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NOTES FROM THE UNDERGROUND
The PWA Health Group Newsletter
"Access to Information Precedes Access to Treatment"
December, 1993
Issue 23

Table of Contents

Michael Callen
1955-1993

Some kind of wonderful, Michael yes you are. Founded by Michael Callen in 1987, the People With AIDS Health Group, the nation's first buyers' club, salutes one of the most outrageously sexy and wise and courageous leaders of our generation, a beacon of hope and humor and eloquence, a passionate voice for the joy of sex and life and surviving in spite of it all. Michael, we cherish every bit of joy you gave us, and we rage against the insipid negligent response of a country all too willing to sacrifice its most brilliant sons and daughters. With great love and respect from the People With AIDS Health Group.

MEPRON Warning
by Sally Cooper and Theo Smart, (with thanks to Gayann Hall, MD, and Don Kotler, MD)

Burroughs Wellcome's new PCP drug, Mepron, also known as atovaquone or 566C80, was approved last year for use in patients with mild to moderate PCP who are intolerant to Bactrim/Septra. Unfortunately, many PWAs have trouble absorbing the drug and their PCP gets worse. In clinical studies, most of the people who failed on Mepron had lower levels of the drug in their blood. We've heard a number of reports about PWAs failing on this drug, and are worried that for an unknown number of people, taking Mepron might equal taking nothing at all.

The problem with absorption is threefold. First - Mepron needs to bind to fat to get absorbed at all, which means you need to make sure you have enough fat in your diet. Burroughs Wellcome originally suggested taking the drug with a high fat diet, which they define as at least 23 grams of fat per meal (2- 3 tablespoons plus of butter). Recently, the Burroughs Wellcome team changed their tune to say that an "average" diet probably provides enough fat for absorbing Mepron, apparently worried that the "high fat diet" requirement was scaring people away. The weighty PR questions aside, if you are taking Mepron, head for the Haagen Daz (or the more politically correct Ben and Jerry's) and don't hesitate to load up on butter. It could save your life.

But - second problem: there is no guarantee that a high fat diet will do the trick. For unknown reasons, some people still don't seem to absorb adequate levels of the drug. Who are these people and how do you know whether you're one of them? Right now, it's hard to say. Burroughs Wellcome has no answers, but has noted that patients with severe diarrhea don't do so well. Can you tell once you're taking Mepron if you're absorbing it well? No. Burroughs Wellcome has offered no tests for you or your doc by which to monitor your blood levels of Mepron once you're taking the drug. Asked if there were even any indirect tests, like elevated enzymes of some sort, that would indicate absorption - Burroughs Wellcome says no. If you take Mepron, monitor your symptoms closely. If you're using it for prophylaxis - don't ignore any dry coughs.

Problem #3 - Mepron gets absorbed over time. Some of the drug is absorbed shortly after you take it, but the bulk of the dose gets released by your liver later. This second release can happen any time from one to four days after you take the first pill. The result is that it can take six or seven days to get effective (PCP fighting) levels of the drug in your blood (if you have enough fat in your diet and you absorb fat well). During this time, your PCP may be progressing from "mild or moderate" to quite severe.

Mepron looks like a good oral drug, well tolerated (not nearly as toxic as iv pentamidine, for example) and very effective in most people. If you can absorb it, it's great to have an alternative, especially if you're allergic to Bactrim. What's scary is that taking it might do nothing for your PCP for several days, and possibly nothing for your PCP at all. So what can you do?

When taking Mepron:

Upping the ante
I suspect (and I'm pretty sure Burroughs Wellcome does too) that one Mepron problem is fat absorption. Many PWAs have problems absorbing fat. One symptom of poor fat absorption is severe diarrhea and since you need to absorb fat to absorb the drug...well, you do the math. If you can absorb Mepron, increasing your body's ability to absorb fat will help you absorb Mepron. On the other hand, if you have severe intestinal problems and can't absorb well, no amount of fat in your diet will help you absorb Mepron.

How do you know if you have trouble absorbing fat? If you're allergic to Bactrim/Septra, it would be useful to know. (It'd be good to know anyway, as lousy fat absorption is an awfully common cause of weight loss, and now there's weight gain products designed for people who can't absorb fat well.) Fat gets absorbed in your small intestine, and it's not easy to know unless you have some clear symptoms, like diarrhea. However, there are several studies documenting poor fat absorption in PWAs without either diarrhea and weight loss.

Unfortunately, there doesn't seem to be any readily available, accurate method for checking fat absorption. The most common way is to measure how much fat you are excreting, to put it as delicately as possible, by eating a regular fat content meal, and having your stool stained in a lab to measure the fat that slipped on through your system. This fecal stain test is quite imprecise. Other possible tests, including lipid levels, albumin to globulin ratios, total proteins, etc., need to be looked at within a broader context of how your small intestine, your liver, etc. are working, but can be indirect indicators of fat malabsorption.

If you can't absorb fat well, one thing to consider is taking Mepron with nutritional supplements made with easy- to- absorb fats, such as Liposorb or Isosource, or the simple fats themselves (the real thing) as in the Mead Johnson product, MCT Oil. These are available at drug stores without a prescription (see NOTES, #22). MCT Oil is sold in quart form only by Mead Johnson, and cheap it's not, running $70- 80/quart. Probably a script is a good idea. You may also absorb fat better if your diet includes essential fatty acids such as those found in flaxseed oil and fish oil, which you can find in health food stores. I asked Dr. Rogers, one of the Burroughs Wellcome docs, about taking Liposorb, and he thought it might help Mepron absorption, and mentioned that they were thinking of running a small study to see if that was true. Think on, Burroughs Wellcome, time's a- wasting.

One idea for coping with how long it may take to absorb sufficient levels of Mepron comes from an interesting little Burroughs Wellcome study mentioned at their community meetings lat fall. For a week or two they gave patients Mepron and Bactrim at the same time. The patients were all allergic to Bactrim, but since it usually takes a week or two for the rash to appear, most patients achieved effective levels of Mepron by the time their rash appeared (at which point they could safely stop taking Bactrim). The company hasn't evaluated other drugs with Mepron, and has no plans to do so in the near future.

The New Atovaquone
Last fall, Burroughs Wellcome's PR machine heard activist rumblings about Mepron breakthroughs and quickly scheduled a series of meetings. The centerpiece of these meetings was a new liquid formulation of the drug which they claim will be absorbed 2 to 3 times more than the current tablets. Well, great, but this formulation won't be available until the end of 1994 at the earliest. We asked Burroughs Wellcome to analyze blood work from the clinical trials in the meantime to see whether any of the indirect measurements used to check fat absorption were correlated with poor Mepron absorption, in hopes of finding some absorption markers for the current formulation. They've agreed to do this, but told us that it would take a few weeks.

Is the liquid formulation released faster in the body once it's absorbed? Recently released pharmacokinetics data from a study of 80 HIV positive patients shows that most patients taking the new liquid formulation get therapeutic levels in their blood by the 2nd day, using a dose of 750 mg 3 x/day with food, (the highest trial dose), and by the 4th day at the latest. Consistent (steady state) levels of Mepron are not achieved until 7 to 10 days after starting therapy.

This liquid formulation is being tested in several trial sites around the country for people with acute PCP who are not allergic to Bactrim/Septra. If you are in this trial, keep track of your symptoms and remember that you have the option to withdraw from the study at any time and get regular PCP therapy with no retribution.

What about prophylaxis? The pill form has never been studied for prophylaxis, and the liquid formulation is in trials now. So we don't know. It may, if you're absorbing it well. And if you're allergic to everything else, it's genuinely encouraging to have an alternative. Just don't ignore any dry coughs. The NIH is running the prophylaxis trial down in Rockville, and they'll fly you down there if you qualify (you have to pay for the first trip).

Ironically, Burroughs Wellcome has placed a price cap on Mepron that you would only reach if you were using this drug over a long period of time, say as a prophylaxis. Gee, does this sound like Burroughs Wellcome might be trying to promote this usage on the sly? M- m- m- maybe. In the meantime, remember Bactrim/Septra just got registered for PCP prophylaxis (believe it or not, it's been off- label all this time) and there's always dapsone or aerosolized pentamidine to reduce the chances of coming down with PCP.

Other options for acute PCP, either for combination with Mepron or alone, include dapsone, which many patients allergic to Bactrim/Septra can still take; a clindamycin/primaquine combination, which is more toxic and less effective; IV pentamidine; or IV trimetrexate, which is available via Treatment IND to anyone who have failed or are intolerant to Bactrim/Septra. Your doctor can enroll you by calling (800) 537- 9978.

In sum, lots of doctors like Mepron - it's safer than pentamidine and works well in most PWAs who take it. And good clinical practice almost always involves balancing an awful amount of ambiguity about the best course of action because of the limitations of drugs, and the complexity of HIV- related absorption problems. All the doctors we interviewed for this piece use Mepron carefully, sometimes using pentamidine and/or Bactrim re- sensitization and/or other therapies. In some ways, the Mepron story seems like a horrific tease: two years ago, we didn't have such a promising alternative for PWAs with Bactrim allergies and now we have one but we can't measure when it's working well or not.

Since PCP is still the number one life threatening infection for PWAs, it's heartening that Mepron's absorption problems are being worked on. This is unusual in the history of AIDS drug development. Although drug absorption problems are common (look at the AZT trials), they remain hidden and by in large un- researched in the context of drug development. Clinical trial participants are handpicked, especially in early pharmacokinetics trials, so once again the American drug development process fails those who need it most, the bulk of the people who will buy and use the drugs. It's estimated that 50- 70% of PWAs suffer from chronic diarrhea, the most common symptom of malabsorption and one of the most common reasons for getting excluded from an early trial. The FDA fails to push companies about the limitations of their absorption studies, but that doesn't mean we can't. In the meantime, some thing else that hasn't changed is that you're the real expert here, you know best how your body is responding. Grace under fire is fighting for your own survival.

Amphobearables

Cryptococcal meningitis (CM) and other severe fungal infections can be very difficult to treat and often wind up killing PWAs. The only drug that works in many of these cases, intravenous Amphotericin B, is often called "amphoterrible" since the toxicities are potentially fatal, and at the very least extremely unpleasant. However, some companies have developed new forms of the drug by enclosing it in a liposome, which is really little more than a tiny bubble of fat. The liposomal form of the drug may reduce toxicity and might even work better.

AmBisome
One such formulation, Vestar's AmBisome, appears to work well with minimal toxicity and is approved for use in several European countries, including the UK, and in Latin America. According to Vestar, it even works in about 60% of the patients who have failed Amphotericin B. Vestar claims that the drug has been used by over 10,000 patients, including 300 PWAs for over two years, but in the US, not only is it unavailable, it hasn't even been in clinical trials.

Why don't we just import the drug here? Because its too damn expensive! Each 50 mg vial costs about $200. Standard therapy for CM requires up to 3 vials a day, for two weeks, (which could then be followed by six weeks of fluconazole, not cheap either, but at least insurance pays for it). This totals around $8,400 for the AmBisome alone, and although AmBisome takes only seven to fifteen days to sterilize the fungus, PWAs can easily become reinfected.

At this time, the only option seems to be getting it approved here in the US. Why hasn't Vestar done that? Because they sold the US license to another small bio-tech Lyphomed, in 1985.

In 1989, Lyphomed was bought by Fujisawa. Fujisawa performed some animal studies and got an IND for AmBisome from the FDA last year. Considering that the drug is approved abroad and has been used in a large number of patients, it shouldn't take much work for Fujisawa to get this drug approved. However, since obtaining their IND, they haven't done a thing. To make things worse, doctors who have begged them for compassionate use have been stonewalled.

What is Fujisawa's problem? They were apparently ready to go ahead with clinical trials to find the maximum tolerated dose last January (never performed by Vestar in Europe). They had all the drug they needed, and a complete protocol for the study. But then a new CEO shifted the company's resources towards getting approval for FK-506, an immune-suppressant like cyclosporine. AmBisome was put on the back burner.

Fujisawa spent a lot to buy Lyphomed, expecting to earn a huge sum on their PCP drug, pentamidine. Unfortunately for Fujisawa, when inexpensive Bactrim/Septra was shown to work better than pentamidine, yearly earning fell about $30 million or so short of what they had expected. In fact, they are almost bankrupt, but if they could get FK-506 approved quickly they would be back in financially safe waters (to the tune of $600-800 million a year).

But what about all the people whose lives might have been saved with AmBisome? Financial constraints might put off trials, but are no excuse not to allow compassionate use of this drug, which is just sitting on their warehouse shelves.

The company has consistently been feeding us lies. In September, Fujisawa reps said they wanted to have a meeting with the FDA by the end of the year to discuss development plans. But, then they admitted that this was "speculative" and that they hadn't even called the FDA to set up an appointment, or had any discussions about AmBisome with the FDA at all, for that matter. In October, they claimed that they were talking with the FDA and planned to start a study in Chicago and Baltimore as soon as November, and that large scale phase II studies comparing the drug with Amphotericin B would begin immediately afterward. But no study started in November. Since then, we've called them repeatedly, and they don't call back.

The CEO is Hatsuo Aoki. The other players at Fujisawa are Dr. Richard Hiles, (708) 317-1094, and Dr. Jim Allen (708) 317-1462. Give 'em hell.

Other Variations on Amphotericin B
Two other "liposomal" formulations of Amphotericin B are in clinical trials. They may not be as effective as AmBisome, but they do seem to be less toxic than plain Amphotericin B. Neither drug is a true liposome.

The Liposome Company's Amphotericin B lipid complex (ABLC) is approved in South Africa and currently in phase III clinical studies throughout the US. Rather than the fat bubble of a true liposome, this drug is more like a tiny ribbon of fat. This may limit how well the drug works, since in a phase II study comparing the drug to Amphotericin B, plain Ampho won out. Apparently, ribbons are not enough.

At least ABLC is available, free, through a compassionate use emergency protocol for patients who have failed are or are intolerant to traditional therapies. Doctors can enroll their patients by calling:

1 (800) 4 ABLC RX, or 1 (800) 422-5279.
The third formulation is called Amphocil, owned by the Liposome Technology, Inc. Amphocil, approved in the UK, is only in phase II trials here. Despite the company's name, this drug is a horse of a different color and not a liposomal drug at all. It appears to work and be safe so far, but we've yet to see how it performs compared to Amphotericin B in PWAs.

Acemannan
byJason Heyman

Acemannan is a polysaccharide, or complex sugar, extracted from the aloe vera plant, Aloe barbardensis Miller. Aloe vera has been used in many cultures as a traditional treatment for burns, digestive problems, and other ailments, and has become a popular alternative treatment for AIDS. It is currently being promoted for use in combination with DNCB, dinitrochlorobenzene, another alternative treatment that has recently been receiving a new round of attention. Acemannan was patented by Carrington Laboratories under the brand name Carrisyn, and has been approved by FDA for the treatment of fibrosarcoma, a form of cancer, in cats and dogs.

Certain laboratory studies have shown that acemannan is capable of inhibiting HIV replication in the test tube, increasing the production of cytokines, and enhancing the efficacy of AZT. Unfortunately, a recently concluded clinical trial could not reproduce these findings.

Results from two studies of acemannan were presented as poster abstracts at the IX International Conference on AIDS in Berlin. One abstract presented the long-awaited results of a placebo-controlled clinical trial of acemannan in combination with AZT or ddI. The trial was conducted by the Canadian HIV Trials Network, and funded by the Canadian government (abstract # PoB 28-2153).

This study enrolled sixty-two patients with t-helper counts between 50-300. The results showed that people taking acemannan declined more slowly than those not taking the drug, but by the end of the 48 week study, both groups had similar losses in t-helper cells. No difference was noted for p24 antigen, and no interaction with the antiretroviral drugs was observed.

In a different study, paid for by Carrington Laboratories, performed by researchers from Carrington Laboratories and Dallas-Fort Worth Medical Center, in Texas, followed the progress of the five survivors of a six year open-label clinical trial (abstract #PoB 29-2179). The t-helper counts of these five patients stayed constant over six years, while their CD8 cells increased from an average of 359 to an average of 1395. It is not specified whether these patients were receiving antiretroviral therapy.

Although their results seem contradictory to those of the larger Canadian trial, the researchers of the open-label study reported that acemannan increased the production of CD8 cells, and cytokines (immune regulators) including IL-6, and TNF-alpha (the same cytokines stimulated by echinacea---see following piece). Based on this information the authors suggest that acemannan increased survival time amongst these patients. According to the abstract, "the clinical deterioration of 10 deceased study patients closely paralleled their compliance for the daily intake of acemannan."

Self-selection in the open label study, as well the inevitable lack of objectivity on the part of the manufacturers of the product may explain the contradictory findings of these two studies.

Aloe Vera: The plot thickens . . . but does the concentrate?

[Ed. note: this piece by Stephen Korsia on the seemy underside of the aloe vera market is an abbreviated reprint from the December, 1991 issue of I Heard It Through The Grapevine, a newslettter from AIDS Project LA. We don't know whether all these suppliers still exist, but this might help you find the highest quality aloe vera, if you think its worth it.]

Many people with HIV are taking commercial aloe vera extracts as a way to access this promising therapy. A word of warning: the large bottles of "100%" aloe vera juice that one can buy in health food stores are nothing but water with a little aloe juice. Receiving a therapeutic amount of acemannan by drinking this type of preparation would require you to drink gallons and gallons a day. Presently, the only way to access a therapeutic amount of acemannan seems to be to get ahold of aloe juice concentrate, a thick brown soup with a tart taste. There are possibly three (as of 1994) companies in the game:

Let's see what each of these companies has to offer.

Lametco produces a cold- processed concentrate, extracted from aloe plants they buy from an outside contractor. Because they do not know how their aloe was grown, the amount of acemannan in their concentrate is likely to change from one batch to the next. One quart of the reconstituted juice (1 part of concentrate in 10 parts water) is supposed to contain an average of 270 mg of Acemannan (30 mg of other solid, potentially active substances).

Cosmetic Specialty Labs offers a heat- pasteurized concentrate. They claim that heat- processing not only does not affect the active substances in the juice, but also decreases the laxative effects of aloe juice. They get their aloe from their own farm, where it is grown under constant conditions, thus allowing a better regularity in the composition of their products. Juice is partially freeze- dried to obtain the concentrate. One quart of the reconstituted juice is supposed to contain 450 mg of acemannan (50 mg other solid substances).

Carrington Labs makes CARRISYN tm which contains 85- 95% acemannan, available in injectable and oral forms. CARRISYN tm is not available for human treatment. However, it was approved recently by the FDA for use in the treatment of fibrosarcoma (a type of cancer) in cats and dogs. At this time, CARRISYN tm should be available to veterinarians through their drug retailers. Maybe it is time for your dog to have fibrosarcoma? We still have no idea of the price. Some have suggested that a full-dose treatment in humans would cost up to $500 a month. Carrington Labs 1 (800) 255-4223, also provides aloe concentrate to a retailer named De Veras in Texas (214- 823- 4659). Their concentrate seems to be somewhat weaker than the two other ones.

There are still major questions regarding the quality of these products. Of particular interest is the fact that acemannan is a mixture of molecules with varied sizes (a mix of polymers, for you scientific minds!). It has been suggested that only the largest molecules (MW 12,000, for you inquiring brains!) are effective. Now, how much of the acemannan present in these concentrates is that large? In the case of CARRISYN tm, how effective is acemannan without the hundreds of substances present in concentrated juice? Aloe contains at least six other anti-infectious substances and one anti-inflammatory agent. Are they enhancing the effectiveness of acemannan? [We also should add that other sources say that these other substances may actually render acemannan inactive] So many questions, so little straight answers!

Echinacea: My Immune Booster May Be Your Downer

Extracts from echinacea, that purple coneflower blooming in your garden, have been used by herbalists since pagan times, and seem to be becoming more and more popular in the back-to-Mother- Earth-'90's. A lot of laboratory work supports what the nature healer-types have contended all along; that echinacea can kick start the immune system into combating infections and maybe even cancerous cells. So echinacea may deserve the tag "immunomodulator", and because of its reputation, a lot of people with HIV use it to try and give their immune system a boost.

Which would be great if the immune system was a simple sort of thing that turns on or off. But its more like a maze of interlaced wires and switches, with hidden feedback loops and all the instructions are in hieroglyphics. Or to use a more natural metaphor, the immune system is like the ecosystem, in which the disappearance of some tiny fish leads to global starvation.

HIV disease uses the complexity of the immune system to defeat it. HIV triggers responses from some parts of the immune system that would normally keep other infections in check, but that wind up only feeding HIV and gradually disturbing the natural balance of all the elements of the immune system. By the time someone has fifty CD4 cells, its not that the immune system is "deficient" so much as it is all out of whack. Any product that claims to be an immune booster should be looked at very carefully to be sure that it isn't just aggravating this imbalance.

So where does echinacea fit into this? Hard to say, since these extracts appear to do a number of different things. Echinacea has been shown to activate cells called macrophages that eat diseased cells or infectious things like bacterias or viruses. Macrophages are very important when it comes to fighting off certain infections such as MAI. In this process the macrophages produce large amounts of chemicals such as IL-1, IL-6, and TNF-alpha. These chemicals stimulate HIV, and a number of other conditions such as KS and wasting. What's worse is that if macrophages clean up cells infected with HIV, they can become infected themselves and act as reservoirs for the virus. There are no studies of whether echinacea causes more of your macrophages to get infected. But there are studies showing that taking echinacea increases levels of IL-1, IL-6, and TNF-alpha in sero-negative people.

On paper this seems like a catch-22. In your body, who knows, it may depend on your stage of disease. Echinacea might help you in one stage, and hurt you in another. It's very hard to get a grasp of the big picture by piecing together these small test tube studies. There are no studies of echinacea in PWAs. It sounds sort of hollow to always this repeat demand for clinical trials, since they take so much time and money to design and implement and there are just so many things to study. Where does that leave you now? Once again with a lot of decisions to make and little more than your good sense to guide you.

Dosage Update: Tinidazole

[Thank you Barbara Starrett]

The standard GIARDIA dose of tinidazole: 2 grams (4 pills) for one day.

The standard AMOEBIASIS dose of tinidazole: 2 grams (4 pills) for three to five days. For severe amoebas, 600 mg 2x/day for 6 days.

These are the standard doses, and not from studies with PWAs, so in some cases, doctors might prescribe a longer doses (@ 3 days for giardia and @ 5 days for amoebas).

Sometimes the Health Group Office can be a soothing oasis from a harsh cruel world. Things are fairly still; we play beautiful music, have charming conversations and the soft lighting makes everyone here look glamorous. Other times it's frankly chaos. All the phones ring at once, with deliveries, pick ups and 5 clients at the register.

Which can make it hard sometimes to negotiate better prices on the drugs we sell, or research potential new treatments, or to meet that publication deadline. There are only a few of us working here, and ever since Garance, we've been used to wearing several hats.

All of this is to say that there are times that it would be very helpful to have a little extra help. Maybe answering phones and taking orders. Maybe copying things on the Xerox or researching treatments.

I, for one, would find it extremely helpful if someone with access to a medical library could occasionally pull journal articles for me, since sometimes I can't get out of the office.

So if you can, come on down and lend us a hand.

NOTES FROM THE UNDERGROUND is published six times a year by People With AIDS Working for Health, Inc., a non-profit buyer's club doing business as the PWA Health Group, and reports on issues pertaining to underground AIDS treatment and access.

Articles in this publication are for informational purposes only, and in no way constitute an endorsement of any particular treatment regimen or strategy. We do not consider ourselves qualified to offer medical advice, and encourage people to consult with their physician prior to taking any medications.

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copyright 1996 by People With AIDS Working For Health, Inc.
REPRODUCTION IS HEARTILY ENCOURAGED.

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