormally; they may produce toxic substances such as gp120, or inappropriate amounts of cytokines, normal chemical "messengers" between cells. This process in not affected by the drugs mentioned above (and probably not by the new class of protease inhibitors, either). An effective anti-tat drug would probably make HIV inactive in these cells, stopping the production of toxic substances -- although it would not kill the virus and, like the other drugs, would need to be taken indefinitely.

* Another major advantage concerns viral resistance. Researchers have suspected that HIV might not be able to develop resistance to an anti-tat drug, because the function of tat may be critical; a mutation which could get around the drug effect would be lethal to the virus. Now there is evidence that this may indeed be the case. At the recent "New Directions in Antiviral Chemotherapy" conference in San Francisco, Douglas Richman, M. D., the leading expert on HIV resistance to antivirals, was asked about his results. In laboratory tests, he could quickly ("as early as one passage, and always within six passages") select for resistance to the non-nucleoside RT inhibitor BI-RG-587 (which, along with the Merck "L-drug", has recently shown major resistance problems in human trials). But in well over a year of tests he has not found any change in sensitivity of HIV to the tat inhibitor (Ro 5-3335, an earlier version of Ro 24-7429, which apparently was abandoned because of kidney toxicity in animal tests).

In the past, one reason for skepticism about the tat inhibitor is that its chemical structure is quite similar to that of BI-RG-587. Some skeptics had thought that the Hoffmann-La Roche drug may have been mistakenly identified as a tat inhibitor, but that it really inhibited reverse transcriptase instead -- in which case it would not be special. The new resistance information (which as far as we know appears in print for the first time in this article) shows that while the two drugs are chemically similar, they are very different in their effects -- apparently because they act against different targets in the virus.

It has also been found that AZT-resistant strains of HIV are equally sensitive to the tat inhibitor as non-resistant strains.

* Ro 24-7429 is synergistic with AZT, meaning that the combination works better than would be expected by adding the separate effects of the two drugs.

* Ro 24-7429 is a "benzodiazepine derivative" -- a member of the class of chemicals which includes the tranquilizers Valium and Librium. The extensive human experience with this kind of chemical may help in the development of the new drug.

There are three main safety concerns with Ro 24-7429. In animal studies (which presumably included much higher doses than will be given to humans) it can cause kidney toxicity. And in the body, the drug is turned into a substance with a strong yellow color, which is seen in the urine; in animals, this substance could also remain in the tissues. The third concern is that many benzodiazepine derivatives can cause central nervous system toxicity; as a result, Ro 24-7429 was carefully tested for this before human trials began.

The first human trial of Ro 24-7429, which administered only one dose of the drug, has now been completed. The second trial is now ongoing at Johns Hopkins University. This trial is designed only as a safety study; according to a spokesperson for Hoffmann-La Roche, no efficacy information is being collected. The three lowest doses (60, 200, and 600 mg) should be tested by early 1992; then the FDA wants to look at the data to decide whether to continue this trial with higher doses.

The corporate future of the tat inhibitor has been insecure since April 1991, when developer Hoffmann-La Roche decided that for business reasons it did not want to develop this drug, and told Johns Hopkins researchers to indefinitely postpone the trial which was scheduled to start at that time. Hoffmann-La Roche is expected to announce soon that it has sold rights to the drug to another pharmaceutical company.

We are concerned that the current trial of Ro 24-7429 is not collecting efficacy information, as is commonly done in other trials of AIDS treatments; we urgently need an early indication of whether or not the drug is working in people as a practical treatment for HIV. The trial has also been criticized for its exclusion criteria, especially its exclusion of women of "childbearing potential"; this trial will end with little or no safety information for women.

No one yet knows if Ro 24-7429 will be successful as a drug. If it is not, then the technology which found it (screening for anti-tat activity) will be vitally important, for searching for other tat drugs. This technology was developed at least in part at public expense; it should be made available. (We have been told that the drug itself, Ro 24-7429, was an off-the-shelf chemical at Hoffmann-La Roche, discovered by luck early in the screening process. How many more tat drugs could be found if the screening were not limited to existing chemicals which a single company has the commercial rights to produce?)

For more background on the history of the tat inhibitor, see "Promising AIDS Drug Looking for a Sponsor," Science, July 19, 1991, pages 262-263, and "Roche Stops Human Tests of Promising AIDS Drug," Wall Street Journal, May 30, 1991, page B4.

Hypericin

Hypericin, an antiviral found in small amounts in the St. John's wort plant, appears to be a broad-spectrum antiviral. It shows good anti-HIV activity in laboratory tests (including tests on "wild" virus strains in freshly-drawn blood from persons with HIV), and was found to be an effective treatment for other retroviral diseases in laboratory animals. It appears to have excellent pharmacokinetic properties: it is orally available, has a long half life, and gets into cells. It has been in human use for years (in low doses), especially in Europe, where herbal extracts have been used as an antidepressant. In animal tests, large doses can be tolerated with little toxicity.

The main potential importance of hypericin is that if it works as an HIV treatment, it would provide a whole range of new treatment options, since its mechanism of action is entirely different from that of other available drugs. Also, laboratory tests have shown activity against CMV, influenza, and other viruses. Recent anecdotal reports have suggested that even the low-dose plant extracts might have a role in treating hepatitis B.

Hypericin which was chemically purified from the plant extracts was ready for human trials three years ago, but it was not tested; instead, research was undertaken to improve the methods for chemically synthesizing the drug (without relying on plants), and this work took longer than expected. The ostensible reason for not testing the plant extract was lack of supply of the drug; but our recent discussions with an underground chemist made it clear that supply for a small trial at least would not have been a problem. Our best guess as to why a trial was not started three years ago is that there has always been general agreement that eventually this drug will be produced synthetically, if used on a large scale. And the FDA, for historical reasons, is divided between "drug" and "biologic" divisions, with different personnel and procedures. If a substance is first tested as a plant extract, and later is manufactured, it would have to start the approval process over again in the other division. The tragedy, of course, is that if the substance did work well in early tests, then resources would have been found to overcome all obstacles, no matter how the drug was manufactured. (Two years ago, the Community Research Alliance, a San Francisco organization co-founded by this writer, had completed a monitoring study of over 30 people who used the St. John's wort extracts available in buyers' clubs and health- food stores. Although T-helper counts did increase among those who started with high baseline counts, the effect was not dramatic enough to attract attention. This study was published in the Sixth International Conference on AIDS, June 1990, abstract #2063.)

The first human trial with pure hypericin (as opposed to crude plant extracts, which cannot supply the doses believed likely to be effective) began a few weeks ago at New York University and two other sites. No efficacy data is yet available, but researchers are encouraged by the good pharmacology of the drug and the lack of serious toxicity. This study is not blinded, and information will be reported as it becomes available; the first two weeks of data was presented recently at a meeting of NIAID's AIDS Clinical Trials Group.

One side effect has been found; a feeling of warmth in the hands and face. It has been described as the feeling of coming into a warm room after being outdoors on a cold day; one volunteer was uncomfortable enough to withdraw from the study as a result. This effect may be due to phototoxicity (abnormal sensitivity to sunlight or other strong light), a side effect expected because it occurs in animals. Volunteers have been given a sunscreen to protect the hands and face from sunlight. And a minor drawback found in this trial is that the hypericin's half-life in humans (24 to 25 hours) is less than in the two species of monkeys in which it has been measured; as a result, the drug may need to be taken three times a week instead of twice, in order to maintain antiviral levels in the blood.

If hypericin does prove useful, there should be little trouble obtaining supplies, either by synthesis or by chemical extraction from plant sources. The plants grow all over the world.

For more information on hypericin, including an extensive list of technical references, see AIDS TREATMENT NEWS #125, April 19, 1991; for background on the current clinical trial, see issue #138, November 1, 1991.

ddC and AZT Combination

This drug combination has become the de facto standard of care (for certain patients) among a number of leading AIDS physicians, even though ddC is not approved. Trial results first came out over a year ago (see AIDS TREATMENT NEWS #115, November 23, 1990); little little new information is now available.

In 1992 we hope and expect to see more information for physicians about how best to use this combination; especially needed is guidance about which patients are most likely to benefit. We also hope and expect to see FDA approval of ddC. Hoffmann-La Roche has applied for approval both for single-drug use and in combination with AZT (see AIDS TREATMENT NEWS #139, November 22, 1991).

Soluble Melanin

We covered this potential treatment extensively last month (issue #139, November 22, 1991), and will not repeat that article here. We have received little new information since that publication; few new people have tried melanin, since it has not been available. We have talked to one person whose T-helper count went down after about a month of the treatment, and who had no symptomatic improvement.

Melanin may be available soon. Here are some points to consider in deciding whether to use it:

* Although researchers who have worked with melanins generally regard them as safe, this chemical has never been through the standard animal toxicity studies required before a drug can first be tested in humans. And the stories we have heard about its effectiveness, while impressive, are anecdotal; there is no proof that the drug works. Anyone considering trying melanin should realize how preliminary and nebulous the current information is.

* In all but one of the (handful of) cases reported to us, there was considerable improvement within five days -- usually within one day. This suggests that those who do decide to try the treatment might try it for only a short time, perhaps a week, and then stop unless it clearly seems to be helping. Why accept the unknown risks of long-term use unless there is a clear benefit in return?

* We would very much like to hear from anyone who has first- hand information about use of melanin as an AIDS/HIV treatment, whether or not it seemed helpful. Include contact information so that we can get in touch with you; we will keep your identity confidential. Write to AIDS TREATMENT NEWS, attn: melanin, P. O. Box 411256, San Francisco, CA 94114, or call 415/255-0588.

The urgent need now is to confirm or deny the suggestion (from the early anecdotal reports we published in issue #139) that this treatment may bring dramatic benefit within days for most persons with HIV-related symptoms. The research mainstream is not constituted to investigate this question properly. If the answer is No -- which historically is the case with most new drugs -- then melanin can go back to the research establishment for eventual determination of its ultimate value in AIDS/HIV treatment.

NAC

We are overdue for an in-depth review of NAC (N- acetylcysteine), which we covered briefly in issue #121, February 15, 1991. Laboratory work continues to look good, and the treatment, available at buyers' clubs and health-food stores, continues to be popular. There is still no efficacy data from clinical trials, which only began recently, although they should have started at least two years ago.

Our impression is that the benefit of NAC appears to be limited; it may slow down the progression of HIV, especially in some patients, but it is unlikely to be a sufficient treatment by itself. This potential treatment is interesting nevertheless, because it has so little "down side"; it appears to be safe, and is inexpensive and available.

Ribavirin and ddI Combination

There have long been hints from laboratory studies that this combination may work well. But it is almost impossible to run trials which combine two unapproved drugs, especially drugs from different companies. Now that ddI has been approved, trials will be easier to initiate.

Antisense Drugs

"Antisense" technology is a means of developing drugs which bind to a specific sequence of DNA or RNA within cells. The purpose is to target and shut down specific genes. Antisense drugs may have great future impact for treating cancer, viral diseases, and other medical conditions.

It is generally believed that practical antisense drugs are years away. But the technology has been advancing faster than expected. We have heard that antisense AIDS treatments might be ready for human trials as early as 1992.

One immediate problem with antisense drugs is that, at present, they are very expensive to produce.

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