Disseminated MAC in industrialized countries

In the era prior to the widespread availability of HAART in North America, Western Europe and Australia, one-third to one-half of AIDS patients in these regions developed disseminated MAC infection. In the USA, a study reported in 1986 that 53% of 79 autopsies of AIDS patients showed evidence of disseminated MAC [3]. In another study from the late 1980s, conducted in patients with advanced HIV disease who had serial blood specimens cultured for mycobacteria over a median 1-year period, the 2-year actuarial incidence of MAC bacteremia was 40% [1]. In Australia during this same time period, 50% of AIDS patients developed disseminated MAC [4]. Similarly, an autopsy study conducted in Japan in the pre-HAART era reported evidence of disseminated MAC in 40% of 43 autopsies [5]. The risk among European patients was more variable, with patients in northern Europe having a similar risk to US patients, whereas those in southwestern Europe had one-sixth that risk [6]. After HAART became available, the incidence of disseminated MAC dramatically decreased and has subsequently stabilized at a much lower level.

Disseminated MAC in resource-poor countries

Disseminated MAC has been less common in parts of the world where tuberculosis is more prevalent, perhaps because of cross-reactive immunity or perhaps because end-organ disease caused by tuberculosis tends to occur earlier in the course of HIV than disease caused by MAC. In the pre-HAART era, MAC was isolated from the blood of 18% of febrile AIDS patients in a study conducted in Brazil [7]. The point prevalence of disseminated MAC in hospitalized AIDS patients in South Africa has been reported to be only 10% [8], and in Thailand, only 1% [9].

Effect of MAC prophylaxis and ART on incidence

With the advent of MAC prophylaxis in the early 1990s, the incidence of the infection began to decline in Western industrialized countries. Between 1993 and 1994, a 40% decrease in the incidence of adult AIDS-defining disseminated MAC was noted by the US Centers for Disease Control (CDC) that almost certainly resulted from the widespread introduction of rifabutin and macrolide MAC prophylaxis into clinical practice during this time period. After early 1996, when HAART became widely available in North America and Western Europe, the incidence decreased by more than 80% compared with the period before 1994. More recently, a similar decrease in MAC bacteremia has been reported in Brazil after the widespread introduction of HAART in that country [10]. In a recently published prospective cohort study of 8,070 HIV-infected patients from the USA with a median CD4 count of 298 cells/mm³, the incidence of disseminated MAC was only 2.5 new cases per 1,000 patient-years between 2003 and 2007 [11].

Acquisition of MAC infection

MAC is a ubiquitous soil and water saprophyte, and epidemiologic data suggest that disseminated MAC infection results from new environmental acquisition of the organism (rather than reactivation of quiescent, endogenous infection). As an example, a common water source nosocomial outbreak of MAC disease was reported in an AIDS ward [12]. The route of MAC infection in AIDS patients may be through the gastrointestinal or respiratory tract. The presence of large clusters of mycobacteria within macrophages of the small bowel lamina propria suggests that the bowel might be the portal of entry. However, respiratory isolation of MAC frequently precedes disseminated infection, suggesting that MAC infection may begin in the lungs as well [13].

Effect of disseminated MAC infection on survival in AIDS

Because most AIDS patients with disseminated MAC infection have other concomitant infections or neoplasms, and because systemic MAC infection appears to cause little inflammatory response or tissue destruction in patients with advanced AIDS, the relationship between constitutional symptoms, organ dysfunction, and MAC infection was initially uncertain. Nevertheless, several large retrospective studies from the pre-HAART era strongly suggested that disseminated MAC increased mortality and morbidity in AIDS patients. Horsburgh and co-workers noted a median 4-month survival among 39 patients with untreated disseminated MAC infection compared with 11 months among 39 controls matched for CD4 lymphocyte count, prior AIDS status, history of antiretroviral therapy, history of Pneumocystis pneumonia (PCP) prophylaxis, and year of diagnosis (p<0.0001) [14]. At San Francisco General Hospital, among 137 consecutive patients who had a sterile body site cultured for mycobacteria within 3 months of their first AIDS-defining episode of PCP, median survival was significantly shorter in those with disseminated MAC infection than in those who had negative cultures (107 vs 275 days; p < 0.01), even after controlling for age, absolute lymphocyte count, and hemoglobin concentration [13].

Clinical presentation of disseminated MAC

The clinical presentation of disseminated MAC infection almost always includes fever and malaise. Weight loss is common, and anemia and/or neutropenia are often present. Diarrhea and malabsorption may occur as a result of MAC invasion of the gut wall. Abdominal pain may be present and can be severe as a result of bulky retroperitoneal adenopathy. Rarely, extrabiliary obstructive jaundice caused by periportal lymphadenopathy occurs. In a prospective natural history study of MAC bacteremia conducted at San Francisco General Hospital in the pre-HAART era, we observed, among patients with CD4 count <50 cells/mm³, that a history of fever for >30 days, a hematocrit <30%, or a serum albumin level <3.0 g/dL were all sensitive predictors of MAC bacteremia [15]. However, neither severe fatigue, diarrhea, weight loss, nor neutropenia discriminated between those who were subsequently found to be blood culture positive or negative for MAC.

MAC immune reconstitution inflammatory syndrome

As noted above, localized, non-disseminated MAC infection associated with granuloma formation, tissue destruction, and abscess formation in lymph nodes or skin can occur in AIDS patients who have recently initiated antiretroviral therapy [2]. The clinical course is sometimes explosive, with large abscess formations and high fever. In general, these MAC IRIS cases have occurred in patients who had an absolute CD4 count <50 cells/mm³ before initiating ART and have presented soon after the absolute CD4 count rises to >100 cells/mm³. MAC IRIS sometimes involves the bone or lungs, with infiltrates apparent on chest X-ray. Mycobacterial blood cultures are usually negative at the time of presentation. MAC IRIS can present either as a recrudescence of a clinically resolved infection (paradoxical IRIS) or as the new clinical appearance of MAC infection that was previously subclinical (unmasking IRIS). In some observational studies, IRIS has occurred in up to one-third of patients who had a diagnosis of disseminated MAC prior to initiating ART and in up to 4% of all patients who initiate ART with a pre-treatment absolute CD4 count <100 cells/mm³. Unlike disseminated infection, these lesions have responded remarkably well to drainage and antimycobacterial therapy, although a short course of prednisone is sometimes needed before fever resolves. There is no need to discontinue ART in such patients.

Macrolides: clarithromycin and azithromycin

In vivo data on microbiologic efficacy against MAC have been most impressive with two macrolides, clarithromycin and azithromycin. A multicenter, randomized, placebo-controlled, dose-ranging trial of clarithromycin monotherapy in patients with previously untreated disseminated MAC reported a median decrease of >2 log in blood colony-forming units—a more potent microbiologic effect than reported in any earlier treatment trials [22]. This microbiologic effect was accompanied by significant clinical improvement in symptoms and quality of life. However, unacceptably high gastrointestinal toxicity occurred at a dose of 2,000 mg twice daily. Although a 1,000 mg twice-daily dose had greater microbiologic efficacy than 500 mg twice daily, there was actually a trend toward increased mortality with the higher dose. This paradoxical dose–response relationship was subsequently confirmed in another study, indicating that the optimal dose for this drug is 500 mg twice daily. Not surprisingly, drug resistance emerged after 2 months of monotherapy in this trial, affecting approximately half of patients in all dosing arms. Hence, one or more other antimycobacterial agents must be co-administered with the macrolide in an attempt to prevent or at least delay emergence of resistance, which is likely to result in relapse and clinical deterioration. On the other hand, these data should reassure clinicians that inadvertently initiating MAC prophylaxis with clarithromycin in patients who already have subclinical MAC infection is unlikely to lead to drug resistance as long as blood cultures are obtained at the time that clarithromycin is started (i.e. blood cultures will be positive and additional medication can be added before the development of macrolide resistance).

Azithromycin is another effective macrolide for the treatment of MAC. The antimycobacterial efficacy of azithromycin or clarithromycin, when combined with other agents, has been compared in two randomized trials. In one study, 246 patients were randomized to an ethambutol-based regimen combined with either azithromycin 250 mg daily, azithromycin 600 mg daily, or clarithromycin 500 mg twice daily [23]. The low-dose azithromycin arm was terminated early in the trial due to poor microbiologic efficacy. There was no significant difference in either microbiologic or survival outcomes between the high-dose azithromycin and the clarithromycin arms; however, there were non-significant trends toward better survival, greater clearance of bacteremia, and lower relapse rates with clarithromycin in this trial. In another trial, 59 patients with disseminated MAC were randomized to receive an ethambutol-based regimen with either clarithromycin 500 mg twice daily or azithromycin 600 mg once daily. Clearance of bacteremia occurred in 86% of subjects assigned to clarithromycin versus only 38% assigned to azithromycin (p < 0.007) [24]. However, only 37 of the 59 patients were evaluable microbiologically, and only two deaths occurred during the short follow-up period, making it difficult to generalize the results of this trial.