Incidence of Disseminated 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. Early in the HIV epidemic, disseminated MAC infection occurred in 15 to 40% of HIV-infected patients, but then dramatically declined 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, 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.[,] A U.S. study found that MAC ranked 4th among opportunistic infections in HIV-infected patients, with a rate of 2.5 per 1000 patient years in 2003 to 2007.
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. 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.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.[,,] Other risk factors for invasive disease include plasma HIV RNA levels greater than 100,000 copies/mL, eating hard cheese, and respiratory or gastrointestinal colonization with MAC.[,] Although MAC colonization is a risk factor for invasive infection,[,] there are no data supporting the incorporation of colonization status into decisions regarding the provision of prophylaxis; initiating MAC prophylaxis is based only on the patient's CD4 cell count.
Recommendations to Prevent Exposure to MAC
Since MAC is ubiquitous, it is impractical to recommend specific measures to prevent or reduce exposure. Accordingly, the 2013 guidelines for the prevention and treatment of opportunistic infections do not contain any specific recommendations regarding behaviors to avoid contact with MAC.
Recommendations for Initiating Primary Prophylaxis
Antimicrobials used to prevent disseminated MAC work by preventing the transition of MAC colonization to invasive disease. The 2013 guidelines for the prevention and treatment of opportunistic infection recommend that all HIV-infected persons with a CD4 count less than 50 cells/mm3 initiate prophylaxis against MAC. 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 and has not been shown to provide added value to using a CD4 cell count threshold.[,] 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 disseminated MAC infection (e.g. weight loss, fever, night sweats, fatigue, diarrhea, anemia), then it is prudent to obtain blood cultures for MAC and wait 3 weeks before starting prophylaxis to avoid treating disseminated MAC infection with monotherapy. If MAC is isolated from blood culture, then the patient should receive combination antibiotic therapy for MAC. 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 2013 opportunistic infections guidelines recommend azithromycin (Zithromax) 1200 mg once weekly, clarithromycin (Biaxin) 500 mg twice daily, or azithromycin 600 mg twice weekly as preferred therapy for prophylaxis against disseminated MAC (Figure 3). Most medical providers prefer using azithromycin given the convenience of weekly dosing and fewer drug-drug interactions with azithromycin than clarithromycin. In a randomized placebo-controlled trial of 182 patients, azithromycin reduced MAC bacteremia by 72% when compared with placebo (8.2% versus 23.3%). In a similar randomized, placebo-controlled trial of 682 patients, clarithromycin reduced disseminated MAC infection by 69% when compared with placebo (6% versus 16%), but clarithromycin-resistant MAC was detected in 58% of the prophylaxis failures. 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 4), and that azithromycin plus rifabutin was the most effective regimen but was poorly tolerated. 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 5), but combination therapy was associated with more side effects. A 2013 Cochrane review confirmed the equivalence of equivalence of azithromycin and clarithromycin in preventing MAC infection and the superiority of either over rifabutin.
Recommended Alternative Prophylaxis Regimens
Patients who are intolerant of both azithromycin and clarithromycin should receive rifabutin. Combined data from two randomized, placebo-controlled studies 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 6). In addition, those 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. 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.
Discontinuing Primary MAC Prophylaxis
Several studies, including two large randomized, placebo-controlled trials and a large observational study have shown that patients receiving suppressive antiretroviral therapy who have sustained CD4 counts that increase above 100 cells/mm3 have an extremely low risk of developing disseminated MAC.[,,,] Accordingly, the 2013 opportunistic infections guidelines recommended that patients should discontinue primary MAC prophylaxis if they have responded to antiretroviral therapy with an increase in their CD4 count to greater than 100 cells/mm3 for at least 3 months. Discontinuing prophylaxis can reduced pill burden, drug-drug interactions, and potential selection of macrolide- or rifabutin-resistant pathogens. Primary prophylaxis should be reinstated in patients who have discontinued MAC prophylaxis and then experience a subsequent decline in CD4 count to less than 50 cells/mm3. One small observational study found no cases of disseminated MAC in patients with baseline CD4 counts less than 50 cells/mm3 who were on suppressive antiretroviral therapy, but follow up was short (6 months). These data need confirmation in larger trials before a change in the MAC prophylaxis guidelines can be made.