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Gay Men's Health Crisis
"Mycobacterium Avium Complex"
Darren Britton
November 15, 1991
GMHC Treatment Issues 1991 Nov; 5(8): 1

Mycobacterium avium complex, or MAC, is a disease made up of different strains of mycobacteria found in AIDS patients, which together form a "complex." M. avium, the most common strain, and M. intracellulare, previously gave the disease its name, MAI (or Mycobacterium avium intracellulare). The new name, MAC, came about when researchers discovered that the illness is actually caused by up to ten different strains of bacteria, which makes the infection notably difficult to treat. The organisms which cause MAC occur naturally in food, water, and soil[1] -- as well as in hospital water supplies.[2] The most common strains found in PWA's are particularly associated with heated water supplies.[3] Avoiding exposure remains difficult at best.

BACKGROUND Before the AIDS epidemic, illness caused by MAC was rare in humans. In fact, in 1980, only 24 cases had ever been reported in medical literature.[4] In 1982, however, reports of MAC infection increased dramatically, and the infection began to be recognized as an AIDS-related illness. In the early days of AIDS, MAC infection was usually identified only at autopsy. Most PWA's dies of other causes, such as PCP, which can now usually be prevented. At that time, doctors and researchers believed that MAC bacteria caused infection in the late stages of HIV disease, but did not cause serious illness, since the bacteria was found at autopsy in people who had dies of other causes. Since then, studies have shown that MAC infection, which spreads to numerous parts of the body (disseminated infection), can cause both illness and death in PWA's.[5] By December 31, 1990, 12,202 cases of disseminated MAC infection were reported in persons with AIDS. This number comprises 7.6% of all AIDS cases reported to the Centers for Disease Control (CDC).

In clinical studies, 76% - 90% of MAC infections come late in the course of HIV, well after AIDS has first been diagnosed.[6] Current estimates indicate that between 15% - 24% of PWA's have symptomatic MAC disease.[7] Applying this ratio to the number of actual reported cases, disseminated MAC infection may affect between 30,000 - 49,000 people with AIDS in the U.S.

According to a report from Florence, MAC and other atypical mycobacterial infections occur in women twice as often as they occur in men.[8] At the National Conference on Women and HIV Infection, similar studies were reported from the Bronx, New York, and Newark, New Jersey, which point to the possibility that MAC may have a different pattern in women than in men.[9] This possibility requires immediate investigation.

SYMPTOMS Symptoms of MAC usually include fevers, chills, weakness, abdominal pains, night sweats, diarrhea, anemia, and weight loss. MAC is a major cause of "wasting syndrome." Though very uncommon, the infection can produce non-specific symptoms, making diagnosis difficult. As people with AIDS live longer, MAC illness continues to occur relatively late. Data indicate that it occurs on average 7 to 15 months after AIDS is diagnosed.[10] Additionally, MAC seems to be associated with advanced immune dysfunction. In fact, the majority of patients with MAC disease seem to have T4 cell counts below 60.[11] DIAGNOSIS MAC remains a challenge to diagnose in PWA's. As with most bacterial infections, people with immunosuppression are often not capable of producing antibody responses to MAC infection.[12] When MAC involves the lungs, pulmonary symptoms may appear, but new studies show that symptoms don't occur in about 4% of PWA's. Chest x-rays may be insufficient to diagnose the illness. Microscopic examination of phlegm with a special acid-fast method of detection is another way do diagnose MAC. However, a positive result could represent other types of mycobacteria and may not be conclusive. Additionally, although lungs may become infected, recent research shows that bacteria first enter the gastrointestinal (GI) tract.[14] In the GI tract, MAC invades the wall of the intestine, liver, and spleen, causing diarrhea and abdominal pain, swelling and often abnormal liver function tests.

Since most PWA's have disseminated disease, it is best to diagnose MAC by blood cultures. Blood culture is a process by which blood is removed from the body and placed in an atmosphere where bacteria, if present, will grow in large numbers for easy detection. Two consecutive blood cultures are usually adequate to make a diagnosis.[15] New techniques are leading to faster blood culturing for MAC. For instance, a French group reported using a 2-step polymerase chain reaction (PCR) test to diagnose MAC in less than 4 hours.[16] Studies have also shown that liver biopsies and bone marrow examinations are rapid ways of diagnosing MAC; however, they are more invasive procedures.

PROMISING MULTI-DRUG THERAPIES Early studies of therapies for disseminated MAC were discouraging. Recently, studies have shown relief of symptoms in most patients with some treatments. The most effective MAC therapies have been shown to be multiple drug combinations of 3-7 drugs.[17] Fever, night sweats, and malaise may respond to combination therapies within two to eight weeks. Diarrhea and weight loss are still difficult to control, and improvement in survival has been modest.

Several studies have demonstrated that combinations of three or more antibiotics can be effective in improving symptoms and clearing bacteria from the blood, although many patients still display MAC in tissue at autopsy. One study, reported in San Francisco last year by Dr. Potage and others, evaluated the response of 20 AIDS patients with disseminated MAC.[18] Patients were treated with a regimen consisting of intravenous amikacin, oral clofazimine, firampin, and ethambutol. Amikacin was given intravenously for 30 days or until a dose-limiting toxicity occurred. Nineteen of the 20 patients had a favorable response with lab blood tests showing clearance of mycobacteria from tissue. One patient's bacterial recurred when amikacin was stopped. Amikacin caused hearing loss in some patients who had been taking it for more than 60 days. The frequency of such hearing loss is significantly diminished when amikacin is used for no longer than 4 weeks. Irreversible ear damage may occur with longer-term use.

In Florence, a study from Sweden was presented in which 31 patients with MAC were treated with the combination therapy: amikacin, ethambutol, and rifabutin. After an average of 14 days of therapy, 71% of patients had improvement in symptoms, including fever, diarrhea and a new sense of well-being.[19] Two other published studies have reported similar successes with combination therapies.[20] AZITHROMYCIN Azithromycin, an antibiotic made by Pfizer, is an experimental option for toxoplasmosis and MAC. The drug penetrates well into tissues with very little toxicity in both animals and humans. A four-week azithromycin study using mice resulted in 95% survival and a significant decrease in bacteria in the blood, liver, and spleen.[21] A phase I human pilot study treated 16 patients with AIDS and MAC bacteria with azithromycin (500 mg per day).[22] Of the 16 patients treated for 20 or 30 days, 14 had improvement of such symptoms as fever, night sweats, fatigue, and weight loss. Blood tests showed a reduction of bacteria. The main side effect was diarrhea.

Azithromycin is available under compassionate use from Pfizer as treatment for toxoplasmosis and MAC. Unfortunately, according to Pfizer, only 20 patients have used the drug through compassionate use for MAC, since advertisement efforts have been minimal. A representative from the company did reveal that plans to get the word out are under way. Additionally, the PWA Health Group sells the drug for $43.00 per six pills at 250 mg. each.

RIFABUTIN Rifabutin, an antibiotic similar to rifampin (used to treat tuberculosis), has been studied as a treatment for MAC for several years. It was originally available from the CDC and from Adria Pharmaceuticals for compassionate use.

One study presented in San Francisco by Dr. Fred Siegal from New York, assessed rifabutin (300-900 mg/day) in 20 PWA's. Compared to an historical control group of 184 patients who did not receive rifabutin, the patients taking the drug for less than 30 days had an improvement in MAC-free survival.[23] In Florence, investigators from Adria Pharmaceuticals presented data on 90 patients with AIDS and MAC treated with rifabutin in a combination regimen.[24] Fever and night sweats resolved in 72% of patients, although there was a minimal decrease in diarrhea. Average survival time was 207 days.

Side effects of Rifabutin include low white blood cell counts, low platelet counts, and rashes. Rifabutin is presently being studied in a large placebo-controlled trial sponsored by Adria for treatment of MAC in combination with ethambutol and clofazimine. In addition, it is being studied for preventing initial MAC infection in patients with T4 cell counts under 200. For more information on these trials in the New York area, patients can call 1-800-TRIALS-A.

CLARITHROMYCIN Clarithromycin is a broad-spectrum antibiotic approved for use in 20 countries to treat respiratory, skin, and gastrointestinal infections. Until now, the drug has been imported from Europe, and costs about $600-$750 per month for six weeks of acute treatment. for maintenance therapy, it costs about $200 per month. It continues to be a hot item at buyers' clubs, such as the PWA Health Group.

Experience using clarithromycin in AIDS patients is limited. One recent study compared a group of patients taking clarithromycin, isoniazid, ethambutol, and clofazimine to a group of patients taking placebo, isoniazid, ethambutol, and clofazimine for six weeks. Then all patients received clarithromycin and combination therapy with rifabutin for an additional six months and finally received clarithromycin alone as therapy to prevent relapse.[25] All patients receiving clarithromycin in combination showed that bacteria cleared from the blood, compared to only two patients of the five receiving placebo and combination therapy. Of six patients receiving clarithromycin alone to prevent recurrence of disease, only 1 in 5 had a relapse.

Early data from Abbott Laboratories, developer of clarithromycin, indicate that the drug reduces blood levels of AZT by 15%-25%, but the significance of this reduction is not yet known.

CLARITHROMYCIN PROPHYLAXIS The prevention of MAC with clarithromycin is controversial. Abbott Laboratories has put on hold until early 1992 a prophylaxis study using clarithromycin. The company claims to be uncertain as to the dose that should be used for prophylaxis. Since prophylaxis usually employs a lower dose than the dose used for treatment of disease, some physicians are recommending clarithromycin for prophylaxis, using doses in a lower range: 250 or 500 mg/day.[26] It should be noted that mycobacteria are known to develop resistance quite easily. Therefore, there is concern that an inadequate dose might promote resistance, making the drug useless for prophylaxis and treatment. The problem is that if MAC becomes resistant to clarithromycin, it may well become resistant to other similar antibiotics, thus erasing treatment options. Since there is much at risk, it is important to consult with physicians and other experts before deciding to prophylax against MAC.

CLARITHROMYCIN EXPANDED ACCESS Abbott Laboratories announced in April the establishment of an expanded access study of clarithromycin for disseminated MAC infection. This study does not enroll patients who have previously used clarithromycin. However, a second expanded access study was recently announced for patients who have taken clarithromycin before. These patients do not have to test positive for MAC. One obstacle to both of these programs is the amount of paperwork required, which inhibits many physicians from obtaining the drug for patients.

Another problem may be single-agent therapy. Despite the fact that there are more data supporting combination therapy, the Abbott-sponsored expanded access studies use clarithromycin alone. Patients with acute MAC are taking the drug for 12 weeks, and are randomized to receive either 500 mg or 1000 mg, each twice per day. Upon the first follow-up visit in the fourth week of using clarithromycin alone, a physician can add additional drugs if the patient is declining. All additional drugs used thereafter must be reported to Abbott with rationale.

Expanded access is intended to offer earlier treatment to those patients without other options while at the same time collecting data that reflect "real world" use. Current trends indicate that clarithromycin in combination with other drugs is akin to "real world" use and, most importantly, is more beneficial for the patient. A formal clinical study with a control group, rather than an expanded access program, may be a better option for collecting complex data about such use of clarithromycin.

SPARFLOXACIN A new antibiotic called sparfloxacin is about to be tested at 12 sites nationwide.[27] Sparfloxacin is more active in the test tube against MAC than older drugs of its class (called quinolones), including ciprofloxacin. The new studies, to be headed by Dr. Lowell Young, will determine the safety of the drug and, to a lesser degree, its efficacy. Sparfloxacin has been tested extensively in Japan to treat gynecological skin, respiratory, and urinary tract infections. The major side effect associated with the drug is skin sensitivity to sun or ultraviolet light.

Five sites in Denver, CO; Irvine, CA; Orange, CA; Portland, OR, and San Francisco, CA are ready to enroll. Other sites will be announced. Parke-Davis is the only U.S. commercial developer of sparfloxacin for the Japanese pharmaceutical company, Dainippon.

CONCLUSION Disseminated MAC infection is increasingly recognized as a significant illness in PWA's. Combined drug therapies can now lead to symptomatic improvement and are becoming more widely used. As always, there is much yet to learn about optimal therapies for treatment and prevention of MAC. Optimal study designs continue to be explored, since studying combination therapy is more complex than studying single agent therapy. Current experimental studies offer eligible patients some, though not many, alternatives to the handful of drugs currently available.

REFERENCES 1. Wolinsky E. Non-tuberculous mycobacteria and associated diseases. Am Rev Respir Dis: 119:107-59, 1979; and Horsburgh C.R., Jr; Mason U.G., III; et al. Disseminated infection with MAI. Medicine (Baltimore) 64:36-48, 1985.

2. Stine TM et al. A pseudoepidemic due to atypical mycobacteria in a hospital hot water supply. JAMA 258:809-11, 1987.

3. Okello DO et al. Absence of bacteremia with MAI in Ugandan patients with AIDS. J. Infect Dis 162:208-10, 1990.

4. Horsburgh CR, Jr et al. Disseminated infection with MAI. Medicine (Baltimore) 64:36-48, 1985.

5. Horsburgh CR, Jr et al. The epidemiology of disseminated nontuberculous mycobacteria in AIDS. Am Rev Respir Dis 139:4-7, 1989.

6. Chiu J et al. Treatment of disseminated MAC in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. Ann Intern Med 113:358-61, 1990 and Hoy J et al. Quadruple drug therapy for MAI bacterium in AIDS patients. J Infect Dis 161:801-5, 1990.

7. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), abstract #297, Atlanta, October, 1990.

8. VII Internat Conf on AIDS, Abstract #M.C. 3115, Florence, June, 1991.

9. Freidland, G. Opportunistic infections in women. Nat Conf on Women and HIV Infection. Washington, D.C., 1990; and Kloser P. Opportunistic infections in women. Nat Conf on Women and HIV Infection, Washington, D.C., 1990.

10. VI Internat Conf on AIDS, Abstract #251. San Francisco, June, 1990.

11. Metroka C. Prophylaxis for Pneumocystis carinii pneumonia and other opportunistic infections. AIDS Targ Inf News 4(6) 1-2, 1990; VII Internat Conf on AIDS, Abstract #M.B. 2365, Florence, June, 1991.

12. Wayne WG et al. Absence of mycobacterial antibody in patients with AIDS. Eur J Clin Microbiol 5:363-5, 1986.

13. Ruf B et al. Pulmonary manifestations due to MAI in AIDS patients. Am Rev Respir Dis 141 (Supp): A611, 1990.

14. Klatt E.C.; Jensen D.F. et al. Pathology of MAI infection in AIDS. Hum Pathol 18:709-14, 1987.

15. Yagipsky P et al. Cumulative positivity rates of multiple blood cultures for MAI and Cryptococcus neoformans in patients with AIDS. Arch Pathol Lab Med; 114:923-5, 1990.

16. VII Internat Conf on AIDS, Abstract #M.B. 2405, Florence, June, 1991.

17. Horsburgh, C.R., Jr. Mycobacterium avium complex infection in AIDS. NEJM 324 (19):1332-7, 1991.

18. VI Internat Conf on AIDS, Abstract #Th.B. 517, San Francisco, June, 1990.

19. VII Internat Conf on AIDS, Abstract #M.B. 2365, Florence, June, 1991.

20. Hoy J. et al. Quadruple drug therapy for MAI bacteremia in AIDS patients, J Infec Dis 161:801, 1990.

21. Young, L et al. In vitro and in vivo activity of azithromycin against MAC. J. Infec Dis 159:994, 1989.

22. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), abstract #294, Chicago, October, 1991.

23. VI Internat Conf on AIDS, Abstract #Th.B. 518. San Francisco, June, 1990.

24. VII Internat Conf on AIDS, Abstract #W.B. 2300, Florence, June, 1991.

25. VII Internat Conf on AIDS, Abstract #W.B. 2358, Florence, June, 1991.

26. Franke-Ruta G. Clarithromycin Confusion Notes From the Underground. July/August, 1991.

27. Smith D. MAC: new drug, sparfloxacin, enters trials. AIDS Treat News 132:5, 1991.

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