Mycobacterium avium and Mycobacterium intracellulare are two non-tuberculous mycobacteria that collectively form a group of organisms known as the Mycobacterium avium complex (MAC). MAC is ubiquitous in the environment. Infections with other non-tuberculous mycobacteria are well recognised in HIV infection but occur rarely. There is a strong relationship between the CD4 T-lymphocyte (CD4) cell count and the presence of disseminated MAC infection, with nearly all cases occurring at a CD4 cell count of < 50 cells/μL.1 A MAC-associated immune reconstitution inflammatory syndrome (MAC-IRIS) may occur at higher CD4 cell counts in the setting of combination antiretroviral therapy (cART), with an incidence rate of 3.5% in people commencing cART with a CD4 cell count < 100 cells/μL.2 Disseminated MAC infection has become rare since the introduction of cART.3
The most common manifestation of MAC infection in people with HIV infection who are not taking cART is that of disseminated disease. The typical clinical scenario is a markedly immunodeﬁcient person (CD4 cell count < 50 cells/μL) with fevers, drenching night sweats, weight loss, anaemia (or pancytopenia), diarrhoea, lymphadenopathy and hepatosplenomegaly with abnormal liver function tests (particularly an elevation of alkaline phosphatase). Intra-abdominal lymphadenopathy may occur and cause signiﬁcant abdominal pain. Although uncommon, pulmonary involvement can present with a persistent dry cough, fever and loss of weight.
MAC-associated Immune reconstitution inflammatory syndrome
Restoration of cell-mediated immunity against MAC was recognised after zidovudine monotherapy for HIV,4 although clinical reports of immune reconstitution inflammatory syndromes have been more frequent following the introduction of cART.5-9 There are three main clinical presentations of MAC-IRIS: peripheral lymphadenitis and fever; intra-abdominal disease (abdominal lymphadenopathy, chylous ascites, peritonitis, abscess and lesions or masses in the bowel); and lung disease (mediastinal lymphadenopathy, inﬁltrates, cavitary lesions and pulmonary nodules).2 The lymphadenopathy may be peripherally located, with sinus formation and chronic percutaneous drainage of purulent material, or intra-abdominal (para-aortic and mesenteric), which is often associated with abdominal pain. A peripheral blood leukocytosis may be present. Biopsy specimens of lymph nodes typically reveal granulomata and acid-fast bacilli may be detected. Osteomyelitis, bursitis, pericarditis, parotitis, cerebral abscess, peritonitis and skin nodules have also been reported. In one study in a resource limited setting, 9 out of 793 (1%) patients developed MAC disease after commencing cART.10
In the event of lymphadenitis caused by MAC-IRIS, treatment should consist of standard therapy for MAC infection. Up to 20% of patients with MAC-IRIS fail to respond to up to 2 years of MAC therapy and experience persistent or relapsing disease. These patients are more likely to have abdominal lymphadenopathy and less likely to have signiﬁcant rises in CD4 cell counts in response to cART.11 In severe cases, a short course of prednisone may be used,2 but some patients relapse on tapering the dose. In rare cases, surgical drainage, lymphadenectomy or the temporary interruption of cART may be required.12
The presence of MAC infection at the time of cART commencement is associated with a poorer recovery of CD4 cells than matched subjects without MAC infection, possibly reflecting the occurrence of inflammation from a mild form of MAC-IRIS that impairs recovery of CD4 cell counts.13
The diagnosis of disseminated MAC infection can be made by culture of blood or histological examination and culture of bone marrow, enlarged lymph nodes or liver. Although the presence of MAC in stool culture has a 60% predictive value for the subsequent development of disseminated disease,14 it is not diagnostic of disseminated disease. A presumptive diagnosis, pending the results of appropriate investigations, may be made in the typical clinical context (a person with a CD4 cell count < 50 cells/μL, not taking MAC prophylaxis, with fevers, night sweats, weight loss and anaemia). Such a presumptive diagnosis may only be conﬁrmed by the presence of MAC bacteraemia or bone marrow culture in approximately 20% of cases.15 It is important to consider other causes of the symptom complex as multiple pathological processes can coexist and mimic one another in people with severe immunodeficiency.
The usual regimen for the treatment of MAC infection is clarithromycin 500 mg twice a day and ethambutol 15 mg/kg/day with or without rifabutin 300 mg daily. Treatment with a three drug regimen was associated with reduced mortality compared with two drugs in one study.16,17 If clarithromycin is not tolerated, then azithromycin 500 mg daily may be substituted. If clarithromycin is not used, then the dose of rifabutin should be increased to 450 mg daily. The dose of clarithromycin should not exceed 500 mg twice daily, as excess mortality has been observed at doses of 1000 mg twice daily.18 Alternative agents, including amikacin, ciproﬂoxacin or clofazimine, should only be used if there is no clinical response to initial therapy after 6 weeks. Antimicrobial-sensitivity testing is not routinely undertaken, but should be performed if a macrolide antibiotic (azithromycin or clarithromycin) has been used for prophylaxis, and breakthrough MAC infection has occurred. Some authors have recommended that macrolide resistance be routinely assessed as two of nine (22%) isolates in one small US study were found to be macrolide resistant despite little or no previous macrolide exposure.19
When cART is used in combination with MAC treatment, consideration of drug interactions between antiretroviral and antimycobacterial agents is required. In all cases where HIV and mycobacterial infections are treated simultaneously, a careful review of potential multi-directional drug interactions should be undertaken, with reference to a pharmacist or reliable drug-interaction website (such as www.hiv-druginteractions.org). The degree of interaction varies, with some combinations being contraindicated and others requiring a dose modiﬁcation of one or both agents..
In general, cART should be commenced within 2 weeks of commencing MAC therapy.20 This may be associated with an immune reconstitution inflammatory syndrome, but most data suggest a reduced risk of mortality.
MAC therapy needs to be lifelong unless cART-associated immune reconstitution occurs. Maintenance therapy may be ceased when the HIV viral load has been suppressed and the CD4 cell count is > 100 cells/μL after treatment for 12 months.21
If a histological diagnosis of mycobacterial infection is made and the results of cultures are unavailable, empirical therapy should cover both MAC and M. tuberculosis infections. In the circumstance of probable MAC infection, isoniazid 300 mg daily and pyridoxine 50 mg daily (to prevent peripheral neuropathy) should be added to the standard MAC regimen of rifabutin, ethambutol and clarithromycin until the identiﬁcation of mycobacterial species is available. Isoniazid and pyridoxine should be ceased as soon as MAC has been identiﬁed. If M. tuberculosis is the most likely diagnosis then therapy should be targeted at this infection, although clarithromycin should be added to increase the spectrum of activity to include MAC until identiﬁcation of the organism is available. If M. tuberculosis may be the aetiological agent and samples of sputum are positive on acid-fast bacilli smear22 or there is respiratory involvement, then respiratory isolation of the patient is required until organism identiﬁcation is complete, or the sputa are negative on the acid-fast bacilli smear, or 2 weeks of eﬀective therapy has been completed.
The side eﬀects of commonly used antimycobacterial agents are listed in Table 1. Regular clinical review should be undertaken while on therapy with at least monthly clinical visits initially. Liver function tests and haematological parameters should be monitored. Ophthalmological complications are extremely rare with a lower dose of ethambutol (15 mg/kg/day) so regular ophthalmological review is not warranted. However, patients should be warned of potential ophthalmological side effects from ethambutol and to report these as soon as they occur.
The prognosis of untreated MAC infection therapy is poor. Combination antimicrobial therapy against MAC improves survival and cART provides an additional survival beneﬁt.23,24
Primary prophylaxis against MAC infection has been shown to reduce the incidence of MAC disease in patients with advanced immunodeﬁciency (CD4 cell count < 50 cells/μL) and probably improves survival.25-28 Three agents have been studied. Azithromycin (1200 mg orally once weekly) is the best tolerated agent with the fewest drug interactions. Clarithromycin (500 mg orally twice daily) or rifabutin (300 mg orally daily) are alternatives. Both of these medications interact with antiretroviral drugs and other agents and dose adjustment or alteration of the cART regimen may be required. Combination therapy with these agents is more eﬃcacious, but is associated with greater toxicity.26
Before instituting prophylaxis for MAC infection, it is important to exclude active MAC or M. tuberculosis infection. Prophylaxis with a single agent during active MAC or M. tuberculosis infection will lead to antimicrobial resistance.
Blood speciﬁcally cultured for MAC, chest radiograph and full investigation of fevers, weight loss, night sweats, anaemia, abnormal liver function tests, hepatosplenomegaly, respiratory symptoms or unexplained lymphadenopathy are required. A stool culture for MAC should be undertaken in people with diarrhoea to exclude MAC enteritis before commencing prophylaxis.
Some authors have suggested that primary prophylaxis for disseminated MAC is not required for those who commence cART with CD4 cell counts below 50 cells/μL, because the risk of disseminated MAC infection is low, and patients can be followed closely for the signs of disseminated MAC infection29 The strength of the evidence for this recommendation is not strong.30
In the event that MAC infection develops despite macrolide prophylaxis, antimicrobial sensitivity testing of MAC to macrolides is warranted, as macrolide resistance is detected in up to 30% of breakthrough isolates after clarithromycin prophylaxis31 and 11% after azithromycin prophylaxis.26
Secondary prophylaxis involves the life-long continuation of therapy for MAC infection unless cART-induced immune reconstitution occurs. As with other mycobacterial infections, a maintenance phase of treatment with two drugs is recommended. Rifabutin is most commonly eliminated, as it is associated with signiﬁcant drug interactions and uveitis. A strategy of 12 months of MAC treatment followed by cessation of treatment if the CD4 cell count is greater than 100 cells/μL while on fully suppressive cART appears to be safe for people that achieve this degree of immune reconstitution.21
Primary prophylaxis against MAC infection may be ceased with cART-associated immune reconstitution when the CD4 cell count is > 100 cells/μL for 3 months in the setting of adequate viral suppression32-34 and after 12 months of MAC treatment in those receiving maintenance treatment (secondary prophylaxis).21
 Crowe SM, Carlin JB, Stewart KI, et al. Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV-infected persons. J Acquir Immune Deﬁc Syndr 1991;4:770-6.
 Phillips P, Bonner S, Gataric N, et al. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis 2005;41:1483-97.
 Tumbarello M, Tacconelli E, de Donati KG, et al. Changes in incidence and risk factors of Mycobacterium avium complex infections in patients with AIDS in the era of new antiretroviral therapies. Eur J Clin Microbiol Infect Dis 2001;20:498-501.
 French MA, Mallal SA, Dawkins RL. Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeﬁcient HIV-infected patients. AIDS 1992;6:1293-7.
 Cabie A, Abel S, Brebion A, et al. Mycobacterial lymphadenitis after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 1998;17:812-13.
 Dworkin MS, Fratkin MD. Mycobacterium avium complex lymph node abscess after use of highly active antiretroviral therapy in a patient with AIDS. Arch Intern Med 1998;158:1828.
 Murray R, Mallal S, Heath C, et al. Cerebral Mycobacterium avium infection in an HIV-infected patient following immune reconstitution and cessation of therapy for disseminated Mycobacterium avium complex infection. Eur J Clin Microbiol Infect Dis 2001;20:199-201.
 Nalaboﬀ KM, Rozenshtein A, Kaplan MH. Imaging of Mycobacterium avium-intracellulare infection in AIDS patients on highly active antiretroviral therapy: reversal syndrome. Am J Roentgenol 2000;175:387-90.
 Phillips P, Kwiatkowski MB, Copland M, et al. Mycobacterial lymphadenitis associated with the initiation of combination antiretroviral therapy. J Acquir Immune Deﬁc Syndr 1999;20:122-8.
 Manosuthi W, Chaovavanich A, Tansuphaswadikul S, et al. Incidence and risk factors of major opportunistic infections after initiation of antiretroviral therapy among advanced HIV-infected patients in a resource-limited setting. J Infect 2007;55:464-9.
 Riddell J 4th, Kaul DR, Karakousis PC, et al. Mycobacterium avium complex immune reconstitution inﬂammatory syndrome: long term outcomes. J Transl Med 2007;5:50.
 Desimone JA Jr, Babinchak TJ, Kaulback KR, et al. Treatment of Mycobacterium avium complex immune reconstitution disease in HIV-1-infected individuals. AIDS Patient Care STDs 2003;17:617-22.
 Lazaro E, Coureau G, Guedj J, et al; ANRS Co3 Aquitaine Cohort. Change in T-lymphocyte count after initiation of highly active antiretroviral therapy in HIV-infected patients with history of Mycobacterium avium complex infection. Antivir Ther 2006;11:343-50.
 Chin DP, Hopewell PC, Yajko DM, et al. Mycobacterium avium complex in the respiratory or gastrointestinal tract and the risk of M. avium complex bacteremia in patients with human immunodeﬁciency virus infection. J Infect Dis 1994;169:289-95.
 MacGregor RR, Hafner R, Wu JW, et al. Clinical, microbiological, and immunological characteristics in HIV-infected subjects at risk for disseminated Mycobacterium avium complex disease: an AACTG study. AIDS Res Hum Retroviruses 2005;21:689-95.
 Benson CA, Williams PL, Currier JS, et al. A prospective, randomized trial examining the eﬃcacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeﬁciency syndrome. Clin Infect Dis 2003;37(9):1234-43.
 Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis 2004;4:557-65.
 Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose- ranging study in patients with AIDS. AIDS Clinical Trials Group Protocol 157 Study Team. Ann Intern Med 1994;121:905-11.
 Gardner EM, Burman WJ, DeGroote MA, et al. Conventional and molecular epidemiology of macrolide resistance among new Mycobacterium avium complex isolates recovered from HIV-infected patients. Clin Infect Dis 2005;41:1041-4.
 Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009;4:e5575
 Aberg JA, Williams PL, Liu T, et al. A study of discontinuing maintenance therapy in human immunodeﬁciency virus-infected subjects with disseminated Mycobacterium avium complex: AIDS Clinical Trial Group 393 Study Team.[erratum in: J Infect Dis 2003;187:1346].
 Hoy JF, Marriott D, Gottlieb T. Managing HIV 5.15 HIV and non- tuberculous mycobacterial infection. Med J Aust 1996;164:543-5.
 Horsburgh CR Jr, Metchock B, Gordon SM,et al. Predictors of survival in patients with AIDS and disseminated Mycobacterium avium complex disease. J Infect Dis 1994;170:573-7.
 Horsburgh CR Jr, Gettings J, Alexander LN, et al. Disseminated Mycobacterium avium complex disease among patients infected with human immunodeﬁciency virus, 1985- 2000. Clin Infect Dis 2001;33:1938-43.
 Oldﬁeld EC 3rd, Fessel WJ, Dunne MW, et al. Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebo- controlled multicenter trial. Clin Infect Dis 1998;26:611-19.
 Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin ,daily rifabutin ,orboth. California Collaborative Treatment Group. N Engl J Med 1996;335:392-8.
 Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeﬁciency syndrome. N Engl J Med 1996;335:384-91.
 Uthman MM, Uthman OA, Yahaya I. Interventions for the prevention of mycobacterium avium complex in adults and children with HIV. Cochrane Database Syst Rev 2013;4:CD007191.
 Lange CG, Woolley IJ, Brodt RH. Disseminated Mycobacterium avium-intracellulare complex (MAC) infection in the era of eﬀective antiretroviral therapy: is prophylaxis still indicated? Drugs 2004;64:679-92.
 Yangco BG, Buchacz K, Baker R, et al; HIV Outpatient Study Investigators. Is primary mycobacterium avium complex prophylaxis necessary in patients with CD4
 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.
 Brooks JT, Song R, Hanson DL, et al; Adult and Adolescent Spectrum of Disease Working Group. Discontinuation of primary prophylaxis against Mycobacterium avium complex infection in HIV-infected persons receiving antiretroviral therapy: observations from a large national cohort in the United States, 1992-2002. Clin Infect Dis 2005;41:549-53.
 Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. A randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team. Ann Intern Med 2000;133:493-503.
 El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS. N Engl J Med 2000;342:1085-92.