PML Treatment Update, Peptide T Possibility

PML (progressive multifocal leukoencephalopathy) is a brain infection caused by a virus, the JC virus. It is relatively rare, diagnosed in only about one percent of people with AIDS. But many cases are misdiagnosed, usually as toxoplasmosis or lymphoma. While PML most often occurs in late-stage AIDS, it can also be found in persons with a relatively high T-helper count; and it can be the first AIDS-related condition diagnosed.

There is no cure for PML, and there are no FDA-approved treatments; therefore, persons who are diagnosed are often told by their doctors that there is no treatment, and that they will die in weeks or months. In fact, there are experimental or possible treatments; and a number of people with PML have stabilized or improved, and have lived relatively healthy lives for years. The treatments remain uncertain, however, because controlled trials have not been done.

The best single source of information on PML treatments is a privately-published book, Progressive Multifocal Leukoencephalopathy (PML): Case Studies and Potential Treatments, by Peter and Lisa Brosnan; the latest edition was printed in July 1993 (see below for how to obtain a copy). The authors are not physicians or medical specialists. Lisa's brother was diagnosed with PML in 1988, and the Brosnans started searching the medical literature for possible treatments. Lisa's brother died in a month, however, before treatment could be started; the Brosnans continued their work, to make the information available to others. Because the disease can progress rapidly, it is important to start treatment as soon as possible.

The book includes a brief description of PML, discussion of treatments which have been tried (ARA-C, or a combination of two or more of: acyclovir, heparin, interferon, NAC, and dexamethasone), and mention of possible treatments which apparently have not yet been tried in people but have some theoretical or laboratory rationale (foscarnet, ganciclovir, isoprinosine, and camptothecin derivatives such as topotecan). Recent anecdotal reports about peptide T arrived too late to be included in the current printing; they are discussed in the interview below.

The book also includes:

* Fifteen case studies, most from medical journals, but some collected by the authors;

* A survey of 21 people with PML, compiled by the authors;

* A resource section, including contact information for leading PML experts your physician can call;

* Over two dozen articles and abstracts from the medical literature, AIDS newsletters, and elsewhere, and references to other articles.

For the most recent information, AIDS TREATMENT NEWS interviewed co-author Peter Brosnan.

Interview with Peter Brosnan:

AIDS TREATMENT NEWS: What is the most important message for our readers?

Brosnan: That there are treatments for PML. I continually hear from people who have been diagnosed with PML and told that there are no treatments. That makes me angry. There are treatments. There are no cures, but there is a wide range of drugs now that have shown themselves to be effective in at least some cases. They are readily available. All the evidence indicates that if treatment is going to be successful, it must be started early and aggressively. And there are a number of treatments to choose from.

ATN: ARA-C (or its relative, ARA-A) is the treatment with the most mainstream medical support, but it also may be the most dangerous -- and there have been no controlled trials. What does the current information suggest?

Brosnan: The jury is still out on ARA-C. I understand that a trial will be starting shortly, comparing intrathecal to intravenous ARA-C. It does seem to help in many cases. In other cases, however, especially intravenously, it can be very dangerous. In somebody who did not have AIDS, it would probably be immediately recommended. In somebody whose immune system or overall health is already compromised, it should be considered very cautiously, I think.

ATN: Do people without immune deficiencies get PML?

Brosnan: Very rarely. Before AIDS, it was usually seen in chemotherapy patients, and those who needed to take immune- suppressive drugs because they had organ transplants. Contagion is not an issue, since almost everybody has the virus already; the immune system keeps it in check.

ATN: You mentioned a number of possible PML treatments that have been tried, alone or in combination: acyclovir, heparin, interferon, dexamethasone, and NAC. What can you say about them?

Brosnan: Acyclovir was a surprise to us when we first began doing this, six years ago. We began hearing more and more from people who claimed that their PML was either stabilized or in remission without any treatment at all. But when we questioned these people carefully, we found out over and over again that they had herpes and were being treated with acyclovir. I understand there are some basic similarities between the JC virus and the herpes virus. And we have seen many people now who seem to be responding to the acyclovir, especially at high oral doses, 2000 to 4000 mg per day.

Heparin [a drug usually used to prevent blood clotting] was first suggested by Dr. Sidney Houff, with the National Institutes of Health and the Veterans Administration near Washington, D.C. His theory was that the JC virus apparently has a receptor on the B lymphocytes, and it is these cells that transport the virus across the blood-brain barrier into the brain. Heparin seems to interfere with that transport, keeping the PML out of the brain. We have heard from a number of people who haven't gotten better, but their PML seemed to stabilize. The drug has few side effects.

Most of the people I have heard of who are using alpha interferon are combining it with something else, such as ddI or acyclovir. There do seem to have been some positive responses, and there are some instances in the medical literature in which either alpha or beta interferon has had a positive effect on PML. Beta interferon is in very short supply right now, after it has been approved for multiple sclerosis.

Multiple sclerosis, like PML, is a disease that destroys myelin. There is one encouraging case in the medical literature, from Japan, in which intrathecal beta interferon seemed to be very effective. As far as I know, that is the only time it has been used for PML.

NAC [n-acetylcysteine, not approved in the U.S. in oral form, but available in buyers' clubs and health-food stores] is listed because, for three or four years now, we have seen improvement of symptoms in people with PML who have taken NAC.

Dexamethasone is a steroid which decreases inflammation -- although it also suppresses the immune response. It is not a primary treatment, but may help with the symptoms in some cases.

The best results we've seen are from people using a combination of these drugs. Whether there is synergy [meaning that the drugs work unexpectedly well together], or whether these people just happened to hit the drug that is right for them, we don't know.

Peptide T

ATN: You mentioned peptide T -- which has long been a popular semi-underground treatment for some other AIDS-related neurological complications. The information is too recent to be included in your current book (third edition, July 1993), however. What are you hearing about it?

Brosnan: Peptide T is something we've had an eye on, ever since starting this in 1988, because it seemed very promising. But because of all the problems peptide T has encountered [political and commercial problems in its development, not problems with the drug itself], there has been little information until recently. Just in the last couple of months we have heard four or five reports of its use against PML, with what seemed in some cases to be promising results. I don't want to get too excited -- we have all seen these kinds of things come and go before. But it does seem very promising. And certainly it is a non-toxic substance.

ATN: Do you think peptide T may be giving only symptomatic relief?

Brosnan: We don't know if we are seeing treatment of symptoms, or treatment of the underlying problem. I am aware of a couple of people who seem to have been stabilized by it, for up to a year. If it were just treating the symptoms, I don't think that would have happened.

I've spoken to one neurologist who is familiar with both PML and peptide T. He sees a couple possibilities. Peptide T may itself be a neurotransmitter. It might also be a very strong anti-TNF factor. And TNF might be involved in demyelination [loss of the myelin sheath from nerve tissue, which happens in PML, and also in other diseases such as multiple sclerosis]. If that is the case, it would be an argument for peptide T directly affecting the PML, not only relieving symptoms.

ATN: You mentioned people stabilizing on peptide T for up to a year. Did they then get worse, or is there only one year's experience at this time?

Brosnan: A doctor in New York called me in March. She had a patient who had completely stabilized for one year after taking peptide T; but now he was beginning to show signs of progression, she was looking for a newer treatment. I believe all he was taking was AZT and peptide T. I have not been able to check up on what has happened since then.

In another case from New York, a man developed PML in the fall of 1993. By December he was unable to walk, and losing a lot of weight. He started taking peptide T, and by January he was fine. Then in February he ran out of money and had to stop taking the peptide T; he got worse. In March he started taking it again; he got better, and he seems to have stabilized.

A week ago I talked to a woman in Louisiana, whose husband has had PML for a year. He had not walked in a year; he had not been able to speak for six months. Two days after starting peptide T he took his first steps, and spoke his first complete sentence.

You don't want to get too excited. But I'd certainly like to see peptide T used more frequently, because it's something we need to look into.

ATN: We should point this out to community-based research groups. This is a study that could be done quickly, to get some more-than-anecdotal data, less affected by self- selection of the group of people who called you. There would be ethical concerns that would have to be addressed carefully in planning any trial. Would a control group be ethical? You could not ask people to avoid other PML treatments. Maybe the way to start would be to give peptide T to all study volunteers, in addition to their other treatments, and carefully collect uncontrolled data.

Brosnan: We have only seen a handful of cases. But it may be the most exciting development in several years, and I'd certainly like to see more studies done.

LTR Inhibitors

ATN: You briefly mentioned the experimental cancer treatments camptothecin and topotecan [the latter is a camptothecin derivative, engineered to have better pharmacologic properties than camptothecin]. AIDS TREATMENT NEWS has covered this class of drugs as potential HIV treatments -- they are in human trials for cancer, but as far as we know no one with HIV has ever taken any of them. In the laboratory these drugs inhibit the LTR (long terminal repeat) of HIV, forcing the virus to remain inactive. How did they come up in relation to PML?

Brosnan: Apparently there have been two separate, unpublished studies that show that these drugs cut off replication of the JC virus, when it is combined with ARA-C. We don't have details at this time.

Diagnosis Problems

Brosnan: I suspect that PML is being greatly underdiagnosed. There have been some consecutive autopsy studies from Europe, in which PML has been seen in from 7 to 18 percent of the people they autopsied. I suspect that some patients who are being unsuccessfully treated for toxoplasmosis are suffering from PML. About two thirds of the people I speak to who have PML were originally misdiagnosed as having toxo -- or strokes, or inner ear infections, but usually toxo. I wish more AIDS doctors would keep PML in the back of their mind as a possibility.

For More Information

You can obtain a copy of Progressive Multifocal Leukoencephalopathy (PML): Case Studies and Potential Treatments, from Peter Brosnan, 1709 N. Fuller Avenue, #25, Los Angeles, CA 90046. To cover his costs, he asks physicians and institutions to send $30, people with AIDS $20, and in cases of hardship he will send it free.

In an emergency, call Peter Brosnan at 213/874-7885, so he can send the book immediately.