AZT, Alternatives, and Public Policy

Published in San Francisco Sentinel, March 27, 1987; also published as AIDS Treatment News #28, same date.


Last week's Federal approval for prescription sale of AZT has raised major concerns of cost and insurance, as well as questions about the objectivity of the regulatory process and the overall direction of U.S. AIDS treatment research.


AZT

Last week the U.S. Food and Drug Administration (FDA) approved limited sale of the AIDS treatment AZT. Because of confusion about exactly what was approved, we here reproduce a text distributed by a physician to the March 20 meeting of the California AIDS Advisory Committee in Sacramento:

"Indicated for the management of certain adult patients with symptomatic HIV infection (AIDS and advanced ARC) who have a history of cytologically confirmed pneumocystis carinii pneumonia or an absolute CD4 (T4 helper/inducer) lymphocyte count of less than 200/mm3 in the peripheral blood before
therapy is begun.

"NOTE: This is the official FDA indication for zidovudine (Retrovir), formerly known as azidothymidine (AZT). This
information was obtained verbally from the Division of Anti-Infective Drug Products of the FDA."

Note that AZT now has two new names: Retrovir, the proprietary trade name, and zidovudine, apparently a new
generic. This writer will continue to use "AZT" as long as it is the one best known to the public. The name is being changed for commercial reasons, despite added confusion for the tens of millions of people who have already heard of AZT.

Two immediate concerns confront persons with AIDS and ARC: the medical merits of AZT, and the serious financial and practical problems likely to develop around it in the coming months.

This writer is not qualified to judge the medical merits, but can only relate impressions from conversations with
physicians and other experts. There seems to be a consensus among most physicians familiar with the drug that AZT can benefit many people. Many others cannot use it because of severe side effects, yet some tolerate it with few side effects or none.

AZT works by providing a counterfeit building block used by the virus in assembling DNA, stopping or hindering
reproduction of the virus. A number of scientists and physicians fear that AZT could have unknown long-term side
effects by interfering with the body's own DNA. No one knows whether this theoretical concern is a real problem. Since the use of AZT started gradually, with a few people initially, any long-term effects will probably show up first in those who have been using the drug the longest, giving some warning to others.

Scientists are developing new drugs which work like AZT but may be less toxic. One example is dideoxycytidine (DDC).

For some people the medical decision to use or not use AZT will be a difficult one. The community could help by insisting on prompt release of detailed scientific results from clinical trials -- which didn't happen after last year's major double- blind study of AZT.


Cost

AZT will cost about $750. to $1000. per month. In California, MediCal will pay, because of a law previously
passed by the legislature. New York's Medicaid will also pay for AZT; each state will make its own decision. However,
Medicare (the Federal program) has announced that it will not pay.

No one knows what private insurance companies will do. The best guess is that most of them will theoretically pay for
AZT like any other prescription drug (commonly 80 percent of cost), but that many will work hard to evade the responsibility.

Companies will probably insist on exact compliance with all rules, such as the official FDA indication quoted above.
If they can find any flaw in the paperwork, they could send the forms back -- after a delay. Meanwhile the patient must front close to a thousand dollars a month; if someone cannot do so and has to go off the drug, the company will not owe for the money not spent. Insurance companies have long known that difficult paperwork, selectively applied, can discourage people and prevent many from ever collecting money due them.

The best defense against such abuses is to support organizations like National Gay Rights Advocates, or
Mobilization Against AIDS (both headquartered in San Francisco). NGRA has been highly effective against
discriminatory practices in the insurance industry, and MAA has stopped other instances of corporate discrimination against persons with AIDS.

Persons without insurance are already making medical decisions based on ability to pay. The expense of AZT will
drain the savings of many individuals, and their families and friends.

Why does AZT cost so much? Prices of proprietary pharmaceuticals have little to do with the cost of manufacture.

Financial analysts expect that the manufacturer of AZT, Burroughs Wellcome, has priced the drug at three times its
usual profit margin and will make $100 million or more profit from AZT alone within the next year, providing no competitor
becomes available. The only other AIDS antiviral which has advanced far enough in the regulatory process for possible U.S. approval within a year is ribavirin. Since hundreds of millions of dollars could rest on the FDA decision of whether or not to approve ribavirin, this decision might not be made solely on scientific and medical merit.

Another possible competitor, AL 721, is well over a year away from completing the steps required for FDA approval. AL 721 is entirely safe; in fact it could legally qualify as a food. It appears to be effective for most patients, but we are
far from having conclusive proof because so little testing has been done -- even though AL 721 has existed for years, and been known to be effective against the AIDS virus since November 1985. The Israeli physician most experienced with AL 721 told this writer that there is no rational reason not to use it now. Yet allowing immediate use would break the rules -- and jeopardize hundreds of millions of dollars of AZT profits, as well as disrupting the business and financial planning which relied on the assurance that no AIDS antiviral except AZT or ribavirin could possibly be approved any time in the near future.

(There may be an alternative outcome for AL 721. Most informed persons known to this writer believe that the patent
on AL 721 is weak and could not survive a serious test in court. And since AL 721 legally qualifies as food, anyone
selling it as a nutritional supplement without medical claims could bypass the FDA entirely. The same name could not be used, but the list of ingredients on the generic products would leave no doubt.)

Another serious concern about Federal drug research and regulation is that U.S. government research agencies have licensing arrangements whereby they will receive royalties from the sale of some AIDS antivirals, but not others. Naturally these agencies are likely to champion the drugs in which they have a financial interest -- a serious conflict when the same agencies also control Federal research funds, which could assist in the development of their rivals. And since the FDA must work with the research agencies in deciding whether to grant drug approvals, the objectivity of the Federal regulatory process could also be affected. Any such conflicts of interest would be extremely serious because they could greatly delay the development and availability of AIDS treatments. This writer cannot personally conduct an adequate investigation of this matter, and suggests that others do so.

AIDS organizations have had no knowledge of research and regulatory issues and no influence on them, as they have refused to involve themselves with treatments not already approved by the FDA.


Alternative and Experimental Treatments

This article is the 28th in the author's series on AIDS/ARC treatments. Earlier articles covered such potential
medicines as AL 721, DNCB, lentinan, aerosol pentamidine, fu zheng, coenzyme Q, BHT, naltrexone, and ribavirin. How do these compare with AZT?

It seems clear that all of them are much safer than AZT. We know less about effectiveness, often much less, because
research hasn't been done. As with AZT, it appears that none of the alternatives is a cure. (Lentinan may have produced a cure in the only case reported; the patient became antibody negative and is healthy three years later. Unfortunately this research, which was published over two years ago, was not followed up. There are now solid rumors of secret corporate research in the United States, and reports of recent clinical trials in Japan. We are seeking more information.)

While none of the above treatments has been proven effective, all are plausible options which might work; most
have little risk. Most can be used in combination, so using one does not rule out other treatment options. The problem is that physicians are seldom familiar with unapproved treatments. Physicians get most of their information about new treatments from drug companies, which are forbidden to tell them about new drugs (or new uses for existing drugs) not already approved by the FDA.

A critical issue now is how to advise persons who are antibody positive, but otherwise healthy or not seriously ill.
Recent statistics have shown that most of those who are antibody positive will eventually develop AIDS or ARC if left
untreated; the risk increases greatly five years after infection. Unfortunately it takes a long time to get good scientific data on preventive treatments, since it is necessary to wait for months or years to see how many of those who are
treated become ill. We don't have the time.

There is a rational approach. Almost all treatments for infection work best in the early stages. Therefore, any safe
treatments which are plausible to use in the later stages of the disease are likely to be plausible as preventives, also.
Why not try harmless treatments like AL 721, lentinan, naltrexone, or imuthiol, where safety is well known, even though we do not have final proof that they work? Even if none works, little harm will have been done; if only one works, that is enough.

The central problem is lack of leadership in getting the safe, plausible treatments available now into widespread,
scientifically appropriate use. The commercial forces driving AIDS treatment research favor high-tech, patentable options -- the very ones which take longest to develop. Simple, available, off-the-shelf treatments, already well known in
human use, could be applied much more quickly; but these kinds of treatments have little commercial potential. And the
champions of the commercial treatments are working hard to shut out each other, as well as anything else which threatens their markets. We can expect less tolerance for alternatives now that there is an official treatment for sale.

Almost all AIDS organizations have completely ignored the politically dangerous area of unapproved treatments. As a result, patients have had no representation or advocacy in treatment research decisions. Grassroots movements like the guerilla clinics have developed without mainstream support.

We are now facing the expected deaths of up to a million or more Americans -- even if all further spread of the virus
could be stopped today. Many improvements but no miracles are about to come out of the research pipeline. There is no excuse for ignoring safe, available, inexpensive treatments, admittedly unproven but supported by all existing evidence, just because they are unpatentable or otherwise lack the profit potential to drive them through the multi-year, multi-million- dollar Federal drug approval process.


AZT Notes

Many researchers suspect that low-dose AZT combined with oral acyclovir may be more effective and less toxic than AZT alone -- and probably much less expensive. But few physicians will prescribe this treatment, as only laboratory results have been published and there are no clinical studies to show safety and effectiveness. At this time the combination is in "phase I" clinical trial, meaning testing for dosage and safety.

Anyone investigating either the medical merits of AZT or the pricing issue should know that the history of the drug has
been edited in a way favorable to the interests of the manufacturer. Most scientists and others believe that antiviral work on AZT started in 1984. In fact, AZT was repeatedly studied for antiviral effects in the 1970s, and apparently given up as too toxic at the high laboratory concentrations tested. Recent papers on AZT blacked out all reference to the earlier work. This writer discovered the missing science by accident during a computer search. (Researchers can find it through two papers by Krieg, Ostertag and others in Experimental Cell Research, volume 116, 1978.)

For more information on treatments mentioned in this article, contact the author at P.O. Box 411256, San Francisco, CA 94141, or call 800-TREAT-1-2.