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(STEP) Recent Development In The Treatment And Prevention Of Disseminated Mycobacterium Avium Complex (MAC)




 

STEP PERSPECTIVE, Volume 8, No. 3 - Winter/1996; A Publication

Disseminated Mycobacterium avium complex (DMAC) is the third most common opportunistic disease in people with AIDS, ultimately infecting 30-50% of the patients with very low CD4+ counts, and significantly reducing the length and quality of life. MAC is a group of closely related bacteria that grow in water even chlorinated water as hot as 125 degrees F), soil, house dust, and some animals. However, it does not appear that the MAC organisms in the environment are the exact same as those in the infected people, thus there are no recommendations for avoiding exposure.

People with CD4 cell counts below 75 who have had a previous AIDS-defining opportunistic infection are at greatest risk for developing DMAC. Symptoms of DMAC include high fever, weight loss, fatigue, diarrhea, poor appetite, night sweats, and anemia (low red blood cell counts). The diagnosis of DMAC is usually made by finding the bacteria present in blood or bone marrow cultures.

Prevention of DMAC and the treatment of people with active infection has been very difficult primarily due to drug side effects and resistance. 23% of people on 500m mg of clarithromycin twice daily and about 50% of people using multi-drug regiments have dose limiting drug reactions. 46% of patients receiving clarithromycin alone developed resistance at a median of 16 weeks. Treatment with combinations of 2-4 drugs have serious side effects, often as a result of their complex drug interactions. This article will focus on a few recent favorable reports concerning both the prevention (prophylaxis) and treatment of DMAC.

Two studies were reported in the New England Journal of Medicine on August 8, 1996 evaluating drug therapy to prevent MAC infection in HIV-infected people with less than 100 CD4+ cells. The first study was a randomized trial in which one half of the participants received an antibiotic, clarithromycin (500 mg twice a day), and one half of the participants received a placebo. After about ten months, MAC infection developed in only six percent of the participants who received the clarithromycin, compared to 16% of the participants who received the placebo ( a 69% risk reduction). 50% of the infections occurred in people with CD 4+ counts in the 0-9 range, and all the infections occurred in people with less than 50 CD4+ cells. In the ten month follow-up period, 32% of the clarithromycin treatment group, and 41% of the placebo group died ( a 26% reduction in mortality). One danger of using a drug to prevent an infection is that people who subsequently develop the infection may have a drug resistant infection, which could be more difficult to treat. In this study, 11 of the 19 people who developed DMAC in the clarithromycin group were resistant to the antibiotic, vs. none in the placebo group. Over the course of the study, the death rate was significantly lower in the group which received clarithromycin ( 32% versus 41%).

The second study compared other antibiotics to prevent MAC. Participants received either azithromycin (1200 mg weekly), rifabutin ( 300 mg daily), or both drugs. All the participants were on either 400 mg fluconazole once a week, or 200 mg daily as well. After one year, the rate of MAC infection was 15.3% with rifabutin, 7.6% with azithromycin, and 2.8% with both drugs. In the group treated with azithromycin who subsequently developed MAC, 11% had azithromycin resistance. Even though the best results were observed in the group which received both drugs, side effects limited tolerance in that group significantly. The most common side effects were gastrointestinal symptoms. However, overall, 23% in the combination group, 16% on rifabutin, and 13% on azithromycin had dose limiting toxic effects. A major advantage of azithromycin is that it only needs to be taken once a week. Once a week azithromycin has been shown to reduce the risk of MAC by 60% when compared to a placebo (19.1% one year rate of DMAC vs. 8.2% with 1200 mg of azithromycin once weekly).There are no data evaluating the concomitant use of azithromycin and protease inhibitors.

What, then, is the preferred choice for the prevention of DMAC? Moreover, when should such prophylactic therapy be initiated? A national panel has recommended considering antimicrobial prophylaxis against M. avium when CD4 lymphocyte count falls below 75 in people who have had opportunistic diseases. Choosing a regimen requires balancing efficacy against tolerability, cost, the potential for drug interaction, and the dangers of resistance to the drug. Administering these drugs together with other medications used to treat people with advanced AIDS has substantial pharmacokinetic implications. Serum levels of both clarithromycin and rifabutin increase when they are taken with fluconazole; HIV-protease inhibitors increase the metabolism of clarithromycin and decrease that of rifabutin. Azithromycin has been less well studied, but has not been reported to interact in these ways. The resistance to clarithromycin and azithromycin is a worrisome development, because resistance to one of the two brings with it resistance to the other, so that people with disease due to resistant organisms have limited options for treatment. The above study by Pierce et al. indicates that the benefit in terms of prevention outweighs the risk of drug-resistant regimens as azithromycin and rifabutin in individuals with CD4 counts less than 10, who have up to a 40% risk of acquiring MAC over the course of one year.

Once M. avium disease occurs, antimycobacterial therapy with a combination of drugs is required. The optimal therapeutic regiment remains to be determined. Current regiments to treat MAC usually include 2-3 drug combinations due to the rapid development of resistance if only a single antibiotic is used. A study of ethambutol (15 mg/kg) added to clarithromycin showed prompt improvement in symptoms and reduction in MAC levels in the blood within several months, and was highly effective in preventing the emergence of resistance to the macrolides. The three drug combination of rifabutin (600 mg daily ), ethambutol ( 15 mg per kg daily), and clarithromycin (1000 mg twice daily) was compared to the four drug combination of rifampin (600 mg daily), ethambutol ( 15 mg per kg daily), clofazimine (100 mg daily ), and ciprofloxacin ( 750 mg twice daily) in a recently published study. A total of 229 individuals with active MAC infection, confirmed by blood culture, were randomized to one of the two regiments.

The study found that people treated with the three drug regimen had a greater chance of removing the bacteria from the blood more rapidly (69% vs. 29%), and their survival rates were better than people treated with the four drug regimen ( 8.6 months vs. 5.2 months). The accompanying editorial, cited above, noted that an earlier study showed that the dose of clarithromycin used in this study ( 1000 mg twice daily) was associated with a decreased survival compared to a lower dose of 500 mg twice daily, and the dose of rifabutin had to be lowered because of a 38% incidence of uveitis (inflammation in the eye). However, it was noted that the treatment of MAC infection once present is inferior to primary prevention. Even though the median survival was around seven months, 20% of the participants in Chaisson's study died in the first 12 weeks of treatment. Other drugs available for use in combination therapy for M. avium disease include, clofazimine, rifampin, ciprofloxacin, and amikacin.

Clofazimine, when given with clarithromycin, neither prevents the emergence of resistance to clarithromycin nor prolongs survival. Indeed, recent studies have shown that there was significantly higher mortality when this drug was used in combination with clarithromycin and ethambutol.

Rifampin offers on therapeutic advantage over rifabutin and appears to have more potential for drug interactions.

Ciprofloxacin is poorly tolerated and has marginal in vitro activity, whereas amikacin adds little to oral regimens.

For those persons intolerant to the multi-drug therapies, or who do not respond well to the therapy, steroid administration can reduce symptoms dramatically. Dorman and Sax showed that the addition of 4 mg/day of dexamethasone to their small group of participants who were worsening after a mean of 30.5 days of anti-mycobacterial treatment, had rapid improvement in symptoms. The duration of this benefit varied from a minimum of three months to a maximum of seven months. There was no apparent worsening of baseline prevalent opportunistic infections. Wormser et al. showed that a dose of two mg dexamethasone, in addition to the anti-mycobacterial therapy for people who had progressive weight loss and persistent fever, and an improved sense of well-being.

One of the most potentially serious toxicities of rifabutin is an inflammation in the eye called uveitis. This condition began to show up when rifabutin was used at very high doses (1200+ mg), and when combined with clarithromycin and fluconazole (with rifabutin doses in the 600 mg range). This has occurred in non-HIV patients infected with MAC as well, but only in conjunction with clarithromycin or fluconazole. Before this condition was well known, a group of opthamologists treated the affected people with intensive topical corticosteroid therapy, and were able to continue rifabutin, sometimes without a dose reduction. This condition developed at a range of 51 to 393 days (median, 79 days) after starting rifabutin, clarithromycin and fluconazole. The interaction of these drugs has been discussed above, showing marked elevations of rifabutin levels when combined with either of these other two drugs. These authors felt it was potentially safe to continue rifabutin at lower doses under close supervision if the clinical situation indicated the need. Horsburgh, in his editorial in the New England Journal of Medicine, states that "there is now strong evidence that primary prophylaxis against M. avium disease has a substantial clinical benefit, and such prophylaxis should be considered the standard of care." The question remains: when to begin therapy, but it appears that azithromycin has the least toxic effects and least drug interactions and equal efficacy. Chaisson suggests that treatment of DMAC initially should be with clarithromycin 500 mg twice daily (or azithromycin 600 mg daily) plus ethambutol 15 mg/kg/daily (maximum 1000 mg) with or without rifabutin (300-450 mg daily). In people who may have antibiotic resistant disease, the three drug combination should be used. Treatment of relapsed disease due to resistance is difficult, as there are no additional agents with proven activity. One option is to add two new agents such as amikacin and ciprofloxacin, though the efficacy of such maneuvers is unknown.

About The Authors Jeffrey Schouten is a general surgeon and co-chair of STEP's Scientific Review Committee.

Stan Whittmore is on STEP's Scientific Review Committee and is a member of the Board of Directors.

These articles were provided by the Seattle Treatment Education Project - Copyright (c) 1997 - Seattle Treatment Education Project. Noncommercial reproduction encouraged. Distributed by AEGIS - http://www.aegis.com



 


Copyright © 1996 -STEP, Publisher. All rights reserved to Seattle Treatment Education Project, 1123 East John Street, Seattle, WA 98102. (206) 329-4857 or (877) 597-STEP [7837] (toll-free, valid only in the Pacific Northwest: Washington, Oregon, Idaho, Alaska, and Montana) e-mail Seattle Treatment Education Project

Information in this article was accurate in December 1, 1996. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.