Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Disseminated Mycobacterium avium Complex Disease
Last Updated: February 15, 2019; Last Reviewed: February 15, 2019
Organisms of the Mycobacterium avium complex (MAC) are ubiquitous in the environment.1-6 In the era prior to the availability of effective antiretroviral therapy (ART), M. avium was the etiologic agent in >95% of people living with HIV with advanced immunosuppression who acquired disseminated MAC disease.4,7-12 Recent studies conducted using newer bacterial typing technology suggest organisms causing bacteremia in people with HIV include a diversity of species, including the M. avium subspecies hominissuis and M. colombiense.13 An estimated 7% to 12% of adults have previously contracted MAC, although rates of disease vary in different geographic locations.2,4,8,11,12 Although epidemiologic associations have been identified, no environmental exposure or behavior has been consistently linked to subsequent risk of developing MAC disease.
The mode of MAC transmission is thought to be through inhalation, ingestion, or inoculation of MAC bacteria via the respiratory or gastrointestinal (GI) tract.1,14 Household or close contacts of those with MAC disease do not appear to be at increased risk of disease, and person-to-person transmission is unlikely.
MAC disease typically occurs in people with HIV with CD4 T lymphocyte (CD4) cell counts <50 cells/mm3. The incidence of disseminated MAC disease is 20% to 40% in people with HIV with advanced immunosuppression in the absence of effective ART or chemoprophylaxis.15,16 The overall incidence of MAC disease among people living with HIV has continued to decline in the modern ART era to current levels of <2 cases of MAC as the first opportunistic infection [OI] per 1,000 person-years for individuals in care.17-20 In addition to CD4 count <50 cells/mm3, factors associated with increased risk for MAC disease identified in recent studies are plasma HIV RNA levels >1,000 copies/mL, ongoing viral replication despite ART, previous or concurrent OIs, and reduced in vitro lymphoproliferative immune responses to M. avium antigens, possibly reflecting defects in T-cell repertoire.18-20
In people living with HIV with advanced immunosuppression who are not on ART, MAC disease often is a disseminated, multi-organ infection, although localized disease may also be seen.21-25 Early symptoms may be minimal and can precede detectable mycobacteremia by several weeks. Symptoms may include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain.8
Laboratory abnormalities particularly associated with disseminated MAC disease include anemia (often out of proportion to that expected for the stage of HIV disease) and elevated liver alkaline phosphatase levels.4,5,7-12,15,16,26,27 Hepatomegaly, splenomegaly, or lymphadenopathy (paratracheal, retroperitoneal, para-aortic, or less commonly peripheral) may be identified on physical examination or by radiographic or other imaging studies. Other focal physical findings or laboratory abnormalities may occur with localized disease.
In comparison to people with HIV who are not receiving or not responding to ART, localized manifestations of MAC disease have been reported more often in people with HIV who are receiving and have responded to ART with an increase in CD4 cell counts, suggesting improved immune function. Localized syndromes include cervical, intraabdominal or mediastinal lymphadenitis, pneumonia, pericarditis, osteomyelitis, skin or soft-tissue abscesses, bursitis, genital ulcers, or central nervous system infection. Localized syndromes may also be manifestations of immune reconstitution inflammatory syndrome (IRIS), as discussed below.
IRIS is recognized as a systemic inflammatory syndrome with signs and symptoms that are clinically indistinguishable from active MAC infection, although bacteremia is generally absent. Similar to tuberculosis (TB), MAC-associated IRIS can occur as “unmasking” IRIS in people with HIV with subclinical (undiagnosed) MAC or “paradoxical” IRIS in those with previously established MAC disease.28-32 Both variants occur primarily in those with advanced immunosuppression who begin ART and have a rapid and marked reduction in plasma HIV RNA.32,33 The syndrome may be benign and self-limited or may result in severe, unremitting symptoms that improve with the use of systemic anti-inflammatory therapy or corticosteroids.
A confirmed diagnosis of disseminated MAC disease is based on compatible clinical signs and symptoms coupled with the isolation of MAC from cultures of blood, lymph node, bone marrow, or other normally sterile tissue or body fluids.16,24,25,34,35 Species identification should be performed using molecular techniques, polymerase chain reaction-based assays, whole genome sequencing, high-performance liquid chromatography, or biochemical tests.
Other ancillary studies provide supportive diagnostic information, including acid-fast bacilli smear and culture of stool or tissue biopsy material, radiographic imaging, or other studies aimed at isolating organisms from focal infection sites.
Detection of MAC organisms in the respiratory or GI tract may represent colonization of these sites and may be a harbinger of disseminated MAC infection. However, no data are available regarding efficacy of treatment with clarithromycin, azithromycin, rifabutin, or other drugs alone or in combination for asymptomatic colonization with MAC organisms at these sites. Therefore, routine screening of respiratory or GI specimens and pre-emptive treatment for MAC is not recommended.
MAC organisms commonly contaminate environmental sources of infection, such as food and water. Available information does not support specific recommendations regarding avoidance of exposure.
Indication for Primary Prophylaxis
Primary prophylaxis against disseminated MAC disease is not recommended for adults and adolescents with HIV who immediately initiate ART (AII). People with HIV who are not receiving ART or who remain viremic on ART but have no current options for a fully suppressive ART regimen should receive chemoprophylaxis against disseminated MAC disease if they have CD4 counts <50 cells/mm3 (AI).
Primary MAC prophylaxis, if previously initiated, should be discontinued in adults and adolescents who are continuing on a fully suppressive ART regimen (AI). Two randomized, placebo-controlled trials and observational data have demonstrated that people with HIV taking ART can discontinue primary prophylaxis with minimal risk of developing MAC disease.36-40
This updated recommendation is based on data from recent observational cohort studies. In an analysis of 369 people with HIV with CD4 counts <50 cells/mm3 while on ART and followed for at least six months, the overall incidence of MAC disease was 0.6 per 100 person-months. No MAC occurred among 71 persons on ART who were virologically suppressed at baseline, including 41 persons who were not receiving primary MAC prophylaxis.41 Another study enrolled 157 people with HIV who had at least one CD4 count <50 cells/mm3 and had started ART between 1998 and 2014. The study compared the incidence of disseminated MAC disease within the 12 months after the first CD4 count <50 cells/mm3 between a group of 33 participants who received primary MAC prophylaxis and a group of 122 participants who received no MAC prophylaxis.20 There were no differences between the groups in the proportion of participants who achieved or the time to achieve a CD4 count >100 cells/mm3 or in the proportion of participants who achieved viral suppression within 12 months. The incidence of MAC disease was not statistically significantly different between the groups; 3.4 per 100 person-years for those on primary prophylaxis versus 0.8 per 100 person-years for those not on primary prophylaxis. In each of these studies, plasma HIV RNA level >1,000 copies/mL was the principal risk factor for developing MAC disease regardless of MAC prophylaxis. In a study from the OI Working Group of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE), the incidence of primary MAC disease was 0.74 per 1,000 person-years (IQ range 0.68 to 0.80) among people living with HIV on ART and not receiving MAC prophylaxis.42 These data suggest that primary MAC prophylaxis provides no additional benefit in patients started on effective ART that results in viral suppression. Additional arguments against primary MAC prophylaxis include the potential for increased cost, adverse effects of the drugs used for prophylaxis, and, for the small number of people with HIV who might develop “unmasking MAC IRIS” after starting ART, the use of monotherapy for MAC prophylaxis may result in acquired drug resistance in those with active MAC disease.43,44
Preferred and Alternative Drugs for Prophylaxis
As previously stated, primary prophylaxis for MAC is not recommended, but for those for whom prophylaxis is being considered, azithromycin45 and clarithromycin5,46 are the preferred prophylactic agents (AI).1,47 The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone for chemoprophylaxis, is associated with a higher rate of adverse effects than either drug alone, and should not be used (AI).5 The combination of azithromycin and rifabutin is more effective than azithromycin alone in preventing MAC disease.45 However, based on the additional cost, increased occurrence of adverse effects, potential for drug interactions, and no greater survival benefit than with azithromycin alone, the combination regimen of azithromycin and rifabutin is not recommended (AI). Azithromycin and clarithromycin also each confer protection against respiratory bacterial infections. In people with HIV who cannot tolerate azithromycin or clarithromycin, rifabutin is an alternative prophylactic agent for MAC disease (BI), although drug interactions may complicate use of this agent. Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment and if appropriate based on that assessment, by obtaining a blood culture for MAC. TB also should be excluded before rifabutin is used for MAC prophylaxis because treatment with rifabutin monotherapy could result in acquired resistance to M. tuberculosis in people with HIV who have active TB.
Initial treatment of MAC disease should consist of two or more antimycobacterial drugs to prevent or delay the emergence of resistance (AI).1,6,11,12,14,48-56 Clarithromycin is the preferred first agent (AI); it has been studied more extensively than azithromycin in people with AIDS and appears to be associated with more rapid clearance of MAC from the blood.6,48,50,54,55,57 However, azithromycin can be substituted for clarithromycin when drug interactions or intolerance preclude the use of clarithromycin (AII). Testing MAC isolates for susceptibility to clarithromycin or azithromycin is recommended for all people with HIV.58,59
Ethambutol is the recommended second drug for the initial treatment of MAC disease (AI). Some clinicians would add rifabutin as a third drug (CI). One randomized clinical trial demonstrated that adding rifabutin to the combination of clarithromycin and ethambutol improved survival, and in two randomized clinical trials, this approach reduced emergence of drug resistance6,50 in individuals with AIDS and disseminated MAC disease. These studies were completed before the availability of effective ART. Whether similar results would be observed for people with HIV receiving effective ART has not been established. Some experts would recommend the addition of a third or fourth drug in settings in which the risk of mortality is increased and emergence of drug resistance is most likely, such as with advanced immunosuppression (CD4 count <50 cells/mm3), high mycobacterial loads (>2 log10 colony-forming units/mL of blood), and/or the absence of effective ART (CIII). The third or fourth drug might include a fluoroquinolone such as levofloxacin or moxifloxacin (CIII), which have in vitro and animal model activity against MAC, or an injectable agent such as amikacin or streptomycin (CIII), although no randomized clinical trials have evaluated the added efficacy of these antibiotics in the setting of clarithromycin or azithromycin treatment or effective ART.58,60
Special Considerations with Regard to Starting Antiretroviral Therapy
ART should be started as soon as possible after the diagnosis of MAC disease, preferably at the same time as initiation of antimycobacterial therapy in people with HIV and disseminated MAC disease who are not receiving effective ART (CIII). The rationale for starting ART as soon as possible is to reduce the risk of further AIDS-defining OIs and to further improve the response to antimycobacterial therapy in the setting of advanced immunosuppression (CIII). If ART has already been initiated, it should be continued. The regimens should be modified when there is any potential for an adverse drug-drug interaction(s) between the antiretroviral and antimycobacterial drugs (CIII). People with HIV will need continuous antimycobacterial treatment unless ART results in immune reconstitution.
Monitoring of Response to Therapy and Adverse Events (including IRIS)
A repeat blood culture for MAC should be obtained 4 weeks to 8 weeks after initiating antimycobacterial therapy only in people with HIV who do not have a clinical response to their initial treatment regimens. Improvement in fever and a decline in quantity of mycobacteria in blood or tissue can be expected within 2 weeks to 4 weeks after initiation of appropriate therapy; clinical response may be delayed, however, in those with more extensive MAC disease or advanced immunosuppression.
Adverse effects with clarithromycin and azithromycin include gastrointestinal upset, metallic taste, elevations in liver transaminase levels or hypersensitivity reactions. These adverse effects may be exacerbated when drug levels are increased due to drug interactions associated with rifabutin or some antiretroviral drugs. Doses of clarithromycin >1 g/day for treatment of disseminated MAC disease have been associated with increased mortality and should not be used (AI).61 When used with clarithromycin or other drugs that inhibit cytochrome P450 (CYP450) isoenzyme 34, rifabutin has been associated with a higher risk of adverse drug interactions.62,63
Given complex drug interactions, if rifabutin is used, dose adjustment is necessary in people with HIV receiving protease inhibitors (PIs), efavirenz, rilpivirine, or doravirine; rifabutin should not be used with elvitegravir/cobicistat or bictegravir.64-71 No dose adjustment for rifabutin or integrase inhibitors, other than elvitegravir/cobicistat or bictegravir, is currently recommended.72,73 The most updated drug-drug interaction information can be found in the Adult and Adolescent Antiretroviral Guidelines. PIs can increase clarithromycin levels, but no recommendation to adjust the dose of either clarithromycin or PIs can be made based on existing data. The ability of efavirenz to induce metabolism of clarithromycin can result in reduced serum concentration of clarithromycin but increased concentration of the 14-OH active metabolite of clarithromycin. Although the clinical significance of this interaction is unknown, it could reduce the efficacy of clarithromycin for MAC prophylaxis. Azithromycin metabolism is not affected by the CYP450 system; azithromycin can be used safely in the presence of PIs, NNRTIs, or integrase inhibitors without concerns about drug interactions.
People with HIV on ART who develop moderate-to-severe symptoms typical of IRIS should receive initial treatment with non-steroidal, anti-inflammatory drugs (CIII). If IRIS symptoms do not improve, short-term (4 weeks–8 weeks) systemic corticosteroid therapy, in doses equivalent to 20 to 40 mg of oral prednisone daily, has been successful in reducing symptoms and morbidity (CII).29,74
Managing Treatment Failure
MAC treatment failure is defined by the absence of a clinical response and the persistence of mycobacteremia after 4 to 8 weeks of treatment. Repeat testing of MAC isolates for susceptibility to clarithromycin or azithromycin is recommended for people with HIV whose disease relapses after an initial response to treatment. Most people with HIV who experience failure of clarithromycin or azithromycin primary prophylaxis in clinical trials had isolates susceptible to these drugs when MAC disease was detected.6,11,12,48,75,76
Because the number of drugs with demonstrated clinical activity against MAC is limited, results of susceptibility testing should be used to construct a new multidrug regimen. The regimen should consist of at least two new drugs (i.e., not previously used) to which the isolate is susceptible. Drugs from which to choose are rifabutin, an injectable aminoglycoside (amikacin or streptomycin), or a fluoroquinolone (levofloxacin or moxifloxacin), although data supporting a survival or microbiologic benefit when these agents are added have not been compelling (CII).11,12,49-53,57,77-81 Data in people without HIV who are being treated for MAC indicate that an injectable aminoglycoside (amikacin or streptomycin) is a viable choice (CIII).58 Continuing clarithromycin or azithromycin despite resistance is generally not recommended as there is likely to be no additional benefit and may be added toxicity. Clofazimine should not be used because randomized trials have demonstrated lack of efficacy and an association with increased mortality (AI).49,51,79 Anecdotal evidence exists for the addition of one or more other second-line agents (e.g., ethionamide, thioacetazone [not available in the United States], cycloserine, or linezolid) to the combination of clarithromycin or azithromycin and other drugs as salvage therapy, but their role in this setting is not well defined. Optimization of ART is an important adjunct to second-line or salvage therapy for MAC disease in people with HIV for whom initial treatment is unsuccessful or who have disease that is resistant to antimycobacterial drugs (AIII).
Adjunctive treatment of MAC disease with immunomodulators has not been thoroughly studied, and data are insufficient to support a recommendation for its routine use.
People with HIV and disseminated MAC disease should continue chronic maintenance therapy (AII) unless ART results in immune reconstitution.37,38
When to Stop Secondary Prophylaxis or Chronic Maintenance Therapy
The risk of MAC recurrence is low in people with HIV who have completed at least a 12-month MAC treatment course, remain asymptomatic with respect to MAC signs and symptoms, and sustain an increase in CD4 count to >100 cells/mm3 for ≥6 months after initiation of ART. In this setting, it is reasonable to discontinue maintenance therapy based on data from studies in people with HIV and inferences from more extensive study data that indicate the safety of discontinuing secondary prophylaxis for other OIs (AI).38,53,82-86 Reintroducing chronic maintenance therapy or secondary prophylaxis for people with HIV for whom a fully suppressive ART regimen is not possible and who have a decline in their CD4 count to levels consistently below 100 cells/mm3 may be indicated (BIII).
Special Considerations During Pregnancy
Primary prophylaxis for MAC disease in pregnant women and adolescents is not recommended (AIII). Because clarithromycin is associated with an increased risk of birth defects based on evidence from certain animal studies, it is not recommended as the first-line agent for prophylaxis or treatment of MAC in pregnancy (BIII). Two studies, each with slightly more than 100 women with first-trimester exposure to clarithromycin, did not demonstrate an increase in or specific pattern of defects, although an increased risk of spontaneous abortion was noted in one study.87,88 Azithromycin did not produce defects in animal studies, but experience is limited with use in humans during the first trimester. A nested case-control study conducted within the large Quebec Pregnancy cohort found an association between azithromycin use and spontaneous miscarriage.89 However, the authors were not able to adjust for severity of infection, an important confounder. Multiple studies, including large cohort studies, have found no association between the use of azithromycins in the first trimester and major congenital malformations, include heart defects.90-92 When primary prophylaxis is required for a pregnant woman who is not being treated with effective ART, azithromycin is the preferred agent (BIII). For secondary prophylaxis (chronic maintenance therapy), azithromycin plus ethambutol is the preferred drug combination (BIII).
Diagnostic considerations and indications for treatment of MAC disease for pregnant women are the same as for women who are not pregnant. On the basis of animal data discussed previously, azithromycin is preferred over clarithromycin as the first-line agent to use in combination with ethambutol for treatment of MAC disease (BIII). Use of ethambutol rather than rifabutin or other agents with the potential for drug-drug interactions should allow initiation of ART as soon as possible during pregnancy to decrease the risk of perinatal transmission of HIV. Pregnant women whose MAC disease fails to respond to a primary regimen should be managed in consultation with infectious disease and obstetrical specialists.
|Preventing First Episode of Disseminated MAC Disease (Primary Prophylaxis)
|Treating Disseminated MAC Disease
The Third or Fourth Drug Options May Include:
- 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(9):557-565. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15336223.
- Hoefsloot W, van Ingen J, Andrejak C, et al. The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. Eur Respir J. 2013;42(6):1604-1613. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23598956.
- Reed C, von Reyn CF, Chamblee S, et al. Environmental risk factors for infection with Mycobacterium avium complex. Am J Epidemiol. 2006;164(1):32-40. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16675537.
- Inderlied PCB. Microbiology and minimum inhibitory concentration testing for Mycobacterium avium complex prophylaxis. Am J Med. 1997;102(5):2-10. Available at: http://linkinghub.elsevier.com/retrieve/pii/S0002934397000375?showall=true.
- 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(4):1289-1297. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10762562.
- 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):1234-1243. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14557969.
- Kemper CA, Havlir D, Bartok AE, et al. Transient bacteremia due to Mycobacterium avium complex in patients with AIDS. J Infect Dis. 1994;170(2):488-493. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8035044.
- Gordin FM, Cohn DL, Sullam PM, Schoenfelder JR, Wynne BA, Horsburgh CR, Jr. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis. 1997;176(1):126-132. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9207358.
- Benson CA, Ellner JJ. Mycobacterium avium complex infection and AIDS: advances in theory and practice. Clin Infect Dis. 1993;17(1):7-20. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8353249.
- Havlik JA, Jr., Horsburgh CR, Jr., Metchock B, Williams PP, Fann SA, Thompson SE, 3rd. Disseminated Mycobacterium avium complex infection: clinical identification and epidemiologic trends. J Infect Dis. 1992;165(3):577-580. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1347060.
- Benson CA. Treatment of disseminated disease due to the Mycobacterium avium complex in patients with AIDS. Clin Infect Dis. 1994;18 Suppl 3:S237-242. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8204776.
- Benson CA. Disease due to the Mycobacterium avium complex in patients with AIDS: epidemiology and clinical syndrome. Clin Infect Dis. 1994;18 Suppl 3:S218-222. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8204773.
- Lee MR, Chien JY, Huang YT, et al. Clinical features of patients with bacteraemia caused by Mycobacterium avium complex species and antimicrobial susceptibility of the isolates at a medical centre in Taiwan, 2008-2014. Int J Antimicrob Agents. 2017;50(1):35-40. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28478210.
- Corti M, Palmero D. Mycobacterium avium complex infection in HIV/AIDS patients. Expert Rev Anti Infect Ther. 2008;6(3):351-363. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18588499.
- 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(6):1082-1085. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1349906.
- Chaisson RE, Moore RD, Richman DD, Keruly J, Creagh T. Incidence and natural history of Mycobacterium avium-complex infections in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group. Am Rev Respir Dis. 1992;146(2):285-289. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1362634.
- Buchacz K, Baker RK, Palella FJ, Jr., et al. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study. AIDS. 2010;24(10):1549-1559. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20502317.
- Buchacz K, Lau B, Jing Y, et al. Incidence of AIDS-defining opportunistic infections in a multicohort analysis of HIV-infected persons in the United States and Canada, 2000-–2010. J Infect Dis. 2016;214(6):862-872. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27559122.
- Collins LF, Clement ME, Stout JE. Incidence, long-term outcomes, and healthcare utilization of patients with human immunodeficiency virus/acquired immune deficiency syndrome and disseminated Mycobacterium avium complex from 1992-2015. Open Forum Infect Dis. 2017;4(3):ofx120. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28748197.
- Jung Y, Song KH, Choe PG, et al. Incidence of disseminated Mycobacterium avium-complex infection in HIV patients receiving antiretroviral therapy with use of Mycobacterium avium-complex prophylaxis. Int J STD AIDS. 2017;28(14):1426-1432. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28592210.
- Barbaro DJ, Orcutt VL, Coldiron BM. Mycobacterium avium-Mycobacterium intracellulare infection limited to the skin and lymph nodes in patients with AIDS. Rev Infect Dis. 1989;11(4):625-628. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2772468.
- Hellyer TJ, Brown IN, Taylor MB, Allen BW, Easmon CS. Gastro-intestinal involvement in Mycobacterium avium-intracellulare infection of patients with HIV. J Infect. 1993;26(1):55-66. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8454889.
- Torriani FJ, McCutchan JA, Bozzette SA, Grafe MR, Havlir DV. Autopsy findings in AIDS patients with Mycobacterium avium complex bacteremia. J Infect Dis. 1994;170(6):1601-1605. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7996004.
- Roth RI, Owen RL, Keren DF, Volberding PA. Intestinal infection with Mycobacterium avium in acquired immune deficiency syndrome (AIDS): histological and clinical comparison with Whipple's disease. Dig Dis Sci. 1985;30(5):497-504. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2580679.
- Gillin JS, Urmacher C, West R, Shike M. Disseminated Mycobacterium avium-intracellulare infection in acquired immunodeficiency syndrome mimicking Whipple's disease. Gastroenterology. 1983;85(5):1187-1191. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6194041.
- Inderlied CB, Kemper CA, Bermudez LE. The Mycobacterium avium complex. Clin Microbiol Rev. 1993;6(3):266-310. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8358707.
- Packer SJ, Cesario T, Williams JH, Jr. Mycobacterium avium complex infection presenting as endobronchial lesions in immunosuppressed patients. Ann Intern Med. 1988;109(5):389-393. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3165608.
- Phillips P, Kwiatkowski MB, Copland M, Craib K, Montaner J. Mycobacterial lymphadenitis associated with the initiation of combination antiretroviral therapy. J Acquir Immune Defic Syndr. 1999;20(2):122-128. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10048898.
- 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(10):1483-1497. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16231262.
- Race EM, Adelson-Mitty J, Kriegel GR, et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet. 1998;351(9098):252-255. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9457095.
- Cabie A, Abel S, Brebion A, Desbois N, Sobesky G. Mycobacterial lymphadenitis after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis. 1998;17(11):812-813. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9923530.
- Smibert OC, Trubiano JA, Cross GB, Hoy JF. Short communication: Mycobacterium avium complex infection and immune reconstitution inflammatory syndrome remain a challenge in the era of effective antiretroviral therapy. AIDS Res Hum Retroviruses. 2017;33(12):1202-1204. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28791872.
- Barber DL, Andrade BB, McBerry C, Sereti I, Sher A. Role of IL-6 in Mycobacterium avium—associated immune reconstitution inflammatory syndrome. J Immunol. 2014;192(2):676-682. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24337386.
- Shanson DC, Dryden MS. Comparison of methods for isolating Mycobacterium avium-intracellulare from blood of patients with AIDS. J Clin Pathol. 1988;41(6):687-690. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3385000.
- Hafner R, Inderlied CB, Peterson DM, et al. Correlation of quantitative bone marrow and blood cultures in AIDS patients with disseminated Mycobacterium avium complex infection. J Infect Dis. 1999;180(2):438-447. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10395860.
- Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis. 2000;182(2):611-615. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10915098.
- 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(15):1085-1092. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10766581.
- 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(7):493-503. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11015162.
- Furrer H, Telenti A, Rossi M, Ledergerber B. Discontinuing or withholding primary prophylaxis against Mycobacterium avium in patients on successful antiretroviral combination therapy. The Swiss HIV Cohort Study. AIDS. 2000;14(10):1409-1412. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10930156.
- Brooks JT, Song R, Hanson DL, et al. 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(4):549-553. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16028167.
- Yangco BG, Buchacz K, Baker R, et al. Is primary Mycobacterium avium complex prophylaxis necessary in patients with CD4 <50 cells/muL who are virologically suppressed on cART? AIDS Patient Care STDS. 2014;28(6):280-283. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24833016.
- Chene G, Phillips A, Costagliola D, et al. Cohort profile: Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Int J Epidemiol. 2017;46(3):797-797n. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27864413.
- 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(7):679-692. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15025543.
- Sax PE. “Choosing wisely” in HIV medicine — should we stop giving MAC prophylaxis? In. HIV and ID Observations. NEJM Journal Watch. 2016. Available at: https://blogs.jwatch.org/hiv-id-observations/index.php/choosing-wisely-in-hiv-medicine-should-we-stop-giving-mac-prophylaxis/2016/03/20/
- 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(6):392-398. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8676932.
- 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(6):384-391. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8663871.
- 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23633339.
- 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(12):905-911. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7978715.
- May T, Brel F, Beuscart C, et al. Comparison of combination therapy regimens for treatment of human immunodeficiency virus-infected patients with disseminated bacteremia due to Mycobacterium avium. ANRS Trial 033 Curavium Group. Agence Nationale de Recherche sur le Sida. Clin Infect Dis. 1997;25(3):621-629. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9314450.
- Gordin FM, Sullam PM, Shafran SD, et al. A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clin Infect Dis. 1999;28(5):1080-1085. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10452638.
- Dube MP, Sattler FR, Torriani FJ, et al. A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin-based combination therapy. California Collaborative Treatment Group. J Infect Dis. 1997;176(5):1225-1232. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9359722.
- Cohn DL, Fisher EJ, Peng GT, et al. A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high-dose clarithromycin. Terry Beirn Community Programs for Clinical Research on AIDS. Clin Infect Dis. 1999;29(1):125-133. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10433575.
- Aberg JA, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated Mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with highly active antiretroviral therapy. J Infect Dis. 1998;178(5):1446-1449. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9780266.
- Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium. Clin Infect Dis. 1998;27(5):1278-1285. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9827282.
- Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus. Clin Infect Dis. 2000;31(5):1245-1252. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11073759.
- Xu HB, Jiang RH, Li L. Treatment outcomes for Mycobacterium avium complex: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis. 2014;33(3):347-358. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23979729.
- Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group. N Engl J Med. 1996;335(6):377-383. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8676931.
- Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17277290.
- Gardner EM, Burman WJ, DeGroote MA, Hildred G, Pace NR. Conventional and molecular epidemiology of macrolide resistance among new Mycobacterium avium complex isolates recovered from HIV-infected patients. Clin Infect Dis. 2005;41(7):1041-1044. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16142672.
- Koh WJ, Hong G, Kim SY, et al. Treatment of refractory Mycobacterium avium complex lung disease with a moxifloxacin-containing regimen. Antimicrob Agents Chemother. 2013;57(5):2281-2285. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23478956.
- Clarithromycin [package insert]. Food and Drug Administration. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050662s058,050698s038,050775s026lbl.pdf.
- Shafran SD, Deschenes J, Miller M, Phillips P, Toma E. Uveitis and pseudojaundice during a regimen of clarithromycin, rifabutin, and ethambutol. MAC Study Group of the Canadian HIV Trials Network. N Engl J Med. 1994;330(6):438-439. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8284019.
- Hafner R, Bethel J, Power M, et al. Tolerance and pharmacokinetic interactions of rifabutin and clarithromycin in human immunodeficiency virus-infected volunteers. Antimicrob Agents Chemother. 1998;42(3):631-639. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9517944.
- Hennig S, Svensson EM, Niebecker R, et al. Population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and HIV PIs. J Antimicrob Chemother. 2016;71(5):1330-1340. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26832753.
- Naiker S, Connolly C, Wiesner L, et al. Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacol Toxicol. 2014;15:61. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25406657.
- Kakuda TN, Woodfall B, De Marez T, et al. Pharmacokinetic evaluation of the interaction between etravirine and rifabutin or clarithromycin in HIV-negative, healthy volunteers: results from two Phase 1 studies. J Antimicrob Chemother. 2014;69(3):728-734. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24155058.
- Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011;50(4):229-244. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21348537.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. 2018. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
- Centers for Disease Control and Prevention. Managing drug interactions in the treatment of HIV-related tuberculosis. 2013. Available at: https://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/default.htm.
- Rilpivirine [package insert]. Janssen Pharmaceuticals. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf.
- Bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) [package insert]. Gilead Sciences. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf.
- Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013;62(1):21-27. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23075918.
- Brainard DM, Kassahun K, Wenning LA, et al. Lack of a clinically meaningful pharmacokinetic effect of rifabutin on raltegravir: in vitro/in vivo correlation. J Clin Pharmacol. 2011;51(6):943-950. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20852006.
- Wormser GP, Horowitz H, Dworkin B. Low-dose dexamethasone as adjunctive therapy for disseminated Mycobacterium avium complex infections in AIDS patients. Antimicrob Agents Chemother. 1994;38(9):2215-2217. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7811052.
- Heifets L, Lindholm LP, Libonati J. Radiometric broth macrodilution method for determination of minimal inhibitory concentrations (MIC) with Mycobacterium avium complex isolates: proposed guidelines. Presented at: National Jewish Center for Immunology and Respiratory Medicine. 1993.
- Heifets L, Mor N, Vanderkolk J. Mycobacterium avium strains resistant to clarithromycin and azithromycin. Antimicrob Agents Chemother. 1993;37(11):2364-2370. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8031351.
- Masur H. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex. N Engl J Med. 1993;329(12):898-904. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8395019.
- Kemper CA, Meng TC, Nussbaum J, et al. Treatment of Mycobacterium avium complex bacteremia in AIDS with a four-drug oral regimen: rifampin, ethambutol, clofazimine, and ciprofloxacin. The California Collaborative Treatment Group. Ann Intern Med. 1992;116(6):466-472. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1739237.
- Chaisson RE, Keiser P, Pierce M, et al. Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium complex disease in patients with HIV infection. AIDS. 1997;11(3):311-317. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9147422.
- Chiu J, Nussbaum J, Bozzette S, et al. Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. California Collaborative Treatment Group. Ann Intern Med. 1990;113(5):358-361. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2382918.
- Rodriguez Diaz JC, Lopez M, Ruiz M, Royo G. In vitro activity of new fluoroquinolones and linezolid against non-tuberculous mycobacteria. Int J Antimicrob Agents. 2003;21(6):585-588. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12791475.
- Aberg J, Powderly W. HIV: primary and secondary prophylaxis for opportunistic infections. BMJ Clin Evid. 2010;2010. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21418688.
- Green H, Hay P, Dunn DT, McCormack S, Investigators S. A prospective multicentre study of discontinuing prophylaxis for opportunistic infections after effective antiretroviral therapy. HIV Med. 2004;5(4):278-283. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15236617.
- Shafran SD, Mashinter LD, Phillips P, et al. Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy. Ann Intern Med. 2002;137(9):734-737. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12416943.
- El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group. N Engl J Med. 1998;339(26):1889-1895. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9862944.
- 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. J Infect Dis. 2003;187(7):1046-1052. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12660918.
- Einarson A, Phillips E, Mawji F, et al. A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol. 1998;15(9):523-525. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9890248.
- Drinkard CR, Shatin D, Clouse J. Postmarketing surveillance of medications and pregnancy outcomes: clarithromycin and birth malformations. Pharmacoepidemiol Drug Saf. 2000;9(7):549-556. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11338912.
- Muanda FT, Sheehy O, Berard A. Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ. 2017;189(17):E625-E633. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28461374.
- Berard A, Sheehy O, Zhao JP, Nordeng H. Use of macrolides during pregnancy and the risk of birth defects: a population-based study. Pharmacoepidemiol Drug Saf. 2015;24(12):1241-1248. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26513406.
- Lin KJ, Mitchell AA, Yau WP, Louik C, Hernandez-Diaz S. Safety of macrolides during pregnancy. Am J Obstet Gynecol. 2013;208(3):221 e221-228. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23254249.
- Bahat Dinur A, Koren G, Matok I, et al. Fetal safety of macrolides. Antimicrob Agents Chemother. 2013;57(7):3307-3311. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23650169.
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