Dextran Sulfate, Imuthiol (DTC) and "Alternative" Trials: Conversations With Donald Abrams, M.D. -- Part II

Part I of this interview (SF Sentinel, April 8) concerned the activities and plans of the County Community Consortium.
Part II concerns dextran sulfate, imuthiol, and other clinical trials at San Francisco General Hospital in which Dr. Abrams
has been an investigator.

Dextran Sulfate

JJ: How did the dextran sulfate trial get started?
DA: After the II International Conference on AIDS (Paris, June 1986) I went to a conference in Japan to do a
presentation, and at that time I was introduced to two people from Ueno Fine Chemical Company in Japan who thought they had something with potential anti-HIV activity in the laboratory. Normally I get mail from people who have the cure for AIDS every day; if I listened to all of them I would spend all my time listening and corresponding with these people.
But the Ueno people showed me a graph of data from Dr. Samuel Broder's lab at NIH, which had some of the preliminary studies on dextran sulfate. And they asked me if I was interested in helping them bring this drug to the U.S. for testing in a carefully controlled phase I trial. They were a chemical company and had no experience doing clinical research. I said, let's do it.
They wouldn't tell me the name of the compound, they said it was confidential and they wanted to make sure I really was going to collaborate, so they gave me the code name, UA001. I wrote a protocol with an unknown substance, using the model of what a phase I study is. Just because something works in a test tube doesn't mean it's going to work in human beings. So what we do when we take a drug that's new is see what its tolerances and toxicities are.
They said that this substance had been used in Japan for 20 years, but unfortunately there was no real background data. Our FDA has some baseline requirements before they allow people to buy and take a prescribed drug, and I think that's there to protect us. I'm not concerned about our FDA. I think that sometimes they can be a little bit much, but overall they are here to protect the consumer.
So I wrote the protocol. We did have a lot of communication between us and the FDA with regard to eligibility, who should be on it, and how to keep the study absolutely pure and make sure the patients were only taking this substance. We needed a group of patients in whom we could really measure the effects of UA001 on their systems.
In a phase I study you just give increasing dosages to see what the maximum dose is. When you find that, then you can see if the drug has any effectiveness. That's called the phase II study, when you're looking for effectiveness. Sometimes with AIDS these two phases are combined, into a phase I/phase II trial.
Then they told me that UA001 was dextran sulfate, and we began a study. I mentioned it to a few people here, and they said it's a non-specific antiviral that they use in culture media; it prevents viruses from entering cells in the culture
media. But it's a large polymer; if you take it by mouth it will be digested and it won't be the same substance that they're using in the test tube that will get to HIV-infected cells, because the body will digest it or won't absorb it, because it's too large a molecule. It could not be pharmaceutically effective, they said, because it has a molecular weight of seven to eight thousand and would not enter cells. People were skeptical, saying this would never work, don't do it.
But we had a study. Recruitment was slow, however, because most people were using AZT, and didn't want to give it
up.
Since we were testing doses that were higher than people ever take in Japan, the FDA required patients to be on the low doses for two weeks (a month at the higher doses) before we could start the next group on the next higher dose.
After a while, people heard that we were testing dextran sulfate, just as people heard that we were testing DTC and
started obtaining DTC by their own means and taking it as well. It seems like every time we try to study something, people think that because it's being studied maybe it's the cure. Or people read the scientific literature about what it does in the test tube.
Here we are doing our dextran sulfate study, and suddenly it's all over the streets. We're told that patients on our
lowest dosages might not be taking the dose that we think they're taking.
We have seen some toxic effects of this drug, especially in patients taking the highest dose.
We are conducting an eight-week study, not using a placebo, but using escalating doses instead. And to be fair to patients who participated for the eight weeks, we let them continue their dose after that if they can tolerate it. Studies don't always do that; but we want to be thankful to our people who are participating, and also gain some information as
to the longer term safety, tolerance, and efficacy of the drug. Eight weeks is a good time to observe for toxicity, but seeing if something works may take longer.
After the eight weeks, we monitor the patients who choose to continue using the drug just as we did during the eight
weeks. But now we learn that some of the people we started to see toxic effects on, at what we thought was the lowest dose, may actually be taking what we're giving them plus some more they're getting on the street. So how can we make any statement now about toxicities or the side effects of this particular dose, when the people that we think are taking it
aren't? A bit of a problem.
JJ: It is a problem. But looking at it from another point of view, it's not right to keep thousands of people from taking
something so that a few can be forced into a study. The approach, then, would be to find people who don't have a strong feeling one way or another about the drug, they're in it not because it's the only way they can get the drug, but they're in it for the free blood work...
DA: Why would thousands of people want to take something if it doesn't work or if it's toxic? This is the same argument we went through with suramin. People demanded that we make suramin available to everybody, and it killed people. If you don't study it, how are you going to know if it does anything or if it's harmful or helpful?
JJ: What about the controversy over whether the oral drug you are using could get into the bloodstream? Why is there any question when this drug has been used orally for 20 years in Japan?
DA: Our phase I study also drew blood from patients so that we could measure the drug, to demonstrate that it got into
the bloodstream. My Japanese collaborators have not been able to demonstrate that this drug has entered into the bloodstream of my patients taking it.
They showed me from healthy people in Japan that they were able to demonstrate that the drug entered the system after being swallowed. But you cannot import HIV-infected blood into Japan. Ueno's researchers took 50 specimens back with them to Japan in January. They tried to get somebody here to do the measuring, but they couldn't find anybody to perform the test satisfactorily.
They had to heat-inactivate the specimens (to legally take them into Japan for testing). By doing that they precipitated the dextran sulfate with the plasma, so they were unable to find it. So there is no evidence that drug is absorbed into anybody's bloodstream, at this point in time, to convince to anybody's satisfaction that there is oral bioavailability.
JJ: I don't understand. People have been using this drug orally for 20 years in Japan. How could it not be absorbed?
DA: The drug isn't licensed in the United States for the same indications.
JJ: You say in Japan they found it got in the bloodstream?
DA: From three healthy volunteers. I've learned to be cautious. I'd like to know what the levels are in my patients.
We've been doing the study now for almost a year and we haven't found any laboratory here (to measure it in the blood). It's a stumbling block.
JJ: What groups of patients enrolled in the dextran sulfate trial?
The patients enrolled mostly had lymphadenopathy. The reason that it's weighted toward these patients is that the
eligibility criteria said they could be on no other medications, because we want to see the effects of dextran sulfate. And it's hard to find a patient with AIDS who isn't taking something. So there are only four people with AIDS in the entire trial. The FDA wants to see what this drug does by itself.
I looked for patients who had a greater then 20 percent increase in their T-helper number from week zero to week eight, and that was one third of the low-dose groups. (The high-dose groups have not yet had their blood work done, so they are not included in this result.) Without a placebo we don't know how many would have shown that increase without treatment.
JJ: As you know, there is a rumor that you were responsible for making it hard for Americans to buy dextran
sulfate. I have never seen evidence for this rumor. Do you want to say anything to clarify the situation?
DA: It's so upsetting to me. When in the course of my day did I have time to deal with whatever agencies are
necessary to block importation of agents into countries? I don't know where this rumor came from. I've heard that it's
very widespread, nationwide, that I am some sort of an ogre who set up roadblocks at borders. How am I so powerful?
JJ: People assumed you must have called Ueno, and Ueno had a way with the Japanese companies to get them to stop selling to Americans, in order to support their trial. That's what some people believe.
DA: We're working together, and they (Ueno) realized that the drug was flooding the market. Whatever happened happened, and I don't know how I could have any control over this. I was told that a patient was trying to bring dextran sulfate in, and also DTC, across the border from Mexico and was allowed to bring his DTC but was told he couldn't bring dextran because there's a study being done in San Francisco. I hear about these things second hand.
JJ: What future plans do you have to study dextran sulfate?
DA: I told the AIDS Clinical Trials Group (at NIH) that I wanted to present a phase II study to evaluate the
antiretroviral activity of dextran sulfate in patients who are P24 antigen positive. The P24 test is what they want now as a
criterion for their studies. I said let's extend this study for six months, no placebo, to get this information.
In the meantime I've asked the Japanese to get me an intravenous preparation of the drug, and I've submitted to the
FDA the protocol we wrote.
Robbie Wong and myself wrote a pharmacology study, intravenous vs oral. We'll measure the levels after an IV dose and compare it to an oral dose.
Also I've just written a protocol for a combination of dextran sulfate and AZT, which we're going to do here.
For me it remains a compound that has some interest, especially because it appears to have a different mechanism of action compared to the other antiretroviral agents, in the test tube.

The Imuthiol (DTC) Study: Why No Results Yet?

Note: We reported on the imuthiol study over a year ago (SF Sentinel April 10, 1987). The San Francisco General
Hospital arm of the study has long been finished. Many people are concerned that the results have not yet been released.
Dr. Abrams discussed this question on several occasions. We summarized the conversations, adding background information to clarify the matter for our readers.
* The imuthiol clinical trial is sponsored and financed by the drug's manufacturer, Institut Merieux, in Lyon, France.
Several U.S. medical centers conducted this placebo-controlled trial.
* Some of the centers were unable to recruit their full quota of patients. As a result, San Francisco General Hospital
was asked to recruit more patients, and did so.
* When there still weren't enough patients, Merieux added two new centers, at Key West, Florida, and Downstate Medical Center in Brooklyn, NY. It naturally took time to set up the program at these centers. (And we heard from another physician--not Dr. Abrams--that at least one of the new centers had serious delays in recruiting.) Some patients are just now starting the trial, meaning that they will not complete it for six months.
* So far Merieux has chosen not to release preliminary data, but to wait until all patients are finished at all
centers, despite repeated pleas from Dr. Abrams. (San Francisco General Hospital does not have the data except from
its own patients, and it does not know which of them were on the placebo.)
* To make the best of the situation, Dr. Abrams asked Merieux to supply additional imuthiol so that patients
finishing the trial could go on "open label", receiving the drug if they chose--whether or not they had been on placebo
originally. Merieux agreed. So these patients are obtaining treatment, and long-term data is being accumulated.
* The larger problem is that physicians and persons with AIDS do not have information they need to make treatment
decisions. And other scientists, even the leading researchers at NIH, do not know how to prioritize DTC for future studies. Dr. Abrams has urged the company to do a preliminary analysis, even if it does not choose to unblind the study (by telling which patients got the placebo). We do not know when results may be released.
"We went to a meeting (with Merieux) in San Diego last Tuesday. I used your story (SF Sentinel, April 8 1988) to take
up to the scientific directors, and said, this is a problem, you have not lived up to your part of the bargain, we have had
patients on this trial for over a year now and there is no cracking of the code, we're dragging our feet, and we are losing the respect of our community that we need to participate in these trials."
At that meeting, Merieux also gave Dr. Abrams its view of whether the prescription drug antabuse would be an effective substitute for imuthiol. The company has a strong interest in this question, because if the answer is yes, then the imuthiol they have been developing for several years may have little commercial value.
"The Merieux people are quite adamant that they have all the data they need to demonstrate that antabuse does not break down into DTC (imuthiol). Robert Gorter (a physician at San Francisco General who worked with Dr. Abrams on the imuthiol trial) is going to try to pursue that further, because it differs from his understanding.
"I told you before about my skepticism about drug companies. That skepticism is important."
Meanwhile, what could be said about DTC, before we have the data?
Dr. Abrams seems happy with the results. There have been surprisingly few deaths in the study, and the patients seem to be doing well.

"Alternative" Treatment Trials: A Hidden History

We learned recently that Dr. Abrams has designed and often conducted a number of clinical trials largely unknown to the AIDS community. Some of these trials tested "alternative" treatments, that is, those initiated by patients themselves
rather than by drug companies or the National Institutes of Health. Dr. Abrams approached these treatments neither as a believer nor disbeliever, but as an investigator who felt that substances people were using deserved scientific study to find out whether they worked or not.
Here is an annotated list of protocols (some for alternative treatments) designed, co-designed or conducted by
Dr. Abrams:

Interferon alpha (1984). This trial involved 18 patients, half on placebo. Dr. Abrams presented the results at the II
International Conference on AIDS (Paris, June 1986), but did not publish them, because the study did not find much; on the whole, patients on the drug did no better than those on the placebo. One of the treatment patients is been a long-time survivor and is still taking the interferon, however.
"Now the wheel has come full circle almost, and Tony Fauci (at NIH) is treating asymptomatic seropositives with interferon alpha."

Isoprinosine (1985). Dr. Abrams became one of the investigators in a multi-centered trial of isoprinosine.
"I did it because there was a lot of interest in the community in isoprinosine. I knew people were going to Mexico
to get it. I knew it was an antiviral and decided to look at it with a placebo-controlled trial.
"We put 24 patients on the trial very quickly. People knew they might get a placebo, but they were taking it only for
one month. Then we followed them for three months.
"I participated, not believing that this was going to be the miracle cure, but to confirm the original data that was
coming from New York, data that was getting people excited. We wanted to see if this drug was worth pursuing.
"But while the study was in progress the drug company got itself into some difficulty by making claims about the drug
that could not be supported."
Due to the political controversy and confusion, Dr. Abrams (and the patients and the public) never learned the results of that trial--not even today, three years later.

Vitamin C (1985). "Through personal friends and acquaintances I met some of the early people who felt that
vitamin C was part of the answer. These contacts in the community put me in touch with investigators at the Linus
Pauling Institute. For a year I informed them about AIDS, and they informed me about their results with vitamin C in cancer patients. We decided what dosage we would try.
"We wrote a protocol and sent it to NIH. We worked for a year and a half trying to get this study funded someplace. The government didn't want it. So we submitted it to the Universitywide Task Force On AIDS, but their reviewers didn't
think it was worth investing in, so we didn't do the study.
"In the meantime, unfortunately, most of the people who helped me realize that the community wanted to look at vitamin C had died of the disease. So it became clear to me that it probably wasn't a cure."

Relaxation and imagery (1986). "There was a movement a few years ago saying that relaxation and positive thinking,
such as the Simonton approach, was the cure. There was a patient written up in the Sunday paper who reportedly was cured of AIDS through positive thinking. Now he has died of the disease, but at that time there was more interest in it.
"I said, OK, nothing I have is the answer, so I'm willing to investigate it. I wrote a study with Inge Corless, who was
a postdoctoral nurse with the Robert Woods Johnson program.
"We did a controlled trial. For six weeks half of the patients were just followed by me in the clinic, the other half
were seen intensively by Inge Corless. She did a program composed of relaxation, imagery, and therapeutic touch.
"We investigated its effects on platelet counts, helper suppressor ratio, and adrenal function. We found no particular
change in these parameters, but patients in the intervention group were less stressed, and had better psychological
adjustment scores.
"This study, as most of the studies I've been involved in, was not funded by any granting agency; it's something I did
because it's an alternative approach that may have some foundation in reality, but it needs to be tested."

Ribavirin (1985). "I felt we should look at ribavirin as well, because so many people were going to Mexico to get it.
For the same reason: if this works, we should know about it; and we're not going to know about it unless we do a controlled study.
"You know the ribavirin mixup?" (Part of this long and controversial story appeared recently in the Wall Street
Journal--April 13, 1988, "Shop Talk" column, page 31).
"I was only peripherally involved in the ribavirin study."

Chinese medicine (1988). Dr. Abrams is working with Barbara Bernie, president of the American Foundation of
Traditional Chinese Medicine. "This study will evaluate certain herbal treatments, breathing exercises, and other
traditional Chinese medical interventions. Since it is currently not funded, and staffing is required for monitoring at the AIDS Clinic, the logistics are becoming difficult. Hopefully we can work something out in the near future."

DNCB. Within the last month Dr. Abrams has worked with Elswood, of the grass-roots DNCB movement in San Francisco, to write a protocol for a scientific test of this AIDS treatment which has been used by thousands of people through "guerilla clinics". He just sent the protocol to the FDA. Even if the FDA approves the study, funding must still be found. Funding may be a problem because DNCB is not patentable so no drug company has any incentive to investigate it; and NIH has not been interested.

Consortium studies. Dr. Abrams is also involved with several studies planned by the County Community Consortium in San Francisco. Their aerosol pentamidine study, which is already in operation, was described at length in part I of this interview.
Other studies now in preparation include:
* An alternative treatment registry. Private-practice physicians will work with their patients to monitor whatever
they are trying, whether or not prescribed by a physician. If the researchers see any trend in either clinical, virologic, or
immunological parameters, the treatments which may be responsible can be studied with more control.
* A zidovudine registry. This will monitor long-term side effects and benefits from AZT (zidovudine).
* A study of prophylaxis against MAI.
* An attempt to alleviate anemia caused by AZT.