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Mycobacterium avium complex (MAC) infections in persons with HIV

Mycobacterium avium complex (MAC) infections in persons with HIV
Literature review current through: Aug 2023.
This topic last updated: Feb 08, 2023.

INTRODUCTION — Mycobacterium avium complex (MAC) refers to infections caused by one of two nontuberculous mycobacterial species, either M. avium or M. intracellulare. Infection with these organisms can occur in patients with or without human immunodeficiency virus (HIV) infection. The two principal forms of MAC infection in patients with HIV are disseminated disease and focal lymphadenitis. By contrast, isolated pulmonary infection is typically seen in immunocompetent patients, often in those with structural lung disease.

Among persons with HIV, MAC infection is most commonly seen among those with a CD4 count <50 cells/microL. Dramatic declines in the rate of new MAC cases accompanied the use of prophylaxis against MAC infection early in the epidemic, and more recently, the widespread use of effective antiretroviral therapy [1-3].

The epidemiology, clinical manifestations, diagnosis, treatment, and prevention of MAC infection in HIV disease will be reviewed here. MAC infections in patients without HIV are discussed separately. (See "Microbiology of nontuberculous mycobacteria" and "Overview of nontuberculous mycobacterial infections" and "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

EPIDEMIOLOGY — The incidence of MAC in persons with HIV has decreased with the widespread use of potent antiretroviral therapy (ART) [4]. In studies published in the early 1990s, the incidence of disseminated MAC ranged from 20 to 40 percent in patients with advanced immunosuppression not receiving MAC prophylaxis [5,6]. However, with the widespread use of effective ART, the incidence has decreased to ≤2 cases per 1000 person-years among individuals in care [7-9].

The risk of MAC infection in patients with HIV increases as the CD4 count declines below 50 cells/microL. Other risk factors include HIV ribonucleic acid (RNA) levels >1000 copies/mL, ongoing viral replication despite ART, and previous or concurrent opportunistic infections (OIs) [4]. In an observational study that included 135 patients who were diagnosed with MAC after the year 2000, most cases were seen in underrepresented groups, and in those with delayed entry and/or failure to consistently engage care [8].

The risk of MAC does not appear to vary by sex, ethnicity, or route of transmission. However, the risk may differ depending upon the geographic location. As an example, in one study rates of MAC disease were higher in the southern than in the northern United States and Canada (22 versus 14 percent) [10]. In addition, MAC infection has been reported to be more common in persons with HIV in the United States than in Europe [11].

One international study found significantly higher rates of disseminated MAC in resource-rich compared with resource-limited countries (10 to 22 percent versus 2 to 3 percent) [12]. In this study, risk factors for disseminated disease in the United States and Finland included low CD4 count, use of an indoor pool for swimming, previous bronchoscopy, repeated consumption of raw or partially cooked fish or shellfish, and therapy with granulocyte stimulating factor.

Patients with disseminated MAC may also have a genetic predisposition to infection. In a nested case-control study from the Multicenter AIDS Cohort that compared 176 patients who had disseminated MAC with 176 matched controls, specific human leukocyte antigen (HLA) class II alleles (DRB1, DQB, DM) were more commonly found in association with disease [13].

TRANSMISSION — The mode of infection for MAC is thought to be through inhalation or ingestion. MAC organisms are ubiquitous in the environment, including water and soil [14]. (See "Epidemiology of nontuberculous mycobacterial infections", section on 'Mycobacterium avium complex'.)

There is no need for isolation of hospitalized patients with MAC infection since person-to-person or common source transmission of MAC appears to be rare. In one report that evaluated 32 patients with acquired immunodeficiency syndrome (AIDS) and MAC from a daycare center in France over a 13-month period, the strains of organisms were heterogeneous by pulsed-field gel electrophoresis [15]. Another series of 130 isolates from children, both HIV-infected and not infected, also failed to show a clonal origin for the strains, although children with HIV were more commonly infected with M. avium than controls (88 versus 38 percent) [16].

PATHOGENESIS — Unlike some other opportunistic infections in patients with AIDS, MAC infection is thought to result from recent acquisition rather than reactivation, since latent infection does not exist with this organism. The portals of entry for the organism appear to be the respiratory and gastrointestinal tract with bacteremia following dissemination via the lymphatics. (See 'Transmission' above.)

Virulence factors for MAC have not been established. One study suggested that differential virulence among strains, as assessed by cell invasion or macrophage replication assays, varies among colonizing strains as compared with those associated with disseminated disease [17].

The mechanisms of interaction among MAC, HIV-1 virus, and the immune system are also incompletely understood. In one study, tumor necrosis factor (TNF)-alpha levels were increased and the HIV macrophage-tropic receptor, CCR5, was upregulated by monocytes exposed in vitro to MAC organisms or antigens [18]. The expression of the T cell-tropic receptor, CXCR4, was not affected. HIV-1 production was also increased in macrophage tissue culture cells previously exposed to MAC antigens. In lymph node tissue coinfected with MAC and HIV-1, increased levels of CCR5 were demonstrated in comparison to lymph nodes infected with HIV-1 alone.

Receipt of granulocyte stimulating factor was identified as a possible epidemiologic risk factor for disseminated MAC [12]. However, in one in vitro study, neutrophils harvested from AIDS patients treated with granulocyte-colony stimulating factor (G-CSF) produced enhanced killing of M. avium compared with cells from patients treated with G-CSF plus rifabutin or rifabutin alone (90 versus 59 and 11 percent, respectively) [19].

CLINICAL MANIFESTATIONS — The two principal forms of MAC infection in HIV are disseminated and localized disease. Isolated pulmonary infection is typically seen in immunocompetent patients. (See "Overview of nontuberculous mycobacterial infections", section on 'Pulmonary disease'.)

Disseminated infection — Prior to the widespread use of potent antiretroviral therapy (ART), MAC most commonly presented as disseminated disease. Symptoms of disseminated MAC are generally nonspecific and include fever, night sweats, abdominal pain, and diarrhea. In one series of nine patients, fever ≥39ºC was found in 78 percent, weight loss in 100 percent, cough in 78 percent, and diarrhea in 44 percent [20]. While lymphadenopathy can occur in disseminated disease, it is more likely to be diffuse and less noticeable than in localized disease. (See 'Lymphadenitis' below.)

Laboratory abnormalities in disseminated infection frequently include anemia and elevated alkaline phosphatase and lactate dehydrogenase. The diagnosis is typically confirmed by the isolation of MAC from the blood. (See 'Diagnosis' below.)

It is well established that disseminated MAC disease was associated with a shortened survival in patients with AIDS prior to the era of potent ART. In one study, a diagnosis of MAC was associated with a threefold increased risk of death, independent of CD4 count [21]. The increased mortality may be explained by upregulation of HIV RNA or by direct effects of MAC infection [22]. (See 'Pathogenesis' above.)

Localized disease

Lymphadenitis — The symptoms of localized adenitis include fever, leukocytosis, and focal inflammation in and enlargement of a lymph node (eg, cervical, intraabdominal, mediastinal). In patients with HIV infection, most cases of MAC lymphadenitis result from an immune reconstitution inflammatory syndrome (IRIS) [23,24]. (See "Immune reconstitution inflammatory syndrome".)

Case series suggest that focal inflammatory lymphadenitis develops approximately four weeks after ART is initiated [23,25-29]. MAC lymphadenitis due to IRIS can present in patients without a prior diagnosis of MAC (the "unmasking" form), or can develop in those with previously diagnosed disseminated infection. (See 'Disseminated infection' above.)

Uncommon manifestations — Unusual presentations of localized MAC infection have been reported in the era of potent ART. As an example, spinal MAC has been described in patients with a more prolonged response to ART after having a nadir CD4 count <50 cell/microL [25,30]. Other unusual manifestations include mastitis [31], necrotic subcutaneous nodules, osteomyelitis, bursitis [32], granulomatous hepatitis, paravertebral abscesses [29], brain abscess [33], worsening lung infiltrates, and diffuse intestinal involvement presenting with abdominal pain [34].

DIAGNOSIS

Radiographic imaging — Abdominal computed tomography (CT) is a valuable part of the initial diagnostic evaluation in patients with suspected localized disease. Such patients typically demonstrate mesenteric/abdominal lymph node enlargement. (See 'Localized disease' above.)

CT imaging may also be helpful in the diagnostic evaluation of disseminated disease. Findings supportive of disseminated infection include lymphadenopathy, hepatosplenomegaly, and/or small bowel thickening. However, one retrospective study of 24 patients with AIDS and positive blood cultures for MAC found this test to be relatively insensitive [35]. Lymphadenopathy, hepatomegaly, and splenomegaly were found in 42, 50, and 46 percent, respectively, and thickening of the small bowel wall was observed in only 14 percent of the scans. Most notably, the CT was normal in 25 percent of the patients.

Identifying the organism

Disseminated disease – The diagnosis of MAC is typically made by isolation of the organism in culture, usually of the blood or lymph node. When the BACTEC culture system is used, the cultures usually become positive in 7 to 10 days. Species identification using DNA probes distinguishes MAC from Mycobacterium tuberculosis. Some labs may quantify the mycobacterial load; high mycobacterial loads (>2 log10 colony-forming units/mL) may be a poor prognostic sign [4].

Bone marrow culture can also yield the organism, sometimes before blood cultures turn positive [36,37]. The organism can also be cultured from a liver biopsy specimen. However, blood cultures are usually the preferred initial diagnostic test as they are less invasive.

There is a limited role in obtaining cultures of respiratory secretions or stool to diagnose MAC. A prospective study documented that colonization of the respiratory and gastrointestinal tract had a sensitivity of approximately 20 percent and a positive predictive value of about 60 percent for detecting disseminated disease [38].

Localized disease – Blood cultures are almost always sterile in patients with localized disease. Thus, the diagnosis is usually confirmed by culture of a tissue aspirate, typically a lymph node. However, in some cases (eg, those already on MAC treatment), the culture may be negative. In this setting, histologic evaluation reveals well-formed granulomas with relatively few visible organisms [39].

THERAPY — For patients with AIDS, treatment of Mycobacterium avium complex (MAC) infection involves combination antimicrobial therapy. (See 'Antimicrobial regimen' below.)

In addition, antiretroviral therapy (ART) should be initiated or modified to suppress viremia. The timing of ART initiation in those who are treatment naïve is discussed below. (See "Immune reconstitution inflammatory syndrome" and 'When to initiate antiretroviral therapy' below.)

Antimicrobial regimen

General principles — For patients with AIDS and disseminated or localized MAC infection, we recommend treatment with combination antimicrobial therapy. Agents with activity against MAC include clarithromycin, azithromycin, ethambutol, rifabutin, amikacin, streptomycin, and fluoroquinolones.

For most patients, we initiate dual therapy with a macrolide plus ethambutol. (See 'Choice of macrolide' below and 'Choice of second agent' below.)

We add a third agent (eg, rifabutin) in patients failing ART and in patients with a high mycobacterial burden (eg, based on quantitation in the blood culture) (see 'Identifying the organism' above and 'When a third agent should be used' below). Liposomal inhaled amikacin can be considered in patients failing therapy. Although its role has not been defined in patients with HIV, it is sometimes used as adjunctive therapy in patients without HIV who fail six months of standard MAC therapy [40-42].

Treatment should be continued for at least 12 months. (See 'Duration of MAC therapy' below.)

Susceptibility testing should be performed on all MAC isolates, most importantly for macrolide sensitivity. However, antimicrobial therapy should not be delayed pending these results. If resistance to macrolides is detected, the regimen can be modified. (See 'If a macrolide cannot be used' below and 'Treatment failure' below.)

Treatment with more than one agent is necessary for treatment of MAC to decrease the risk of drug resistance. In a study of 154 patients with AIDS and MAC bacteremia treated with clarithromycin monotherapy, resistance emerged in 46 percent at a median of 16 weeks [43]. By contrast, when combination therapy was used, resistance as low as 3 percent was reported [44]. Combination therapy is also associated with more rapid clearance of MAC from the bloodstream [45].

Choice of macrolide — Azithromycin (500 to 600 mg daily) or clarithromycin (500 mg twice daily) should be used as part of the dual therapy regimen. Regimens that include macrolides appear to be the most effective [46,47].

Although clarithromycin is preferred by guideline panels [4], azithromycin is an acceptable initial treatment that is used frequently, particularly if there are concerns for drug interactions or intolerance. Before the introduction of potent ART, clarithromycin was found to have superior efficacy as compared with azithromycin and was therefore recommended as first-line treatment [48]. However, there are no comparative studies in the era of potent ART.

Choice of second agent — Ethambutol (15 mg/kg by mouth [PO] once daily) is the preferred second agent based upon data from four randomized trials of MAC therapy in patients with AIDS [44,46,49,50]. These trials found that ethambutol-containing regimens lowered the rate of relapse compared with other regimens.

Rifabutin can also be used as the second agent, but it is typically administered only if ethambutol is not tolerated. Information on dosing is found below. (See 'When a third agent should be used' below.)

There is less experience using rifabutin as part of a two drug regimen, and rifabutin is associated with an increased risk of drug interactions (especially if clarithromycin is used as the macrolide). There is a bidirectional drug interaction between clarithromycin and rifabutin, producing lower levels of clarithromycin and higher levels of both rifabutin and 14-OH-clarithromycin (the major metabolite of clarithromycin) [51]. In one study, uveitis secondary to rifabutin occurred in a substantial proportion of patients when rifabutin (600 mg daily) was combined with clarithromycin [52]. The dose of rifabutin and lower body weight were associated with an increased risk of uveitis. The incidence of uveitis was 14 percent in patients weighing >65 kg, 45 percent in patients between 55 and 65 kg, and 64 percent in patients <55 kg. By contrast, the risk of uveitis was decreased when a lower dose of rifabutin (300 mg daily) was used.

Since rifabutin inhibits CYPA4, there are also drug interactions with HIV protease inhibitors and integrase strand transfer inhibitors. As an example, the dose of rifabutin must be reduced in patients receiving a protease inhibitor. In addition, rifabutin should be avoided in patients receiving bictegravir, since rifabutin significantly decreases serum concentration of bictegravir. More detailed information on specific drug interactions can be found within the individual drug monographs within UpToDate and within separate topic reviews. (See "Overview of antiretroviral agents used to treat HIV".)

When a third agent should be used — We suggest a third drug be added in patients failing ART. The third agent can be discontinued if the HIV viral load becomes suppressed. It is also reasonable to add a third agent if there is evidence of a high mycobacterial burden (eg, >2 log10 colony-forming units/mL of blood) [4]; however, the duration of treatment with a third agent in this setting is unclear since many labs do not routinely quantify the mycobacterial load and there is less experience treating patients when the mycobacterial load is used as the indication for adding additional agents.

Our approach to choosing a third agent is as follows:

If possible, we prefer rifabutin (300 mg PO daily), since combination therapy with rifabutin as the third agent has been supported in a randomized trial [45]. The dose of rifabutin may need to be adjusted based upon drug-drug interactions (eg, if ritonavir is used as part of the patient’s antiretroviral regimen). In addition, rifabutin should not be co-administered with bictegravir, as discussed above. Detailed information on drug interactions can be found in the Lexicomp drug interaction program within UpToDate.

If rifabutin cannot be used as the third agent, fluoroquinolones can be administered (eg, levofloxacin 500 mg PO daily or moxifloxacin 400 mg PO daily). If fluoroquinolones cannot be used, a parenteral aminoglycoside can be administered (eg, amikacin 10 to 15 mg/kg intravenous [IV] for approximately two to four months). The efficacy of these drugs as third agents has not been documented in clinical trials. A newer option, liposomal inhaled amikacin, has not been studied in the setting of HIV but is recommended as an option for patients failing MAC treatment in other settings [42]. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults", section on 'Cavitary or severe nodular bronchiectatic disease' and "Treatment of Mycobacterium avium complex pulmonary infection in adults", section on 'Efficacy of alternative agents'.)

Clofazimine should generally be avoided in patients with HIV who have MAC, although data are limited from the current HIV treatment era. In one study of 106 patients with AIDS and MAC bacteremia who were randomly assigned to treatment with a two-drug (clarithromycin and ethambutol) or three-drug (the same two drugs plus clofazimine) regimen, the clofazimine regimen was associated with a higher mortality rate (61 versus 38 percent) [49].

AIDS Clinical Trials Group Study 223, conducted during the pre-combination ART era, compared three clarithromycin-containing regimens for the treatment of disseminated MAC [45]. Mycobacteremic patients were randomized to open-label therapy with clarithromycin plus ethambutol, clarithromycin plus rifabutin, or the three-drug combination of clarithromycin, ethambutol, and rifabutin. The rates of complete microbiologic response were the same in all three treatment groups at 12 weeks (40, 42, and 51 percent, respectively). However, the group who received the three-drug combination had significantly improved survival compared with the group who received clarithromycin and ethambutol (hazard ratio [HR] 0.44; 95% CI 0.23-0.83) and the group who received clarithromycin and rifabutin (HR 0.49; 95% CI, 0.26-0.92). Although this study was conducted during a time period that spanned the introduction of protease inhibitors (35 percent of subjects reported taking a protease inhibitor prior to or during the study), the survival benefit from the three-drug arm persisted after controlling for protease inhibitor use.

If a macrolide cannot be used — If possible, a macrolide should be included as part of the regimen used to treat MAC. (See 'Choice of macrolide' above.)

However, on occasion a patient may have a history of an allergy to macrolides, or the organism may not be sensitive. In this setting, at least two agents should be used. A regimen such as rifabutin plus ethambutol with or without a third agent such as a quinolone is reasonable (see 'When a third agent should be used' above). The ultimate combination depends upon the results of susceptibility testing.

Patient monitoring

Response to treatment — Improvement in the fever curve should be seen two to four weeks after initiation of therapy. If no clinical improvement is seen, a repeat blood culture should be obtained to determine if the patient has ongoing mycobacteremia.

For patients with ongoing mycobacteremia, drug resistance testing should be performed, particularly if the patient developed MAC disease while taking prophylaxis. Although macrolide resistance is common in the setting of monotherapy, some studies have demonstrated azithromycin and clarithromycin sensitivity in patients who failed primary prophylaxis [4,53]. (See 'Prevention of MAC disease' below.)

The management of patients with treatment failure is discussed below. (See 'Treatment failure' below.)

Adverse events — Potential adverse events associated with treatment of MAC infection include gastrointestinal intolerance, abnormal liver function tests related to macrolides, uveitis related to rifabutin, and optic neuritis related to ethambutol. Patients should have baseline and monthly testing for color vision and visual acuity during ethambutol therapy.

More detailed information on the adverse effects of these agents, as well as alternative agents (eg, quinolones, aminoglycosides) are found in the Lexicomp drug information topics within UpToDate and in separate topic reviews. (See "Azithromycin and clarithromycin", section on 'Adverse reactions' and "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Rifabutin' and "Ethambutol: An overview", section on 'Adverse reactions' and "Fluoroquinolones", section on 'Adverse effects' and "Aminoglycosides", section on 'Toxicity'.)

Duration of MAC therapy — All patients with HIV who are diagnosed with MAC infection should receive a minimum of 12 months of MAC therapy. However, the ultimate duration depends upon how fast the patient has recovery of their immunologic function after initiating ART since the CD4 count should be stably above 100 cells/microL for at least six months before discontinuing MAC treatment [4]. (See 'When to initiate antiretroviral therapy' below.)

After discontinuing treatment, patients should be followed to ensure continued suppression of the HIV viral load and maintenance of CD4 cell counts. If the CD4 count falls to <50 cells/microL, MAC prophylaxis should be started. (See 'Prevention of MAC disease' below.)

Several studies support that MAC therapy can be safely discontinued in patients receiving ART after recovery of immune function [54-56].

The largest study was a prospective observational cohort that included patients from Europe. In this cohort, 103 patients had disseminated MAC and were treated with ethambutol plus clarithromycin or azithromycin, with or without rifabutin [54]. Maintenance therapy for the infection was stopped at a median CD4 count of 190 cells/microL (range, 129 to 290), and 80 percent of patients had viral loads <500 copies/mL (range, <500 to 1183). Two patients relapsed for a relapse rate of 1 per 100 person-years of follow-up.

A retrospective analysis evaluated 52 patients who discontinued MAC therapy after viral load reduction; patients had been on MAC therapy for a median of 32 months (range 4 to 87), and follow-up after cessation of treatment was for a median of 20 months (4 to 52 months) [55]. One patient experienced relapse two months following discontinuation of ART for an increased viral load.

Another series prospectively followed 48 patients with median CD4 counts of 240/microL who discontinued maintenance MAC therapy after receiving macrolide-based treatment for at least 12 months and ART for a minimum of 16 weeks [56]. During a median of 77 weeks of follow-up, one patient developed osteomyelitis due to MAC while the other 47 patients remained free of MAC infection, for an incidence of 1.44 cases per 100 person-years.

Special considerations

When to initiate antiretroviral therapy — If a patient is on ART at the time of diagnosis, ART should be continued and optimized if viremia is not suppressed. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

If a patient is treatment-naïve or is not currently taking ART, ART should be initiated as soon as possible after MAC therapy has been started. Early ART is beneficial in patients with most opportunistic infections and can prevent the development of a second opportunistic infection [57-60]. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Patients with opportunistic infections'.)

Detailed discussions of selecting an ART regimen are presented separately. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Overview of antiretroviral agents used to treat HIV".)

Treatment failure — Treatment failure is defined by lack of clinical response in the setting of ongoing mycobacteremia. (See 'Response to treatment' above.)

Results of susceptibility testing should be used to construct a new multidrug regimen with at least two new agents. A macrolide should be continued if the isolate remains susceptible. Other agents may include: ethambutol, rifabutin, ciprofloxacin or levofloxacin, or amikacin. More detailed discussions of these agents are found above. (See 'When a third agent should be used' above and 'If a macrolide cannot be used' above.)

Optimizing ART is also an important adjunct to therapy. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Adjunctive therapy for IRIS — For patients who develop IRIS related to MAC infection, ART should be continued. Although symptoms related to IRIS may last for weeks, most patients are treated successfully with antimicrobial therapy alone. (See 'Therapy' above.)

However, for patients with severe symptoms and a prominent inflammatory component, certain adjunctive treatments may be used in conjunction with antimicrobial therapy. These include drainage or aspiration of the inflamed lymph nodes, nonsteroidal anti-inflammatory agents, and/or adjunctive corticosteroids (eg, the equivalent of 20 to 40 mg prednisone for four to eight weeks) [4].

PREVENTION OF MAC DISEASE — For patients with a CD4 count <50 cells/microL who are initiating antiretroviral therapy (ART), we do not routinely administer antimicrobial prophylaxis to prevent Mycobacterium avium complex (MAC). This approach is consistent with recommendations from the International Antiviral Society-USA (IAS-USA) guidelines panel and the Department of Health and Human Services Opportunistic Infections guidelines [4,61]. The exception to this includes patients with a CD4 count <50 cells/microL who are not on fully suppressive ART. In this setting, if there are concerns that the patient may have active MAC infection (eg, fevers, weight loss), a mycobacterial blood culture should first be obtained, and prophylaxis should be delayed for 7 to 10 days, pending the results. (See 'Clinical manifestations' above and 'Diagnosis' above.)

When prophylaxis is indicated, we prefer weekly azithromycin (1200 mg once weekly) or daily clarithromycin (500 mg twice daily). Rifabutin (300 mg daily) is an alternative; however, if rifabutin is used for prophylaxis, active tuberculosis should be ruled out before starting therapy. In placebo-controlled trials, clarithromycin, azithromycin, and rifabutin have each been shown to be effective in reducing the incidence of MAC and reducing mortality in patients with HIV infection [53,62,63], although rifabutin is less effective than the macrolides. MAC prophylaxis can later be stopped six months after the patient achieves viral suppression on ART.

The use of MAC prophylaxis was common practice for all patients with HIV and a CD4 count <50 cells/microL prior to the introduction of potent ART. However, our approach has changed since the risk of MAC infection appears low in patients receiving potent ART, and the benefit of MAC prophylaxis is unclear in this setting [64-66]. As an example, the incidence of MAC was 0.6 per 100 person-months in an observational study of 369 patients with HIV and a CD4 count <50 cells/microL who were on ART and followed for at least six months [65]. Furthermore, in this study, none of the 71 patients who had a viral load <1,000 copies/mL developed MAC; this included 41 persons who were not receiving MAC prophylaxis. In another study, in which patients on ART with a CD4 count <50 cells/microL were followed for 12 months, there was no significant difference in the incidence of MAC among the 33 who received primary MAC prophylaxis versus the 122 who did not (3.4/100 person-years versus 0.8/100 person-years, respectively) [66].

In addition to the apparent lack of benefit of primary MAC prophylaxis in patients receiving potent ART, potential harms include adverse drug reactions, drug interactions, and on rare occasion, the risk of acquired drug resistance [4]. (See 'Treatment failure' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)

SUMMARY AND RECOMMENDATIONS

Definition Mycobacterium avium complex (MAC) refers to infections caused by one of two nontuberculous mycobacterial species: M. avium or M. intracellulare. MAC infection is most commonly seen among patients with AIDS and a CD4 count <50 cells/microL. (See 'Introduction' above.)

Epidemiology These organisms are ubiquitous in the environment, including water and soil. Infection probably occurs most often through inhalation. There is no need for isolation of hospitalized patients with MAC infection since person-to-person transmission does not appear to be common. (See 'Epidemiology' above.)

Clinical manifestations The two principal forms of MAC infection in HIV are disseminated and localized disease. (See 'Clinical manifestations' above.)

Disseminated disease The most common symptoms of disseminated MAC include fever, night sweats, abdominal pain, diarrhea, and weight loss. Laboratory abnormalities frequently include anemia and elevated alkaline phosphatase and lactate dehydrogenase. (See 'Disseminated infection' above.)

Localized disease Localized disease typically occurs in patients with immune reconstitution inflammatory syndrome after initiation of antiretroviral therapy (ART). The symptoms of localized disease generally include fever, leukocytosis, and focal inflammation in a lymph node (cervical, intraabdominal, mediastinal). (See 'Localized disease' above.)

Diagnosis The diagnosis of MAC is typically confirmed by the isolation of MAC from the blood in patients with disseminated disease or by isolation of the organism from a lymph node in localized disease. Species identification using DNA probes distinguishes MAC from Mycobacterium tuberculosis. (See 'Disseminated infection' above.)

Management

Antimicrobial therapy

-For patients with confirmed MAC infection, we recommend combination therapy (Grade 1B). We administer a macrolide (clarithromycin or azithromycin) in combination with ethambutol. Azithromycin is typically preferred if there are concerns for drug interactions or intolerance. (See 'Antimicrobial regimen' above.)

-For those failing ART, we suggest that a third agent be added for the treatment of MAC (Grade 2B). If possible, we prefer rifabutin. However, if rifabutin cannot be used, fluoroquinolones or a parenteral aminoglycoside can be administered. (See 'When a third agent should be used' above.)

When to initiate antiretroviral therapy If a patient is on ART at the time of MAC diagnosis, ART should be continued and optimized if viremia is not suppressed. If a patient is treatment naïve or is not currently taking ART, we recommend that HIV ART be started soon (typically a few days) after starting MAC therapy (Grade 1B). (See 'When to initiate antiretroviral therapy' above.)

Duration of MAC therapy All patients with HIV who are diagnosed with MAC infection should receive a minimum of 12 months of MAC therapy. In addition, the CD4 count should be stably above 100 cells/microL for at least six months before discontinuing treatment. (See 'Duration of MAC therapy' above.)

Prevention For patients with a CD4 count <50 cells/microL who are initiating ART, we suggest that antimicrobial prophylaxis to prevent MAC disease not be routinely administered (Grade 2C). However, prophylaxis is reasonable for patients with a CD4 count <50 cells/microL who are not on fully suppressive ART. Although MAC prophylaxis had been common practice for all patients with a CD4 count <50 cells/microL prior to the introduction of potent ART, the risk of MAC infection is low in the setting of effective ART. (See 'Prevention of MAC disease' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

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