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Case 3: Discussion

Incidence of MAC

Mycobacterium avium complex (MAC) is group of non-tuberculous mycobacteria comprised of three species, two of which are human pathogens (M. avium and M. intracellulare). Among HIV-infected patients with disseminated MAC, more than 90% of cases are caused by M. avium[1]. In the pre-HAART era, disseminated MAC infection occurred in 15 to 40% of HIV-infected patients[2], but then dramatically declined[3] after the introduction and widespread use of effective antiretroviral therapy (Figure 1). Nevertheless, MAC remains one of the most common and important opportunistic infections encountered in HIV-infected patients with advanced immunosuppression[4], mainly occurring in HIV-infected persons who do not know their HIV diagnosis, do not access health care, or choose to not take antiretroviral therapy[5]. A recent US study found that MAC ranked 4th among opportunistic infections in HIV-infected patients, with a rate of 2.5 per 1000 patient years between 2003 to 2007[3].

Pathogenesis of Disseminated MAC

Mycobacterium avium complex organisms are ubiquitous and are found in soil, water, and a variety of animals, thus making exposure unavoidable[2]. Humans are intermittently colonized with MAC, but rarely develop clinically significant infection in the absence of structural lung disease or immune deficits. Acquisition presumably occurs by ingestion or inhalation. Among immunocompetent hosts, tissue macrophages ordinarily ingest and kill colonizing MAC organisms and abort infection. In patients with advanced HIV disease, defective macrophage-mediated killing permits uncontrolled, intracellular replication of MAC. Infected macrophages then rupture and release organisms that spread locally to other macrophages and disseminate throughout lymphatics and the bloodstream[6]. The major identified risk factor for disseminated MAC is advanced HIV disease (Figure 2); and patients who develop disseminated MAC almost always have a CD4 count of less than 50 cells/mm3[2,7,8]. Although respiratory and gastrointestinal colonization without clinically-evident infection can occur, 50 to 60% of advanced-stage AIDS patients who are colonized and do not receive MAC prophylaxis or effective antiretroviral therapy will develop disseminated MAC disease within 1 year[9,10].

Recommendations to Prevent Exposure to MAC

Since MAC is ubiquitous, it is impractical to recommend specific measures to prevent or reduce exposure. In turn, the 2009 United States guidelines for the prevention and treatment of opportunistic infections in HIV-infected persons do not contain any recommendations to avoid contact with MAC[1].

Recommendations for Initiating Primary Prophylaxis

The strategy of screening respiratory or gastrointestinal specimens for MAC to identify patients who are more likely to develop invasive disease is not recommended because screening has low sensitivity[10]. Antimicrobials work to prevent disseminated MAC by halting the transition of MAC colonization to invasive disease. The 2009 opportunistic infection guidelines recommend that all HIV-infected persons with CD4 counts less than 50 cells/mm3 initiate prophylaxis against disseminated MAC (Figure 3); these guidelines include a rating scheme indicating the strength of the recommendation (A-E) and the quality of evidence supporting the recommendation (I-III) (Figure 4). Prior to initiating prophylaxis, patients should be evaluated for active MAC infection by clinical assessment that may include a blood culture for MAC. If patients exhibit signs and symptoms suggesting occult infection (e.g. weight loss, fever, night sweats, fatigue, diarrhea, anemia), then it is prudent to wait 2 weeks for blood cultures to return before starting prophylaxis to avoid treating cryptic MAC infection with monotherapy. In addition, it is important to avoid rifabutin for MAC prophylaxis in any patient with possible active tuberculosis, since the use of rifabutin in such patients could result in the rapid emergence of rifabutin and rifampin resistant M. tuberculosis.

Recommended First Choice Prophylaxis Regimens

The 2009 opportunistic infections guidelines[1] recommend azithromycin (Zithromax) 1200 mg once weekly or clarithromycin (Biaxin) 500 mg twice daily as preferred choices for prophylaxis against disseminated MAC (Figure 3). Most medical providers prefer the once weekly azithromycin given the convenience of weekly dosing and fewer drug-drug interactions with azithromycin than clarithromycin. For those patients with gastrointestinal intolerance due to the once weekly azithromycin dosing (1200 mg), the azithromycin dose can be divided into two 600 mg doses taken at least 24 hours apart. In a randomized placebo-controlled trial[11] of 182 patients, azithromycin reduced MAC bacteremia by 72% (23.3 versus 8.2%, on treatment)[11]. In a similar randomized, placebo-controlled trial of 682 patients, clarithromycin reduced disseminated MAC infection by 69% (6% versus 16%), but clarithromycin-resistant MAC was detected in 58% of the prophylaxis failures[12]. The California Collaborative Treatment group compared weekly azithromycin, daily rifabutin (Mycobutin), or both in preventing disseminated MAC and found that azithromycin was more effective than rifabutin (Figure 5), and that azithromycin plus rifabutin was the most effective regimen but was poorly tolerated[13]. Similarly, in an AIDS Clinical Trials Group study, clarithromycin and the combination clarithromycin plus rifabutin were more effective in preventing disseminated MAC than rifabutin alone (Figure 6), but, again, combination therapy was associated with more side effects[14].

Recommended Alternative Prophylaxis Regimens

Patients who are intolerant of both azithromycin and clarithromycin should receive rifabutin[1]. Combined data from two randomized, placebo-controlled studies[15] of patients with CD4 counts less than 200 cells/mm3 showed an approximate 50% decrease in the incidence of MAC bacteremia among those taking rifabutin (Figure 7). In addition, those patients with breakthrough bacteremia on rifabutin did not have an increase in rifabutin-resistant MAC and a follow-up analysis of all study participants revealed improved survival in the rifabutin treated subjects[16]. Rifabutin is a CYP3A inducer and substrate and significant drug-drug interactions may occur when using this medication; dose adjustments of rifabutin and other medications may be necessary[1].

Discontinuing Primary MAC Prophylaxis

Several studies, including two large randomized, placebo-controlled trials, have shown that patients receiving effective antiretroviral therapy who have CD4 counts that increase to above 100 cells/mm3 for at least 3 months have an extremely low risk of developing disseminated MAC[17,18,19]. These studies included two large randomized, placebo-controlled trials[17,18], and in these studies, patients generally had sustained excellent responses to antiretroviral therapy. Accordingly,the 2009 USPHS opportunistic infections guidelines recommended that patients should disconti nue primary MAC prophylaxis if they have responded to effective antiretroviral therapy with an increase in their CD4 count to greater than 100 cells/mm3 for at least 3 months[1].Discontinuing prophylaxis can reduce pill burden, cost, the potential for drug toxicity, and the risk of developing resistant infectious pathogens. One large retrospective study of patients who discontinued primary prophylaxis against MAC in line with recommended guidelines demonstrated no increased risk for disseminated MAC infection[20]. If patients stop MAC prophylaxis and then experience a subsequent decline in CD4 count that subsequently decreases to less than 50 cells/mm3, they should restart prophylaxis[1].

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    Figure 1. Incidence of Disseminated <em>Mycobacterium</em> <em>avium</em> Complex Infections in US. The HIV Outpatient Study 1994-2007

    This figure is based on data from Buchacz K, Baker RK, Palella FJ Jr, et al. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study.  AIDS. 2010;24:1549-59.


    Figure 1
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    Figure 2. Risk of Developing MAC Bacteremia Related to CD4 Cell Count

    This figure is based on data from from Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis. 1992;165:1082-5.


    Figure 2
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    Figure 3. Primary Prophylaxis for Disseminated <em>Mycobacterium</em> <em>avium</em> Complex

    This figure is adapted from Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 3
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    Figure 4. Rating Scheme for Opportunistic Infections Prevention and Treatment Recommendations

    This figure is adapted from Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 4
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    Figure 5. Rifabutin versus Azithromycin versus Rifabutin plus Azithromycin for Prevention of Disseminated MAC

    Abbreviations: ITT = intent to treat. This figure is based on data from Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group. N Engl J Med. 1996;335:392-8.


    Figure 5
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    Figure 6. Rifabutin versus Clarithromycin versus Rifabutin plus Clarithromycin for Prevention of Disseminated MAC

    Abbreviations: ITT = intent to treat. This figure is based on data from Benson CA, Williams PL, Cohn DL, et al. Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: A randomized, double-blind, placebo-controlled trial. The AIDS Clinical Trials Group 196/Terry Beirn Community Programs for Clinical Research on AIDS 009 Protocol Team. J Infect Dis. 2000;181:1289-97.


    Figure 6
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    Figure 7. Risk of Developing MAC Bacteremia in Two Trials Comparing Rifabutin and Placebo

    This figure is based on data from Nightingale SD, Cameron DW, Gordin FM, et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med. 1993;329:828-33.


    Figure 7