PML, TOXOPLASMOSIS AND MAI: SURVEYING THE OPTIONS

The early years of the epidemic made clear that people who are immunocompromised are susceptible to infections from various bacteria, fungi, viruses and protozoa which would ordinarily be harmless. Since these microorganisms take advantage of a disarmed immune system, they are described as "opportunistic" infections (OIs).

The most familiar of these is a pneumonia caused by the organism Pneumocystis carinii (PCP). P. carinii is found everywhere in the environment and exposure to it is impossible to avoid. But PCP has become one of the most treatable of OIs, if diagnosed early enough. And the FDA recently acknowledged what thousands of people with HIV and their physicians already knew: that a decline in T-helper cells to 200 or less warrants the use of a prophylaxis (preventive measure) such as dapsone, sulfa trimethoprim or aerosol pentamidine to ward off even a first bout with PCP.

Other opportunistic infections have generally been handled less successfully than PCP, particularly MAI, toxoplasmosis and PML. But new experimental approaches to all three of these are receiving attention, and it is possible that the risk for developing the first two can be lessened by avoiding routine exposure to the responsible pathogens. This article suggests some precautions, and surveys the drugs now being tried or considered to control active infections. Many of the drugs mentioned are FDA approved, and a doctor can prescribe them as she or he determines appropriate for any condition. If they are only investigational in the U.S. we will indicate so, although new guidelines allow the importation of drugs approved in other countries if prescribed by a physician for personal use. As any treatments, approved or unapproved, gain a strong consensus as effective (or ineffective) therapies, we will report on them in depth. Until then we want to name the possibilities we are aware of in order to maximize the choices of people with these diagnoses and their physicians.

PML

Progressive multifocal leukoencephalopathy (PML) is an uncommon but devastating brain infection with an historically bleak outlook, and many physicians have opted not to initiate treatment, or simply rely hopefully on AZT for its antiviral and CNS access capacity. The results of intervention in the progress of PML have increased the possible options, however, enough to justify an aggressive attempt to treat.

This OI probably results from reactivation of a latent papovavirus to which most people gain immunity after childhood exposure. Some symptoms of PML, such as headaches, confusion, visual impairment in one or both eyes, aphasia (difficulty with verbal comprehension or expression) or loss of muscle coordination on one side of the body, can resemble toxoplasmosis, herpes encephalitis or meningitis. Each of those infections, as well as PML, can be imminently life-threatening and should be seen immediately by an AIDS-knowledgeable physician, who may consult a neurologist. Someone experiencing these symptoms may become too disoriented to respond quickly to the situation, so the observant help of friends or family could make a difference. The time from appearance of symptoms to diagnosis to treatment is crucial for PML or other AIDS-related neurological infections.

AIDS TREATMENT NEWS recommends to interested readers a very comprehensive, well-researched report on experimental treatments for PML compiled by two concerned AIDS activists in Los Angeles, Lisa A. Muller and Peter L. Brosnan, with an introduction by Ronald Webeck, a long-term survivor of PML. The treatments discussed in this report were drawn from current medical literature and include beta interferon, vidarabine (adenine arabinoside, or ARA-A), cytarabine (cytosine arabinoside, or ARA-C), alpha-2 interferon, acyclovir, clonazepam, trimethoprim with sulfamethoxazole, and dexamethasone combined first with sulfadiazine and then with pyrimethamine. The first three in the list appeared to be more effective when administered intrathecally (injected into the spinal fluid) instead of intravenously. The others were tried only intravenously. (Clonazepam is probably useful to control convulsions which may accompany PML, but not as a primary treatment.)

Some of these drugs have side effects which people with HIV and their doctors would usually weigh carefully, but the gravity of an untreated PML infection may override these concerns, and AIDS-experienced physicians often make similar compromises in treating other OIs. None of these drugs have been proven to work repeatedly, but accumulated attempts to treat PML have resulted in better survival rates than nontreatment. The articles referenced from the literature are included in entirety in the reportUs appendix, making it self-contained and practical for outpatient clinics and AIDS-care health professionals. A copy of the report can be obtained by sending a request (with $10 donation or more to cover the cost of printing and mailing) to Lisa Muller, 4015 Bemis, Los Angeles, CA 90039.

Toxoplasmosis

AIDS-related toxoplasmosis is a serious infection of the central nervous system caused by the protozoan Toxoplasma gondii. The symptoms of toxoplasmic encephalitis can be difficult to diagnose with certainty, but as mentioned above call for urgent attention.

Various mammals and birds can be infected with T. gondii, but only cats appear to harbor the reproductive forms of the organism. Resting forms called oocysts are shed by cats in their feces, where they can survive in the soil for more than a year. Here they are a ready source of infection for other animals and humans. In humans the oocysts themselves are not damaging, but when the multiplicative forms, or active parasites, break out of the cysts they are capable of causing disease in infants and immunosuppressed adults. Active parasite forms of T. gondii can also be transmitted to people in undercooked meat.

The standard treatment for toxoplasmosis is pyrimethamine with sulfadiazine. These drugs are effective against the
parasite, but they do not destroy oocysts, so a continuous maintenance dose is necessary to squelch emerging parasites. Some people reach toxic intolerance of these drugs, and folinic acid (Leucovorin) is then used to diminish this toxicity. Pyrimethamine is also being studied in combinations with dapsone, trimetrexate, clindamycin and spiramycin (investigational), instead of sulfadiazine. Clindamycin is probably substituted most often.

Infrequently, pyrimethamine fails altogether and amphotericin B has been tried next. This drug can cause severe side effects, however, as many people who received it for cryptococcal meningitis will verify. An investigational drug, fluconazole, has been substituted effectively for this kind of meningitis, and tolerated more easily. Accordingly, fluconazole has been sug- gested for the treatment of toxoplasmosis. The FDA will probably approve fluconazole later this year (for background, see AIDS TREATMENT NEWS #58), but it may be accessible now with the help of buyersU clubs in New York and San Francisco (see "Obtaining Treatments from Abroad" in AIDS TREATMENT NEWS#78). Incidentally, researchers at the Universite Paris VI have found a new, less toxic derivative of amphotericin B called N-fru-AmB which demon- strated antibiotic and immune boosting effects in mice. It is not yet clear if it will be of use in humans, or for which infections.

Issue #75 of AIDS TREATMENT NEWS reported on two other promising options for toxoplasmosis: roxithromycin, approved in France, and azithromycin, approved in Yugoslavia. They may be as effective as pyrimethamine/sulfadiazine but more easily tolerated. However, we do not know results of human use for toxoplasmosis at this time. Roxithromycin might be obtainable through buyersU clubs (see paragraph above).

The abstracts of the 1988 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) presented results of varying combinations of pyrimethamine, sulfadiazine and arprinocid (investigational) against T. gondii in mice. Arprinocid was found to work poorly when combined with pyrimethamine, and pyrimethamine alone was somewhat more effective that either sulfadiazine or arprinocid alone. But arprinocid and sulfadiazine together worked synergistically, the best combination tried. Additionally, a metabolite of arprinocid called arprinocid-N-oxide was more effective alone in smaller doses than arprinocid (Luft and Frankel, abstract number 1420). Unfortunately, another study found that AZT made pyrimethamine much less effective in animal tests (Israelski, Tom, and Remington, abstract number 349).

In January 1988 in The Journal of Infectious Diseases, Drs. Benjamin L. Luft and Jack S. Remington authored a comprehensive discussion of diagnostic procedures and potential therapies for toxoplasmosis. In addition to many of the drugs mentioned above they proposed the investigational agents gamma interferon and interleukin-2 as candidates against T. gondii.

Lastly, researchers at the Robert Koch Institute in Berlin found that monophosphoryl lipid A, or MPL (not FDA approved), enhanced resistance in mice when administered before or at the same time they were injected with T. gondii (Masihi and others, 1988). This raises the possibility of prophylaxis or chronic suppressive therapy for toxoplasmosis. Also, we have heard anecdotally that people who are taking Septra for PCP show a reduced incidence of toxoplasmosis. Hopefully some trends will be identified for practical use.

Most physicians we spoke with feel that AIDS-related toxoplasmosis is a reactivated infection from early, common exposure to T. gondii; and indeed a large portion of the worldUs population is chronically but asymptomatically infected. Of people with AIDS who have the antibodies which verify this latent infection, at least 30% develop toxoplasmic encephalitis. This incidence may reflect the comparative virulence of different parasite strains operating within a context of immunodeficiency. But another consideration factor for the progression from latent to symptomatic infection is inoculum threshold the amount or concentration necessary to cause illness in someone. "Superinfection", or repeated exposure, could be a mode of reaching this threshold. It seems reasonably possible, especially for an immunocompromised person, that some infections might be avoided or suppressed by minimizing exposure to the organism.

Obviously, cat litter boxes could be kept away from food preparation and eating areas, and the litter disposed of by someone who is not at risk for toxoplasmosis. Cats should not be fed raw meat, and anyone who handles a cat or changes the litter should wash their hands thoroughly afterward. In this regard, toxoplasmosis is a "zoonotic" disease, one that can be transmitted from animals to humans.(1) Since birds, cats, fish, reptiles and rodents can all carry various zoonotic diseases, people with pets should observe careful handwashing after handling pets and before meals or food preparation.

MAI

MAI (Mycobacterium avium intracellulare) is one of a group of mycobacteria, others of which can cause tuberculosis and HansenUs disease (leprosy). MAI is found widely in soil, dust, untreated water and bird droppings. Formerly a lung infection occurring primarily in people who have chronic lung disease or are on steroids, MAI infection (or M. avium ComplexQMAC) in PWAs is usually disseminated throughout the body and can cause fatigue, fever, sweats, anemia, diarrhea and serious weight loss. There are quite a few drugs being tried for MAI, although it appears to respond very slowly.

The March 30, 1989 edition of Treatment Issues, published by the Gay MenUs Health Crisis, reports on the following drugs for consideration in the treatment of MAI: isoniazid (INH), rifampin (Rifadin), rifabutin (Ansamycin), ethambutol (Myambutol), amikacin (Amikin), imipenem (Primaxin), ethionamide (Trecator), clofazimine (Lamprene), ciprofloxacin (Cipro), ofloxacin, cycloserine (Seromycin), erythromycin (Robimycin) and azithromycin. Usually several of these are tried in combination. The article includes diagnostic information about MAI, as well as MTB (Mycobacterium tuberculosis), for which PWAs are also at risk. To obtain this article, write to GMHC, Department of Medical Information, 129 West 20th Street, New York, NY 10011. Be sure to specify volume 3, number 2 on mycobacterial infections. We spoke with Shelley M. Gordon, M.D. who is an infectious disease specialist with Pacific-Presbyterian Medical Center in San Francisco. She has observed the best response so far in MAC from a combination of rifampin, ethambutol and clofazimine, with amikacin included as warranted.

Researchers at Shimane Medical University in Japan have strengthened the rifampin activity against M. avium-infected macrophages in mice by encapsulating rifampin in liposomes. Liposomal vescicles are already widely used to enhance the delivery of other antimicrobial drugs, and the researchers suggest that this technique is particularly suited to treat persistent infections like MAI. Of related interest, three separate studies presented at last yearUs International Conference on AIDS in Stockholm suggested that rifabutin in vitro demonstrated anti-HIV activity, especially when combined with heparin. This could provide an option for many people with MAI who cannot take AZT, although some physicians, including Dr. Gordon, feel it is neither convincingly active against HIV nor noticeably better than rifampin for treating MAI. Despite its investigational status, rifabutin was widely available to physicians who wished to prescribe it; recently the manufacturer cut off compassionate access for new patients.

Amikacin, azithromycin and roxithromycin have been examined in various combinations with tumor necrosis factor (TNF), a natural product of the immune system which is synthesized and being tested for other diagnoses, particularly KaposiUs sarcoma. M. avium-infected human macrophages were more susceptible in vitro to each antibiotic when tried with TNF than compared to any antibiotic alone. The mycobactericidal action was strongest when TNF was combined with both amikacin and roxithromycin. The researchers of that study suggest that the pairing of immunomodulators with antimicrobial agents could be a useful treatment for MAI. In addition to some of the drugs mentioned above three more possibilities were presented at the 1988 ICAAC conference: fusidic acid (Fusidin), which may also have anti-HIV activity and which is approved in Canada and the U.K. but not in the U.S., temafloxacin, and sulfisoxazole (Gantrisin).

As a prophylactic measure to keep a latent MAI infection inactive, San Francisco physicians working with the County Community Consortium are studying the effect of low-dose clofazimine (50 mg daily). People taking clofazimine, however, should be aware that in rare cases it can accumulate as crystals in various parts of the body, including the liver, spleen and intestinal membranes. One friend of ours who was taking clofazimine experienced a mildly enlarged liver and elevated liver enzymes which eluded diagnosis. He looked up the warnings for the drug in the Physicians Desk Reference and brought this to his doctorUs attention. The clofazimine was discontinued but it is too early to draw a clear connection. We hope physicians prescribing MAI treatments carefully explain any side effects to watch for (such as anemia, dizziness, allergic rashes, kidney impairment, emotional depression, skin discoloration, etc), especially since some drug side effects can be confused with symptoms of AIDS-related infections.

As with toxoplasmosis, active symptoms of M. avium are often assumed to originate from an old exposure which remained unnoticed as a latent, immune-controlled infection. Although MAI is widely present in water and soil, it may be feasible and advantageous to decrease exposure to it. Keith Barton, M.D., of Berkeley recommends to all his patients with AIDS that they not eat raw foods, especially salad and root vegetables, or unpasteurized milk or cheese, and that the water they drink be boiled. The bacteria are killed at around 80 degrees centigrade, which means any conventional cooking (oven, stove, steamer) is sufficient to neutralize MAI in vegetables and meat. An alternative to cooking vegetables or fresh fruit is to peel and rinse any surface which could have been exposed to soil or irrigation water. Of Dr. BartonUs patients who follow this advice, only three have developed an active MAI infection, a much lower incidence than he would have expected otherwise. This suggests that while it is not possible to avoid exposure to MAI completely, it may be worth taking precautions to minimize the risk.

We want to acknowledge that many physicians and people with HIV discount the practicality of avoiding microorganisms which are pervasive in the environment. While the measures suggested above may not completely eliminate exposure to pathogens like M. avium or T. gondii, they might keep the quantity and frequency of exposure below a disease-causing threshold. More importantly, the search for the optimum treatments of these infections should be intensified before they surpass the toll wrought by PCP early in the epidemic.

For example, we have heard from some readers that their doctors do not attempt to treat an MAI infection on the lethargic assumption that there is no treatment proven conclusively to control MAI. When we called the offices of the National Institute of Allergy and Infectious Diseases (NIAID) to clarify the status of some promising drugs, the person we spoke with was very helpful but repeated the same idea with nearly the same words: NIAID does not recommend a treatment for MAI because none has been shown to be so effective that it could win FDA approval as an MAI treatment, even though most of them are approved for other infections and have been available to physicians for the entire epidemic. While waiting for the perfect treatment, disregarding some that only might be useful, how many people with MAI (or Kaposi's sarcoma, or plummeting T-helper cells) discovered the consequences of waiting?

Current medical literature sometimes asks a more laissezfaire question: "Did this patient die with MAI or from MAI?". The question would be unnecessary if new potential treatments were pursued aggressively and intelligently until a potent choice or combination of choices surfaced. MAI, like HIV, is damaging partly for its tendency to invade the disease-fighting cells called macrophages. An unchallenged MAI infection could tip the scales on a depleted immune system, clearing the path for other opportunistic infections and providing another reason for treating MAI. The approach to toxoplasmosis has a similarly pessimistic history but for different reasons. The drugs of choice have been clearer than for those for MAI, but they are seriously limited by toxicity. Now the possibilities for treating toxoplasmosis are growing, those for MAI are being refined, and some for PML are getting initial recognition. The pessimistic prognosis surrounding these OIs appears to be changing, and the rate of change could use a push by recognizing these infections early and intervening with as many treatment options necessary.

References

Hawkins, CC and others. Mycobacterium avium Complex infections in Patients with the Acquired Immunodeficiency Syndrome. Annals of Internal Medicine, volume 105, pages 184-188, August 1986.

Bermudez, LEM and Young, LS. Activities of Amikacin, Roxithromycin, and Azithromycin Alone or in Combination with Tumor Necrosis Factor against Mycobacterium avium Complex. Antimicrobial Agents and Chemotherapy, volume 32, number 8, pages 1149-1153, August 1988.

Henry-Toulme, N and others. Immunomodulating properties of the N-(1-deoxy-D-fructos-lyl) derivative of amphotericin B in mice. Immunology Letters, volume 20, pages 63-67, 1989.

Masihi, K. Noel and others. Effects of Nontoxic Lipid A and Endotoxin on Resistance of Mice to Toxoplasma gondii. Journal of Biological Response Modifiers, volume 7, number 6, pages 535-539, 1988.

Suzuki, Y and others. Differences in Virulence and Development of Encephalitis During Chronic Infection with the Strain of Toxoplasma gondii. The Journal of Infectious Diseases, volume 159, number 4, pages 790-794, April 1989.

Hajime,S and Haruaki, T. Therapeutic Efficacy of Liposome-Entrapped Rifampin against Mycobacterium avium Complex Infection Induced in Mice. Antimicrobial Agents and Chemotherapy, volume 3, number 4, pages 429-433, April 1989.

(1) People often derive therapeutic companionship from pets and do not need to choose between staying healthy and having a pet. A San Francisco organization, Pets Are Wonderful Support (PAWS), acknowledges the value of a pet while encouraging people to observe precautions which minimize the risk of contracting infections from an animal. To receive their Safe Pet Guidelines, write to PAWS, P.O. Box 460489, San Francisco, CA 94146.


STATEMENT OF PURPOSE

AIDS TREATMENT NEWS reports on experimental and complementary treatments, especially those available now. It collects information from medical journals, and from interviews with scientists physicians, and other health practitioners, and persons with AIDS or ARC.

Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS TREATMENT NEWS does not recommend particular therapies, but seeks to increase the options available.

We also examine the ethical and public-policy issues around AIDS treatment research.