COULD YOU GET AZT?

Update 1989: Naturally much has changed on AZT since November 1986. These early articles are mainly of historical interest.

The third human drug trial of AZT is beginning now. About half of people with AIDS will be allowed to use AZT in this trial. The rules about who can and cannot get AZT can seem bizarre; and physicians are not allowed to override them even when urgently necessary for the best interest of the patient. We here reprint the entire patient selection criteria, normally sent
only to physicians, so that you can tell in advance whether you or a friend probably would or would not be allowed to use AZT at this time. And we spotlight some urgent ethical issues of this trial, and what the community can do to promote more rational and humane treatment development in the future.

Note:

* This article looks at who has the option to use AZT, not whether it is wise to do so. Surprisingly few patients have chosen to sign up so far.

This author's bias is to favor AZT, but with strong reservations. It clearly has saved lives; the latest statistics (November 12) are three deaths in the AZT group, in the double- blind study just completed, compared to 30 with the placebo. AZT can cause serious side effects; about 25 percent of the patients who have received it so far have needed at least one blood
transfusion, often many transfusions. Doctors and scientists are seriously concerned that there may be unknown long-term dangers, but no one has yet used AZT long enough to know whether there will be such problems or not. The drug is not a cure, but a treatment that needs to be continued indefinitely, until something better is available. We will knoiw more about AZT when
detailed results of the recently completed study are released.

* Anyone considering AZT should know about alternative AIDS treatments -- none of them yet recognized by U.S. medicine. Ribavirin is the closest to being recognized. Other articles by this author have documented five treatment possibilities with strong scientific indications taht they might be helpful, but with little medical attention or testing so far: these are DNCB,
AL 721, BHT, naltrexone, and glycyrrhizin. I reviewed these treatments because they have been largely unknown or ignored, and urgently deserve more attention.

In addition, persons with AIDS and ARC have tried many treatments including herbs, other Chinese medical approaches, vitamins, nutrition, exercise, and healthy emotions and attitudes. Typically, those who have survived in reasonably good health for three years or longer after an AIDS diagnosis have tried many different approaches and put together their own
individual programs out of the ones that worked for them. You can learn moire about these alternatives through organizations such as the San Francisco AIDS Alternative Healing Project (an organization that refers people with AIDS or ARC to holistic practitioners or to relevant books and articles. A new book, Psychoimmunity and the Healing Process (edited by Jason Serinus,
published by Celestial Arts) discusses many of these options.

* The rules on who can get AZT apply only to the current study. There will be other studies, with different rules. And when AZT is licensed, physicians will be able to prescribe it whenever it is in their patients' best interest.

We have heard reports that better forms of AZT, equally effective but much less toxic, have been developed but not yet tested on humans; the decision may be to rush these through testing instead of making AZT itself generally available. If these reports are true, the bad side of the good news is that licensing could be delayed.

* The current study will not use a placebo; everyone will get AZT. Some future studies probably will use a placebo, usually for patients less severely ill, probably to see whether the benefits of AZT as an AIDS preventive outweigh its side effects and dangers.

* Although the current study provides the AZT without charge, patients will still be billed for visits, for required lab tests, and for any treatments required for side effects caused by the AZT. Insurance companies might not pay these costs, because the treatment is considered experimental.

At a public forum on AZT, sponsored by Mobilization Against AIDS in San Francisco, Paul Volberding, M.D., chief of the AIDS Activities Division at San Francisco General Hospital and one of the foremost experts on AZT and on the treatment of AIDS, said that MediCal would pay for these costs for persons with AIDS (ARC is a separate problem). He thought that other states would pay through comparable programs (all these programs
are tied to Federal standards). He thought it was likely that private insurance companies would be willing to pay, when they realized that the alternative would be to pay much greater costs due to the progression of AIDS.

When AZT is licensed, it will be available through physicians without arbitrary restrictions, but it will no longer be free. Probably it will be very expensive.

Who Can Get AZT Now?

Physicians who want to use AZT must obtain a packet of instructions and paperwork; they can get this information by calling the AZT hotline. Anyone can call for AZT information, but the packet sent to non-physicians contains little detailed information.

Here are the patient selection rules, sent to physicians:

3.0 Patient Selection

3.1 Inclusion Criteria

3.12 AIDS patients who have recovered from one or more episodes of histologically confirmed pneumocystis carinii pneumonia without AIDS-defining condition(s) (see MMWR May 23, 1986) presently requiring systemic chemotherapy.

3.13 All patients must have Karnofsky performance status >= 60 at entry.

3.14 Laboratory parameters -- All patients will have the following present at entry:

a. Total granulocyte count >= 1000/cubic milliliter

b. Hemoglobin >= 9.0 gm/dl

c. Platelet count >= 50,000

d. SGOT <= 3 times upper limit of normal value e. Serum creatinine <= 1.5 mg/dl. (or upper limit of normal)

f. Positive antibody for HTLV-III/LAV confirmed by any federally licensed ELISA test kit.

3.2 Exclusion Criteria

3.21 Patients younger than 12 years of age.

3.22 Pregnant women, nursing mothers or women of childbearing potential not employing barrier contraception or abstinence.

3.23 Patients receiving any potentially myelosuppressive drug (such as trimethoprim-sulfamethoxazole (Septra -- ed.), pyrimethamine-sulfa or DHPG), nephrotoxic agent (such as amphotericin B or aminoglycosides), or cytotoxic or other experimental chemotherapy for any reason.

There is no section 3.11 [nor 3.14 e].

Comments on Patient Selection

* Persons with ARC are excluded, even though they were included as part of the last study. This decision might be due to limited supplies of the drug; we have heard conflicting reports on whether or not there are supply problems.

It is possible that persons with ARC benefitted less from AZT than persons with AIDS, in the last trial. We don't know because very little of the results have yet been released. We have heard that while AZT greatly reduced the death rate compared to the placebo, it had only a small effect on the number of opportunistic infections, and was not very good either at getting
rid of the virus or at restoring the immune system.

* Persons with KS but not pneumocystis are excluded. Again we don't know why, although in the very earliest test, with 19 patients, AZT seemed less helpful for the 5 patients with KS.

A new study now being planned will test AZT on some persons with KS. The plans call for using low and high dose groups, and a placebo.

* The blood counts are apparently required because a prominent side effect, in some patients, is a reduction in these counts, probably due to bone-marrow damage.

But even with rational medical justification, these rules still presents ethical problems. They demand a blanket exclusion which ignores everything about the individual case, shutting the patient and the physician out of any role in the decision.

Children and the Disabled

The inocuous-sounding "Karnofsky performance status" rule (in the exclusion criteria) excludes anyone ill enough to be disabled. The Karnofsky scale rates how sick a person is; it goes from 100 (no evidence of disease) to zero (dead). The level 60, required to get AZT in this trial, is "requires occasional assistance but is able to care for most of his needs." Anyone
more seriously ill cannot get AZT at this time.

It is hard to find any medical grounds for this exclusion. AZT has shown good results in people who have been seriously ill. These are the people who have the most need for the drug and the most reason to risk its dangers.

Volberding thought that one reason for excluding the seriously ill might have been fear of biasing the study. If people took AZT and died anyway, the licensing authority might think that AZT had killed them.

(We would suggest separate categories in the study to avoid that problem, essentially giving AZT on a compassionate basis to those will now be excluded because they are too ill. But it looks like the real bottom line is cost, as the manufacturer would be paying to provide the drug without getting back the data it wanted to support licensing. Regulations do not
allow patients themselves to reimburse this cost.) The automatic exclusion of children also makes no sense from the viewpoint of patients' welfare. It may stem from scientific and administrative convenience. AIDS is different in infants, so their results might need to be analyzed separately. And including children would force dosage to be calculated by body
weight, whereas the current study gives the same dose to everyone, allowing all the pills to be the same.

Whatever the reasons for these exclusions, an all-too- obvious political reality makes it easier to get away with them. The disabled are too ill to organize much protest in their behalf. And of children with AIDS, 80 percent are black or Hispanic, often of impoverished parents who acquired AIDS from needles. These parents are unlikely to generate effective protest or political pressure for their children.

Humane Treatment and Medical Ethics

The handling of AZT shows how patients are treated when the medical-regulatory system completely controls the only recognized promising treatment for a deadly disease.

* Life and death decisions are simply announced with no input whatsoever from most of the persons affected, or their physicians.

* Secret plans go through secret regulatory review, then get approved as a unit. Therefore short of an act of Congress, it is seldom possible to negotiate any change after the plans become public. Too many different organizations would have to sign off on the change.

* The decisions of who does or does not get experimental drugs are not made primarily for the patients' benefit, but for the convenience of those most influential in the conduct of the trials. Corporate profit comes first, since without the money incentive the tests would never happen at all. Then come the needs for institutional and administrative convenience, clean data, and elegant science (whether necessary or not for the
emergency at hand). All these take priority over getting the medicine to persons who need it.

* During the placebo trials recently completed, a serious, repeated argument for denying AZT to ten thousand people with AIDS was to force a few hundred into the placebo study as their only chance to get the drug (Discover magazine, August 1986, p. 78). Experimenters feared that they wouldn't have subjects if people could get AZT any other way.

* Congress appropriated 47 million dollars to make AZT available to people with AIDS. But only about half of them will be able to get it. Did Congress intend that children under 12, and anyone ill enough to be disabled, would be automatically excluded from receiving AZT? * Where did the money go? Burroughs-Wellcome says that AZT is very expensive to produce.
Maybe so -- but without a public accounting, we cannot know.

The "cost" of a project like this, carried out within the ongoing operations of a large organization, can easily depend more on accounting decisions than anything else. For example, capital expenses such as plant construction may serve both this and other projects; how do they get allocated? Chemical companies often do batch runs which in a few days may produce a
year's supply of a substance -- leaving the equipment free for other uses the rest of the time.

* The real information usually gets withheld from the public, which instead gets whatever PR insiders choose to put out. For example, people are deciding whether or not to sign up for AZT, and at this time they cannot now get the results of the study just completed. These results should be released immediately, not wait for publication delays so that some medical journal can enhance its reputation.

What Can We Do?

* Organizations can influence treatment policy, and they need our support.

For one example, take Mobilization Against AIDS (MAA), which organized the recent public forum with Volberding. According to Paul Boneberg of MAA, in July 1985 they were the only organization to call for a massive increase of Federal AIDS research funding to 500 million dollars in fiscal year 1987 (beginning October 1986). MAA successfully converted the other
AIDS organizations, and then many members of Congress, to support massive increases.

The House Budget Committee scheduled hearings in five cities, and AIDS was not on the agenda. In four of those cities, the local AIDS organizations did not know that the hearings were coming. MAA got themj to organize an AIDS presence at the hearings, and call for the 500 million.

In January of this year professional lobbyists were saying that massive increases for AIDS research were impossible because of the budget crisis, and that it would be a miracle to avoid cuts. Friends in Congress thought it was irresponsible to demand the impossible from them. But Congressional committees discussed amounts from 500 million down. And the final result
was over 400 million dollars appropriated for the current fiscal year, up from about 220 million the year before.

This victory represents the work of many people and organizations. The unique contribution of MAA was to put the massive increases on the agenda. You can help in future projects by contacting Mobilization Against AIDS and offering your support.

* The best way you can contribute is to get involved in the organization or project of your choice, enough to learn what is going on. Financial support is urgently needed; and since AIDS organizations are typically very efficient in their use of funds, your contribution can go a long way.

* The recent report of the National Academy of Sciences, entitled "Confronting AIDS," is a milestone in the development of a serious national commitment against AIDS. We can all work to make sure that its recommendations are followed. (A copy of the report can be ordered from the National Academy of Sciences.)

* Today we are seeing the beginnings of a sensible attitude toward AIDS in the national mainstream -- reflected, for example, in the Surgeon General's report, the recent CBS documentary, and the National Academy of Sciences report mentioned above. Still needed, though, is a humane and rational approach to treatment development. Persons with AIDS or ARC, and their physicians, need much more influence in the conduct of
human trials, so that the interest of the patient will be represented.

* Perhaps we could form alliances with those concerned with other diseases, such as Alzheimer's, on treatment issues. Alzheimer's disease is as severe as AIDS, and affects millions of people. Recently a major breakthrough discovered an effective treatment (not a cure), but red tape threatens to delay it for years. The discoverers are still trying to get a patent on
pharmaceutical use of the chemical -- which has been known for decades -- so that some drug company will get interested and then begin the long process of obtaining Federal approval. Nothing can justify so cruel and unworkable an approach to providing treatments for a fatal disease.

We also need a national commitment to test the simple AIDS treatment possibilities like DNCB and BHT -- relatively safe, well known in human use, inexpensive, easy to use, readily available or easy to manufacture, unproven because they have not been well tested, but overwhelmingly supported by all available information as likely to be helpful, although not a magic cure.

As AIDS becomes a mainstream issue, the gay community will have a crucial role in pointing out what is actually going on, and making sure that the newly-minted institutional commitment gets translated into effective action.