Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV

Epidemiology

Organisms of the Mycobacterium avium complex (MAC) are ubiquitous in the environment.^1-6 In the era before effective antiretroviral therapy (ART) was available, M. avium was the etiologic agent in >95% of people with HIV with advanced immunosuppression who acquired disseminated MAC disease.^4,7-12 Newer bacterial typing technology suggests organisms causing bacteremia in people with HIV represent a diversity of species, including the M. avium subspecies hominissuis and M. colombiense and other non-MAC species, including M. genavense, M. kansasii, M. simiae, M. mycogenicum, and others.^13-16 These comprise what was historically referred to as disseminated MAC. An estimated 7% to 12% of adults with HIV have been previously infected with MAC, although rates of disease vary in different geographic locations.^2,4,8,11,12 In particular, disseminated MAC in people with HIV has been described more frequently in the United States and Europe than in resource-limited settings.¹⁷

Although epidemiologic associations with infection have been identified, no singular environmental exposure or behavior has been consistently linked to subsequent increased risk of developing MAC disease. The mode of MAC infection is thought to be through repeated inhalation or ingestion of MAC bacteria via the respiratory or gastrointestinal (GI) tract, likely from environmental exposure.^1,18 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.¹⁹

MAC disease typically occurs in people with HIV with CD4 T lymphocyte (CD4) cell counts <50 cells/mm³. The previously reported incidence of disseminated MAC disease ranged from 20% to 40% in people with HIV with advanced immunosuppression in the absence of effective ART or chemoprophylaxis.^20,21 However, the overall incidence of MAC disease among people with HIV has declined substantially 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, even among those not receiving effective ART.^22-26 In addition to a CD4 count <50 cells/mm³, factors associated with increased risk for MAC disease are ongoing HIV viral replication despite ART, previous or concurrent OIs, reduced in vitro lymphoproliferative immune responses to M. avium antigens (possibly reflecting defects in T-cell repertoire), and genetic predisposition in some populations.^24-27 While effective ART has clearly been associated with dramatic reductions in risk of developing MAC disease, MAC disease still can occur in people with HIV on suppressive ART, and the clinical presentation may differ from what is seen in people with untreated HIV. In one retrospective case series following people with HIV mostly on ART, nontuberculous mycobacterial (NTM) disease occurred in nine people who were virologically suppressed on ART at the time of their diagnosis—seven with pulmonary NTM only and two with extrapulmonary disease. MAC was the most common NTM pathogen, isolated in 19 of the 34 cases.¹³ Those with extrapulmonary disease were younger and had higher viral loads and lower CD4 counts at diagnosis.

Clinical Manifestations

In people with HIV with advanced immunosuppression who are not on ART, MAC disease generally presents as a disseminated, multi-organ infection, although localized disease may also be seen.^28-32 Early symptoms may be minimal and can precede mycobacteremia or positive tissue cultures by several weeks. Symptoms are nonspecific and include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain.^8,13-15

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.^{4,5,7-12,20,21,33,34} 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.

Localized MAC disease occurs more often in people with HIV on suppressive ART with increased CD4 counts than in people with HIV not on ART, suggesting improved immune function is associated with more localized disease. Localized syndromes include cervical, intraabdominal, or mediastinal lymphadenitis; pneumonia; pericarditis; osteomyelitis; skin or soft-tissue abscesses; bursitis; genital ulcers; and central nervous system infection. Localized syndromes may also be manifestations of immune reconstitution inflammatory syndrome (IRIS), as discussed below.

Diagnosis

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 fluid, bone marrow, or other normally sterile tissue or body fluids, although data suggest that bone marrow cultures have low yield for detection of MAC in this setting, particularly if blood cultures are negative.^{21,31,32,35-40} 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 tissue, radiographic imaging, or other studies aimed at isolating organisms from focal infection sites.

Although isolated pulmonary MAC disease is not often observed in people with advanced HIV-associated immunosuppression, occasionally MAC disease may be limited to the lung in people with HIV who are virologically suppressed on ART. Diagnostic criteria for disease limited to the lung in this setting should follow those established by the American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and the Infectious Disease Society of America (IDSA) joint guideline on Treatment of Nontuberculous Mycobacterial Pulmonary Disease, which include pulmonary clinical signs and symptoms, exclusion of other alternative diagnoses, nodular or cavitary disease on lung imaging, and a positive culture for MAC from at least two sputum specimens or at least one bronchoalveolar lavage or biopsy sample.⁴¹

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 for asymptomatic colonization with MAC organisms at these sites. Therefore, routine screening of respiratory or GI specimens and preemptive treatment for MAC is not recommended.

Preventing Exposure

MAC organisms commonly contaminate environmental sources of infection, such as food and water. Available information does not support specific recommendations regarding avoidance of exposure.

Preventing Disease

Indication for Primary Prophylaxis

Primary prophylaxis against disseminated MAC disease is not recommended for adults and adolescents with HIV who immediately initiate ART, regardless of CD4 count (AII). People with HIV who have CD4 counts <50 cells/mm³ and who are not receiving ART, remain viremic on ART, or have no options for a fully suppressive ART regimen should receive chemoprophylaxis against disseminated MAC (AI). 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. MAC prophylaxis should be delayed until results are available to avoid exposing patients to monotherapy and the attendant risk of drug resistance (AI).

When to Stop Primary Prophylaxis

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 several large observational cohort studies have demonstrated that people with HIV taking ART can discontinue primary prophylaxis with minimal risk of developing MAC disease, particularly if they are virologically suppressed.^42-47 Conclusions from these studies indicate that the overall incidence of disseminated MAC within 6 to 12 months after stopping primary prophylaxis in these circumstances, regardless of CD4 count, was 0.6 to 0.8 per 100 person-years. 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. However, in a study from the TREAT Asia HIV Observational Database, which evaluated the impact of MAC prophylaxis on AIDS-defining conditions and HIV-associated mortality in people with HIV on ART from September 2015 onward, macrolide use within 3 months of starting ART for those with a CD4 count <50 at ART initiation was associated with a decreased risk of HIV-associated mortality (HR 0.10; 95% CI, 0.01–0.80; P = 0.031) but not with the combined outcome of developing an AIDS-defining condition or death.⁴⁸ Despite this finding, only 10.6% of the 1,345 participants in the cohort eligible for MAC prophylaxis received it. The authors concluded that there may be an additive protective effect of macrolide prophylaxis in reducing overall HIV-related mortality among Asians with HIV and CD4 counts <50 even though they received effective ART. Despite some differences among these published data, for most individuals, particularly in higher resourced settings, the preponderance of current data suggest that primary MAC prophylaxis provides no additional benefit in people started on effective ART that results in viral suppression. Additional arguments against primary MAC prophylaxis while prioritizing effective ART to achieve viral suppression include (1) the potential for adding additional cost and adverse effects of the drugs used for prophylaxis; (2) the likelihood that only a small number of people with HIV will develop “unmasking MAC IRIS” (i.e., active MAC disease after starting ART); (3) the potential for acquired drug resistance if people fail monotherapy for MAC prophylaxis; and (4) limiting polypharmacy to assist with adherence to ART.^49-51

Preferred and Alternative Drugs for Prophylaxis

As previously stated, primary prophylaxis for MAC is not recommended for people on effective ART, but for those for whom prophylaxis is being considered, azithromycin⁵² and clarithromycin^5,53 are the preferred prophylactic agents (AI).^1,54 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.⁵² However, based on the additional cost, increased occurrence of adverse effects, potential for drug interactions, and lack of greater survival benefit than with azithromycin alone, the combination regimen of azithromycin and rifabutin is not recommended (AI). In people with HIV who cannot tolerate azithromycin or clarithromycin, rifabutin can be used as a prophylactic agent for MAC disease (BI), although drug interactions may complicate use of this agent. Moreover, tuberculosis (TB) should be excluded before rifabutin is used to avoid monotherapy in the setting of active TB, which could result in acquired rifamycin resistance.

Treating Disease

Initial treatment of MAC disease should consist of two or more antimycobacterial drugs to prevent or delay the emergence of resistance (AI).^{1,6,11,12,18,55-63} Clarithromycin (AI) or azithromycin (AII) are preferred first agents; published data are more extensive for clarithromycin than for azithromycin in people with advanced HIV disease, and clarithromycin appears to be associated with more rapid clearance of MAC from the blood.^{6,55,57,61,62,64} However, azithromycin is acceptable when drug interactions or intolerance preclude the use of clarithromycin (AII). Doses of clarithromycin >1 g/day for treatment of disseminated MAC disease have been associated with increased mortality and should not be used (AI).⁶⁵ Testing MAC isolates for susceptibility to clarithromycin or azithromycin is recommended for all people with HIV, particularly those who developed MAC disease while receiving prophylaxis with one of these agents.^66,67 In three randomized clinical trials, clarithromycin-resistant isolates were reported in 29% and 58% of people with HIV who developed MAC bacteremia during prophylaxis with clarithromycin, and azithromycin-resistant isolates were recovered from 11% of those who developed bacteremia while on azithromycin prophylaxis.^5,52,53,68 More advanced immunosuppression at prophylaxis initiation and longer duration of MAC prophylaxis are associated with higher rates of clarithromycin resistance at the time of MAC prophylaxis failure.⁶⁸

Ethambutol is the recommended second drug for the initial treatment of MAC disease (AI) based on randomized trials of MAC therapy that indicate its use in the regimen is associated with lower rates of relapse.^56,58,64,69 Rifabutin can be used as a third drug (CI) with or without a fluoroquinolone (levofloxacin or moxifloxacin) (CIII), or an injectable aminoglycoside (amikacin or streptomycin) (CIII) can be used as a fourth drug if more severe disease is present; the risk of mortality is high; emergence of drug resistance is likely (e.g., after failure of MAC prophylaxis); or in the setting of advanced immunosuppression (CD4 count <50 cells/mm³), high mycobacterial loads (>2 log₁₀ colony-forming units/mL of blood), or the absence of effective ART (CIII). 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 resistance^6,57 in individuals with advanced HIV and disseminated MAC disease. These studies were completed before the availability of effective ART. It has not been established whether similar results would be observed for people with HIV receiving effective ART. The fluoroquinolones levofloxacin and moxifloxacin and amikacin have in vitro and animal model activity against MAC, although randomized trials evaluating the efficacy of adding a fluoroquinolone or injectable aminoglycoside as part of a multidrug regimen for treatment of MAC have not been done. Injectable aminoglycosides should generally be avoided except in the setting of refractory disease when other alternative agents are not available or tolerated.^66,70 Additional drugs with in vitro activity against clinical isolates of MAC include bedaquiline, tedizolid, linezolid, and omadacycline; these might also be considered in people with refractory MAC disease.^71-75

While not specifically applicable to people with HIV (who more often have disseminated MAC disease than isolated pulmonary disease), in 2020, the ATS/ERS/ESCMID/IDSA updated their jointly sponsored clinical guideline for treatment of nontuberculous mycobacterial pulmonary disease, including pulmonary MAC.⁴¹ People with HIV fully suppressed on ART with higher CD4 counts may present with localized pulmonary or other local organ system MAC disease that may clinically resemble such disease in people without HIV. Following the ATS/ERS/ESCMID/IDSA guidelines would be reasonable in such settings. The recommended treatment includes an initial three-drug regimen containing a macrolide and ethambutol for those with macrolide-susceptible pulmonary MAC disease. Addition of an aminoglycoside, which in refractory cases can be given as inhalation suspension, is recommended if cavitary or severe bronchiectatic disease is present or if macrolide resistance is suspected.⁷⁶

People with HIV and disseminated MAC disease should be treated for a minimum duration of 12 months (AII). Shorter duration of treatment may be considered depending on the degree of immunologic recovery following initiation of ART (CIII); the CD4 count should be maintained above 100 cells/mm³ for at least 6 months before discontinuing MAC treatment.^77-79

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 (BIII). ART is recommended as soon as possible to reduce the risk of further AIDS-defining OIs and to further improve the response to antimycobacterial therapy in the setting of advanced immunosuppression (BIII). 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 (ARV) and antimycobacterial drugs (BIII). Information on drug–drug interactions can be found in the Adult and Adolescent Antiretroviral Guidelines. People with HIV will need continuous antimycobacterial treatment until ART results in sustained immune reconstitution, as indicated above (CD4 count maintained above 100 cells/mm³ for at least 6 months).

Monitoring of Response to Therapy and Adverse Events (including IRIS)

A repeat blood culture for MAC should be obtained 4 to 8 weeks after initiating antimycobacterial therapy in people with HIV who do not have a clinical response to their initial treatment regimens. Improvement in fever and other systemic symptoms and a decline in quantity of mycobacteria in blood or tissue can be expected within 2 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 of clarithromycin and azithromycin include GI upset, metallic taste, elevations in liver transaminase levels, and hypersensitivity reactions. Clarithromycin’s adverse effects may be exacerbated when drug levels are increased due to drug interactions associated with some ARV 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).⁶⁵ Protease inhibitors (PIs) can increase clarithromycin levels; clarithromycin dose adjustment or switching clarithromycin to azithromycin may be necessary. Azithromycin metabolism is not affected by the cytochrome P450 (CYP) system; azithromycin can be used safely in the presence of PIs, non-nucleoside reverse transcriptase inhibitors, or integrase inhibitors without concerns about drug interactions.

When used with clarithromycin or other drugs that inhibit CYP isoenzyme 3A4, rifabutin has been associated with a higher risk of adverse drug interactions, in particular sight-threatening uveitis and neutropenia.^80-82 Rifabutin adverse effects are concentration related; therapeutic drug level monitoring may be considered to reduce the potential for adverse effects. Rifabutin must be dose adjusted in people with HIV receiving PIs or efavirenz. Rifabutin should not be coadministered with cobicistat-boosted PIs, long-acting injectable cabotegravir/rilpivirine, bictegravir, elvitegravir/cobicistat, fostemsavir, or lenacapavir.^82-86 Rilpivirine and doravirine must be dose adjusted if either is coadministered with rifabutin. No dose adjustment for rifabutin or the integrase inhibitors dolutegravir or raltegravir or injectable cabotegravir alone is currently recommended, although at least one study suggested that compared with people without TB or MAC, lower trough concentrations were observed when once daily dolutegravir was used together with rifabutin.^87-89 The most updated drug–drug interaction information can be found in the Adult and Adolescent Antiretroviral Guidelines. Therapeutic drug monitoring may be helpful for optimizing drug dosing in the context of complex drug–drug interactions.⁹⁰

IRIS associated with MAC disease is recognized as a systemic inflammatory syndrome, with signs and symptoms clinically indistinguishable from active MAC infection, although bacteremia is generally absent. Similar to 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.^91-95 Both variants occur primarily in those with advanced immunosuppression who begin ART and have a rapid and marked reduction in plasma HIV RNA.^95,96 Elevated alkaline phosphatase levels may be a predictor of MAC-associated IRIS.⁹⁷ 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.

People with HIV on ART who develop moderate to severe symptoms typical of IRIS should receive initial treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) (BIII). If IRIS symptoms do not improve, short-term (4–8 weeks) systemic corticosteroid therapy, in doses equivalent to 20 to 40 mg of oral prednisone daily, can be used to reduce symptoms and morbidity (BII).^92,98 Severe forms of MAC IRIS with a hemophagocytic lymphohistiocytosis (HLH) phenotype may occur, and a lower hemoglobin prior to ART may help predict this more severe form of IRIS.^97,99 Patients with this more severe form may have a genetic predisposition, and cases of MAC IRIS and other NTM IRIS requiring additional immunosuppression in addition to corticosteroids have been reported.^99,100

Managing Treatment Failure

MAC treatment failure is defined by the absence of a clinical response and the persistence of mycobacteremia (or persistently positive tissue cultures from other sites) 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.

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 include rifabutin, fluoroquinolone (levofloxacin or moxifloxacin), an injectable aminoglycoside (amikacin or streptomycin), or possibly bedaquiline, tedizolid, linezolid, or omadacycline, although data supporting a survival or microbiologic benefit when these agents are added are limited.^{11,12,41,56-60,64,69,72-75,101-104} Continuing clarithromycin or azithromycin despite resistance is not recommended (BIII), as there is likely to be no additional benefit and may have added toxicity. Clofazimine should generally not be used because randomized trials have demonstrated lack of efficacy and an association with increased mortality (AI).^56,58,69 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).

Although anecdotal data and individual case reports suggest potential benefit, adjunctive treatment of MAC disease with immunomodulators has not been thoroughly studied, and data are insufficient to support a recommendation for routine use, except in the setting of familial immunodeficiencies associated with increased risk of MAC disease.¹⁰⁵

Preventing Recurrence

As indicated above, people with HIV and disseminated MAC disease should be treated for a minimum duration of 12 months (AII). Shorter duration of treatment may be considered depending on the degree of immunologic recovery following initiation of ART; the CD4 count should be maintained above 100 cells/mm³ for at least 6 months before discontinuing MAC treatment. If ART initiation does not result in immune reconstitution, people with HIV and disseminated MAC disease should continue chronic maintenance therapy (AII).^77-79

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).^{44,60,77-79,106-108} 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 people who immediately initiate ART is not recommended (AIII). When primary prophylaxis is required for a pregnant person 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). 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.^109,110

Azithromycin did not produce defects in animal studies, but experience with use in humans during the first trimester is limited. A nested case-control study conducted within the large Quebec Pregnancy cohort found an association between azithromycin use and spontaneous miscarriage¹¹¹; 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 azithromycin in the first trimester and major congenital malformations, including heart defects.^112-114 A systematic review of pregnancy outcomes following macrolide use found no significant increased risks for major congenital malformations or congenital heart defects following all macrolide use in the first trimester, but a small but significant increased rate of major congenital malformations with azithromycin though maternal confounders could not be excluded. In a Cochrane systematic review of Chlamydia trachomatis infection treatment in pregnancy, there was no apparent difference between azithromycin and other agents in terms of efficacy and pregnancy complications.¹¹⁵

References

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Lee EH, Chin B, Kim YK, et al. Clinical characteristics of nontuberculous mycobacterial disease in people living with HIV/AIDS in South Korea: A multi-center, retrospective study. PLoS One. 2022;17(11):e0276484. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36355915.
14. Ricotta EE, Adjemian J, Blakney RA, Lai YL, Kadri SS, Prevots DR. Extrapulmonary nontuberculous mycobacteria infections in hospitalized patients, United States, 2009-2014. Emerg Infect Dis. 2021;27(3):845-852. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33622461.
15. Wetzstein N, Geil A, Kann G, et al. Disseminated disease due to non-tuberculous mycobacteria in HIV positive patients: A retrospective case control study. PLoS One. 2021;16(7):e0254607. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34255788.
16. 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.
17. Heidary M, Nasiri MJ, Mirsaeidi M, et al. Mycobacterium avium complex infection in patients with human immunodeficiency virus: A systematic review and meta-analysis. J Cell Physiol. 2019;234(7):9994-10001. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30548598.
18. 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.
19. Carbonne A, Lemaitre N, Bochet M, et al. Mycobacterium avium complex common-source or cross-infection in AIDS patients attending the same day-care facility. Infect Control Hosp Epidemiol. 1998;19(10):784-786. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9801289.
20. 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.
21. 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.
22. Marochi-Telles JP, Muniz R, Jr., Sztajnbok J, Cosme-de Oliveira A. Disseminated mycobacterium avium on HIV/AIDS: historical and current literature review. AIDS Rev. 2020;22(1):9-15. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32167509.
23. 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.
24. 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: https://www.ncbi.nlm.nih.gov/pubmed/27559122.
25. 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.
26. 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.
27. Hsu DC, Breglio KF, Pei L, et al. Emergence of polyfunctional cytotoxic CD4+ T cells in mycobacterium avium immune reconstitution inflammatory syndrome in human immunodeficiency virus-infected patients. Clin Infect Dis. 2018;67(3):437-446. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29538651.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. 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.
37. Cornejo-Juárez P, Islas-Muñoz B, Ramírez-Ibarguen AF, et al. Bone Marrow Culture Yield for the Diagnosis of Opportunistic Diseases in Patients with AIDS and Disseminated Kaposi Sarcoma. Curr HIV Res. 2020;18(4):277-282. Available at: https://pubmed.ncbi.nlm.nih.gov/32493198/.
38. Prabhu V, Coelho S, Achappa B, Baliga S, Sharon L, Shah J. Role of fluorescence in situ hybridization in detecting mycobacterium avium complex presenting as fever in treatment failure HIV. J Clin Tuberc Other Mycobact Dis. 2020;21:100188. Available at: https://pubmed.ncbi.nlm.nih.gov/32995570/.
39. Sharma S, Latawa R, Wanchu A, Verma I. Differential diagnosis of disseminated Mycobacterium avium and Mycobacterium tuberculosis infection in HIV patients using duplex PCR. Future Microbiol. 2021;16(3):159-173. Available at: https://pubmed.ncbi.nlm.nih.gov/33528278/.
40. Sharvit G, Schwartz D, Heering G, et al. Evaluation of the clinical impact of bone marrow cultures in current medical practice. Sci Rep. 2022;12(1):9664. Available at: https://pubmed.ncbi.nlm.nih.gov/35690634/.
41. Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline. Clin Infect Dis. 2020;71(4):e1-e36. Available at: https://pubmed.ncbi.nlm.nih.gov/32628747/.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.
48. Pasayan MKU, ML SM, Boettiger D, et al. Effect of Macrolide Prophylactic Therapy on AIDS-Defining Conditions and HIV-Associated Mortality. J Acquir Immune Defic Syndr. 2019;80(4):436-443. Available at: https://pubmed.ncbi.nlm.nih.gov/30550488/.
49. 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.
50. Sax PE. “Choosing wisely” in HIV medicine — should we stop giving MAC prophylaxis? HIV and ID Observations. 2016;2018(3/20/2016). 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/.
51. Vervoort SC, Borleffs JC, Hoepelman AI, Grypdonck MH. Adherence in antiretroviral therapy: a review of qualitative studies. AIDS. 2007;21(3):271-281. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17255734.
52. 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.
53. 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.
54. 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.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. 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.
64. 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.
65. Food and Drug Administration. Clarithromycin [package insert]. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050662s058,050698s038,050775s026lbl.pdf
66. 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.
67. 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.
68. Craft JC, Notario GF, Grosset JH, Heifets LB. Clarithromycin resistance and susceptibility patterns of Mycobacterium avium strains isolated during prophylaxis for disseminated infection in patients with AIDS. Clin Infect Dis. 1998;27(4):807-812. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9798037.
69. 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.
70. 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.
71. Chapagain M, Pasipanodya JG, Athale S, et al. Omadacycline efficacy in the hollow fibre system model of pulmonary Mycobacterium avium complex and potency at clinically attainable doses. Journal of Antimicrobial Chemotherapy. 2022;77(6):1694-1705. Available at: <Go to ISI>://WOS:000767401100001.
72. Litvinov V, Makarova M, Kudlay D, Nikolenko N, Mikhailova J. In vitro activity of bedaquiline against Mycobacterium avium complex. J Med Microbiol. 2021;70(10). Available at: https://pubmed.ncbi.nlm.nih.gov/34668850/.
73. Lin S, Hua W, Wang S, et al. In vitro assessment of 17 antimicrobial agents against clinical Mycobacterium avium complex isolates. BMC Microbiol. 2022;22(1):175. Available at: https://pubmed.ncbi.nlm.nih.gov/35804298/.
74. Gil E, Sweeney N, Barrett V, et al. Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV. Emerg Infect Dis. 2021;27(3):944-948. Available at: https://pubmed.ncbi.nlm.nih.gov/33622490/.
75. Philley JV, Wallace RJ, Jr., Benwill JL, et al. Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease. Chest. 2015;148(2):499-506. Available at: https://pubmed.ncbi.nlm.nih.gov/25675393/.
76. Shirley M. Amikacin Liposome Inhalation Suspension: A Review in Mycobacterium avium Complex Lung Disease. Drugs. 2019;79(5):555-562. Available at: https://pubmed.ncbi.nlm.nih.gov/30877642/.
77. 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.
78. 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.
79. Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med. 2002;137(4):239-250. Available at: https://pubmed.ncbi.nlm.nih.gov/12186514/.
80. 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.
81. 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.
82. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. 2023. Available at: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/drug-interactions-overview?view=full
83. 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.
84. 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.
85. 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.
86. 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.
87. 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.
88. 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.
89. Le X, Guo X, Sun J, et al. Pharmacokinetic features of dolutegravir with rifampicin and rifabutin among patients coinfected with human immunodeficiency virus and tuberculosis/mycobacterium avium complex. Int J Infect Dis. 2022;116:147-150. Available at: https://pubmed.ncbi.nlm.nih.gov/34999246/.
90. Alffenaar JW, Martson AG, Heysell SK, et al. Therapeutic Drug Monitoring in Non-Tuberculosis Mycobacteria Infections. Clin Pharmacokinet. 2021;60(6):711-725. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33751415.
91. 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.
92. 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.
93. 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.
94. 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.
95. 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.
96. 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.
97. Breglio KF, Vinhaes CL, Arriaga MB, et al. Clinical and Immunologic Predictors of Mycobacterium avium Complex Immune Reconstitution Inflammatory Syndrome in a Contemporary Cohort of Patients With Human Immunodeficiency Virus. J Infect Dis. 2021;223(12):2124-2135. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205640/.
98. 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.
99. Rocco JM, Laidlaw E, Galindo F, et al. Severe mycobacterial immune reconstitution inflammatory syndrome (IRIS) in advanced human immunodeficiency virus (HIV) has features of hemophagocytic lymphohistiocytosis and requires prolonged immune suppression. Clin Infect Dis. 2023;76(3):e561-e570. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36048425.
100. Rocco JM, Laidlaw E, Galindo F, et al. Mycobacterial immune reconstitution inflammatory syndrome in HIV is associated with protein-altering variants in hemophagocytic lymphohistiocytosis-related genes. J Infect Dis. 2023;228(2):111-115. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37040388.
101. 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.
102. 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.
103. 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.
104. 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.
105. Liu L, Song Z, Xun J, et al. PD-1 inhibitor for disseminated mycobacterium avium infection in a person with HIV. Open Forum Infect Dis. 2023;10(1):ofac700. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36686637.
106. 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.
107. 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.
108. 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.
109. 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.
110. 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.
111. 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.
112. 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.
113. 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.
114. 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.
115. Cluver C, Novikova N, Eriksson DO, Bengtsson K, Lingman GK. Interventions for treating genital Chlamydia trachomatis infection in pregnancy. Cochrane Database Syst Rev. 2017;9(9):CD010485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28937705.