{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:04:47Z","timestamp":1792789487190,"version":"4.5.0"},"reference-count":104,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH-NHLBI","award":["2R15HL143545-02"],"award-info":[{"award-number":["2R15HL143545-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>For drug-susceptible TB, the WHO-endorsed first-line regimen (isoniazid, rifampicin, ethambutol, pyrazinamide) remains the global reference. Therapy must always be tailored to drug susceptibility, especially in MDR- and XDR-TB. HIV-associated mycobacterial infections\u2014including Mycobacterium tuberculosis (TB), disseminated Mycobacterium avium complex (MAC), and Mycobacterium leprae (M. leprae)\u2014remain leading causes of morbidity and mortality in people living with HIV (PLWH). TB continues to account for the highest burden of AIDS-related deaths worldwide, while MAC and leprosy complicate care in advanced immunosuppression. This review synthesizes current evidence on epidemiology, clinical features, and management challenges of HIV\u2013mycobacterial co-infections. We discuss drug-susceptible and drug-resistant TB therapies, drug\u2013drug interactions with antiretroviral therapy (ART), and the clinical impact of immune reconstitution inflammatory syndrome (IRIS). Beyond established regimens, we highlight host-directed strategies such as metformin, glutathione augmentation, mTOR modulation, and vitamin D; immunotherapies including interferon-\u03b3, GM-CSF, and IL-7; and therapeutic vaccines (M72\/AS01E, MTBVAC, VPM1002) as promising adjuncts. Distinct from guideline-focused overviews, this review emphasizes non-tuberculous mycobacterial disease (NTM, including MAC) and leprosy in PLWH and synthesizes host-directed and adjunctive strategies with their translational prospects, including ART compatibility and IRIS. By integrating TB, NTM, and leprosy across the HIV care continuum, we highlight opportunities not treated in detail elsewhere\u2014particularly HDT-enabled approaches and implementation considerations in PLWH.<\/jats:p>","DOI":"10.3390\/ijms262110325","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:47:36Z","timestamp":1761266856000},"page":"10325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Overcoming Treatment Challenges in HIV-Associated Mycobacterial Diseases: New Therapeutic Frontiers"],"prefix":"10.3390","volume":"26","author":[{"given":"Omid","family":"Nikjeh","sequence":"first","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyedehparmis","family":"Rejali","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4299-3621","authenticated-orcid":false,"given":"Kayvan","family":"Sasaninia","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-1160","authenticated-orcid":false,"given":"Vishwanath","family":"Venketaraman","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1007\/BF02599253","article-title":"Mycobacterial Disease Associated with HIV Infection","volume":"6","author":"Beck","year":"1991","journal-title":"J. Gen. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1590\/S0037-86822007000600004","article-title":"Clinical and Radiographic Features of HIV-Related Pulmonary Tuberculosis According to the Level of Immunosuppression","volume":"40","author":"Garcia","year":"2007","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1183\/09031936.00110210","article-title":"Clinical Management of Tuberculosis and HIV-1 Co-Infection","volume":"36","author":"Schutz","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_4","unstructured":"(2025, March 22). Disseminated Mycobacterium avium Complex: Adult and Adolescent OIs | NIH, Available online: https:\/\/clinicalinfo.hiv.gov\/en\/guidelines\/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections\/disseminated."},{"key":"ref_5","unstructured":"Akram, S.M., and Attia, F.N. (2025). Mycobacterium avium Complex. StatPearls, StatPearls Publishing."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"ofae466","DOI":"10.1093\/ofid\/ofae466","article-title":"Incidence Rate and Risk Factors for Developing Active Tuberculosis Among People Living with HIV in Georgia 2019\u20132020 Cohort","volume":"11","author":"Buziashvili","year":"2024","journal-title":"Open Forum Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"284","DOI":"10.5588\/ijtld.22.0685","article-title":"Epidemiology, Pathogenesis, Clinical Presentation and Management of TB in Patients with HIV and Diabetes","volume":"27","author":"Goletti","year":"2023","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_8","first-page":"e9223","article-title":"A Case of Isolated Pulmonary Mycobacterium avium Complex Being the First Presentation of a Newly Diagnosed HIV\/AIDS","volume":"12","author":"Abaleka","year":"2020","journal-title":"Cureus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S1473-3099(06)70493-5","article-title":"Interactions between HIV Infection and Leprosy: A Paradox","volume":"6","author":"Ustianowski","year":"2006","journal-title":"Lancet Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1177\/003335490812300213","article-title":"HIV-M. Leprae Interaction: Can HAART Modify the Course of Leprosy?","volume":"123","author":"Sarno","year":"2008","journal-title":"Public Health Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"da Silva, T.P., Bittencourt, T.L., de Oliveira, A.L., Prata, R.B.d.S., Menezes, V., Ferreira, H., Nery, J.A.d.C., de Oliveira, E.B., Sperandio da Silva, G.M., and Sarno, E.N. (2020). Macrophage Polarization in Leprosy\u2013HIV Co-Infected Patients. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01493"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pires, C.A.A., Neto, F.O.M.J., de Albuquerque, N.C., Macedo, G.M.M., Batista, K.d.N.M., and Xavier, M.B. (2015). Leprosy Reactions in Patients Coinfected with HIV: Clinical Aspects and Outcomes in Two Comparative Cohorts in the Amazon Region, Brazil. PLoS Neglected Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003818"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103690","DOI":"10.1016\/j.jddst.2022.103690","article-title":"Recent Developments, Challenges and Future Prospects in Advanced Drug Delivery Systems in the Management of Tuberculosis","volume":"75","author":"Verma","year":"2022","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_14","unstructured":"CDCTB (2025, March 21). Tuberculosis (TB)\u2014Treatment of LTBI and TB for Persons with HIV, Available online: https:\/\/www.cdc.gov\/tb\/topic\/treatment\/tbhiv.htm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e130","DOI":"10.1016\/S2352-3018(21)00324-6","article-title":"Use of Integrase Inhibitors in HIV-Associated Tuberculosis in High-Burden Settings: Implementation Challenges and Research Gaps","volume":"9","author":"Naidoo","year":"2022","journal-title":"Lancet HIV"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1001\/jama.2024.24543","article-title":"Antiretroviral Drugs for Treatment and Prevention of HIV in Adults: 2024 Recommendations of the International Antiviral Society\u2013USA Panel","volume":"333","author":"Gandhi","year":"2025","journal-title":"JAMA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"a017863","DOI":"10.1101\/cshperspect.a017863","article-title":"Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis","volume":"5","author":"Seung","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jinf.2017.10.007","article-title":"Management of MDR-TB in HIV Co-Infected Patients in Eastern Europe: Results from the TB:HIV Study","volume":"76","author":"Efsen","year":"2018","journal-title":"J. Infect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ijtb.2017.03.006","article-title":"Extensively Drug-Resistant Tuberculosis (XDR-TB): A Daunting Challenge to the Current End TB Strategy and Policy Recommendations","volume":"64","author":"Rahman","year":"2017","journal-title":"Indian J. Tuberc."},{"key":"ref_20","unstructured":"World Health Organization (2012). WHO Expert Committee on Leprosy: Eighth Report, World Health Organization."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, M.-G., Wu, S.-Q., and He, J.-Q. (2021). Efficacy of Bedaquiline in the Treatment of Drug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis. BMC Infect. Dis., 21.","DOI":"10.1186\/s12879-021-06666-8"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1056\/NEJMoa2119430","article-title":"Bedaquiline\u2013Pretomanid\u2013Linezolid Regimens for Drug-Resistant Tuberculosis","volume":"387","author":"Conradie","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1177\/2325957415599210","article-title":"The Effect of Early Initiation of Antiretroviral Therapy in TB\/HIV-Coinfected Patients: A Systematic Review and Meta-Analysis","volume":"14","author":"Abay","year":"2015","journal-title":"J. Int. Assoc. Provid. AIDS Care JIAPAC"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/S1473-3099(14)70733-9","article-title":"Early versus Delayed Initiation of Highly Active Antiretroviral Therapy for HIV-Positive Adults with Newly Diagnosed Pulmonary Tuberculosis (TB-HAART): A Prospective, International, Randomised, Placebo-Controlled Trial","volume":"14","author":"Mfinanga","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"ref_25","unstructured":"CDC (2025, June 24). CDC Releases New Provisional Guidance for the Use of Pretomanid as Part of a Regimen [Bedaquiline, Pretomanid, and Linezolid (BPaL)] to Treat Drug-Resistant Tuberculosis Disease, Available online: https:\/\/archive.cdc.gov\/www_cdc_gov\/tb\/php\/dear-colleague-letters\/2022-bpal-guidance.html."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1089\/apc.2013.0270","article-title":"Is Primary Mycobacterium avium Complex Prophylaxis Necessary in Patients with CD4 < 50 Cells\/\u03bcL Who Are Virologically Suppressed on cART?","volume":"28","author":"Yangco","year":"2014","journal-title":"AIDS Patient Care STDs"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e01019-18","DOI":"10.1128\/AAC.01019-18","article-title":"Ambroxol Induces Autophagy and Potentiates Rifampin Activity Against Mycobacterium tuberculosis","volume":"62","author":"Choi","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Pooranagangadevi, N., and Padmapriyadarsini, C. (2022). Treatment of Tuberculosis and the Drug Interactions Associated With HIV-TB Co-Infection Treatment. Front. Trop. Dis., 3.","DOI":"10.3389\/fitd.2022.834013"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sultana, Z.Z., Hoque, F.U., Beyene, J., Akhlak-Ul-Islam, M., Khan, M.H.R., Ahmed, S., Hawlader, D.H., and Hossain, A. (2021). HIV Infection and Multidrug Resistant Tuberculosis: A Systematic Review and Meta-Analysis. BMC Infect. Dis., 21, Correction in BMC Infect. Dis. 2021, 21, 86.","DOI":"10.1186\/s12879-021-05799-0"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"416","DOI":"10.3201\/eid1903.120998","article-title":"Treatment Outcomes for Extensively Drug-Resistant Tuberculosis and HIV Co-Infection","volume":"19","author":"Padayatchi","year":"2013","journal-title":"Emerg. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1016\/j.ijid.2019.02.006","article-title":"The Changing Treatment Landscape for MDR\/XDR-TB\u2014Can Current Clinical Trials Revolutionise and Inform a Brave New World?","volume":"80","author":"Honeyborne","year":"2019","journal-title":"Int. J. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1086\/433187","article-title":"Conventional and Molecular Epidemiology of Macrolide Resistance among New Mycobacterium avium Complex Isolates Recovered from HIV-Infected Patients","volume":"41","author":"Gardner","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/S0002-9343(97)00041-7","article-title":"Alternative Regimens for the Prophylaxis of Mycobacterium avium Complex in Acquired Immune Deficiency Syndrome (AIDS)","volume":"102","author":"Currier","year":"1997","journal-title":"Am. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1164\/rccm.200603-450OC","article-title":"Clinical and Molecular Analysis of Macrolide Resistance in Mycobacterium avium Complex Lung Disease","volume":"174","author":"Griffith","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kadota, T., Matsui, H., Hirose, T., Suzuki, J., Saito, M., Akaba, T., Kobayashi, K., Akashi, S., Kawashima, M., and Tamura, A. (2016). Analysis of Drug Treatment Outcome in Clarithromycin-Resistant Mycobacterium avium Complex Lung Disease. BMC Infect. Dis., 16.","DOI":"10.1186\/s12879-016-1384-7"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1378\/chest.124.4.1482","article-title":"Treatment of Mycobacterium avium-Intracellulare Complex Lung Disease with a Macrolide, Ethambutol, and Clofazimine","volume":"124","author":"Field","year":"2003","journal-title":"Chest"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"102711","DOI":"10.1016\/j.jiph.2025.102711","article-title":"Two-Drug versus Three-Drug Regimens for Treating Mycobacterium avium Complex Infection: A Systematic Review and Meta-Analysis","volume":"18","author":"Nguyen","year":"2025","journal-title":"J. Infect. Public Health"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1128\/microbiolspec.TNMI7-0033-2016","article-title":"Paradoxical Reactions and the Immune Reconstitution Inflammatory Syndrome","volume":"5","author":"Church","year":"2017","journal-title":"Microbiol. Spectr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1164\/ajrccm.164.1.2101133","article-title":"Treatment of HIV-Related Tuberculosis in the Era of Effective Antiretroviral Therapy","volume":"164","author":"Burman","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_40","unstructured":"Schaaf, H.S., Zumla, A.I., Grange, J.M., Raviglione, M.C., Yew, W.W., Starke, J.R., Pai, M., and Donald, P.R. (2009). Chapter 29\u2014Pulmonary Tuberculosis in Adults. Tuberculosis, W.B. Saunders."},{"key":"ref_41","unstructured":"New York State Department of Health AIDS Institute (2025, July 09). Management of Immune Reconstitution Inflammatory Syndrome (IRIS). 7 March 2024 (Updated 11 July 2025). Available online: https:\/\/www.hivguidelines.org\/guideline\/hiv-iris\/."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/S1473-3099(08)70184-1","article-title":"Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome: Case Definitions for Use in Resource-Limited Settings","volume":"8","author":"Meintjes","year":"2008","journal-title":"Lancet Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"A5595","DOI":"10.1016\/j.chest.2024.06.3318","article-title":"Mycobacterium avium Complex (MAC) and Immune Reconstitution Inflammatory Syndrome (IRIS) in a Patient with Myelodysplastic Syndrome","volume":"166","author":"Pennington","year":"2024","journal-title":"Chest"},{"key":"ref_44","unstructured":"Kandikattu, D.P. (2025, June 24). What Is Rifampicin Toxicity?. Available online: https:\/\/www.icliniq.com\/articles\/drug-and-supplements\/rifampicin-toxicity."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2147\/IDR.S228336","article-title":"Role of Vitamin-D Supplementation In TB\/HIV Co-Infected Patients","volume":"13","author":"Ayelign","year":"2020","journal-title":"Infect. Drug Resist."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"82","DOI":"10.4046\/trd.2022.0148","article-title":"Improving Tuberculosis Medication Adherence: The Potential of Integrating Digital Technology and Health Belief Model","volume":"86","author":"Sazali","year":"2022","journal-title":"Tuberc. Respir. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2980141","DOI":"10.1155\/2022\/2980141","article-title":"Treatment Adherence among HIV and TB Patients Using Single and Double Way Mobile Phone Text Messages: A Randomized Controlled Trial","volume":"2022","author":"Kibu","year":"2022","journal-title":"J. Trop. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/QCO.0b013e3283210020","article-title":"Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: Consequences for the Global HIV Community","volume":"22","author":"Shenoi","year":"2009","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1124\/jpet.109.164970","article-title":"Metformin, an Antidiabetic Agent, Suppresses the Production of Tumor Necrosis Factor and Tissue Factor by Inhibiting Early Growth Response Factor-1 Expression in Human Monocytes in Vitro","volume":"334","author":"Arai","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/infdis\/jiz064","article-title":"Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects","volume":"220","author":"Lachmandas","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrd.2017.162","article-title":"Host-Directed Therapies for Bacterial and Viral Infections","volume":"17","author":"Kaufmann","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Larcombe, L., Orr, P., Turner-Brannen, E., Slivinski, C.R., Nickerson, P.W., and Mookherjee, N. (2012). Effect of Vitamin D Supplementation on Mycobacterium tuberculosis-Induced Innate Immune Responses in a Canadian Den\u00e9 First Nations Cohort. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040692"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: From Mechanisms of Action to Therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Naicker, N., Sigal, A., and Naidoo, K. (2020). Metformin as Host-Directed Therapy for TB Treatment: Scoping Review. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.00435"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Nabipur, L., Mouawad, M., and Venketaraman, V. (2025). Additive Effects of Glutathione in Improving Antibiotic Efficacy in HIV\u2013M.Tb Co-Infection in the Central Nervous System: A Systematic Review. Viruses, 17.","DOI":"10.3390\/v17010127"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1128\/IAI.73.3.1886-1889.2005","article-title":"Glutathione and Nitrosoglutathione in Macrophage Defense against Mycobacterium tuberculosis","volume":"73","author":"Venketaraman","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_57","first-page":"734125","article-title":"Unveiling the Mechanisms for Decreased Glutathione in Individuals with HIV Infection","volume":"2012","author":"Morris","year":"2012","journal-title":"J. Immunol. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"dmm049018","DOI":"10.1242\/dmm.049018","article-title":"Rapamycin Modulates Pulmonary Pathology in a Murine Model of Mycobacterium tuberculosis Infection","volume":"14","author":"Bhatt","year":"2021","journal-title":"Dis. Model. Mech."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Patel, A., Nguyen, L., Shea, C., Singh, S., and Venketaraman, V. (2024). The Role of mTOR in Mycobacterium tuberculosis Infection. Biomedicines, 12.","DOI":"10.3390\/biomedicines12102238"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s12253-020-00796-1","article-title":"mTOR in Lung Neoplasms","volume":"26","author":"Krencz","year":"2020","journal-title":"Pathol. Oncol. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S1473-3099(12)70321-3","article-title":"Corticosteroids for Prevention of Mortality in People with Tuberculosis: A Systematic Review and Meta-Analysis","volume":"13","author":"Critchley","year":"2013","journal-title":"Lancet Infect. Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.clineuro.2011.12.013","article-title":"Adjuvant Interferon-\u03b3 Treatment in Two Cases of Refractory Tuberculosis of the Brain","volume":"114","author":"Lee","year":"2012","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s00431-006-0339-1","article-title":"Adjunctive Treatment of Disseminated Mycobacterium avium Complex Infection with Interferon Alpha-2b in a Patient with Complete Interferon-Gamma Receptor R1 Deficiency","volume":"166","author":"Ward","year":"2007","journal-title":"Eur. J. Pediatr."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"S154","DOI":"10.1016\/j.anai.2024.08.614","article-title":"Interferon-Gamma Therapy Augments Antimicrobial Treatment of Mycobacterium avium Complex Infection in a Patient with MSMD","volume":"133","author":"Lam","year":"2024","journal-title":"Ann. Allergy. Asthma. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1097\/00062752-199704030-00008","article-title":"Role of Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor in the Treatment of Patients with HIV Infection","volume":"4","author":"Frumkin","year":"1997","journal-title":"Curr. Opin. Hematol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1182\/blood.V75.6.1215.1215","article-title":"Effect of Zidovudine and Granulocyte-Macrophage Colony-Stimulating Factor on Human Immunodeficiency Virus Replication in Alveolar Macrophages","volume":"75","author":"Hammer","year":"1990","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1182\/blood.V88.9.3474.bloodjournal8893474","article-title":"Differential Regulation of Proinflammatory and Hematopoietic Cytokines in Human Macrophages after Infection with Human Immunodeficiency Virus","volume":"88","author":"Esser","year":"1996","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1476-8518-3-3","article-title":"Granulocyte-Macrophage Colony-Stimulating Factor as an Immune-Based Therapy in HIV Infection","volume":"3","author":"Brown","year":"2005","journal-title":"J. Immune Based Ther. Vaccines"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e207","DOI":"10.1016\/j.jinf.2006.11.005","article-title":"The Use of Adjuvant Granulocyte-Macrophage Colony-Stimulating Factor in HIV-Related Disseminated Atypical Mycobacterial Infection","volume":"54","author":"Cope","year":"2007","journal-title":"J. Infect."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Mishra, A., Singh, V.K., Actor, J.K., Hunter, R.L., Jagannath, C., Subbian, S., and Khan, A. (2020). GM-CSF Dependent Differential Control of Mycobacterium tuberculosis Infection in Human and Mouse Macrophages: Is Macrophage Source of GM-CSF Critical to Tuberculosis Immunity?. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01599"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e98960","DOI":"10.1172\/jci.insight.98960","article-title":"Interleukin-7 Restores Lymphocytes in Septic Shock: The IRIS-7 Randomized Clinical Trial","volume":"3","author":"Francois","year":"2018","journal-title":"JCI Insight"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6304","DOI":"10.1182\/blood-2008-10-186601","article-title":"IL-7 Administration Drives T Cell\u2013Cycle Entry and Expansion in HIV-1 Infection","volume":"113","author":"Sereti","year":"2009","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1093\/infdis\/jiad100","article-title":"The Immunopathogenesis of Immune Reconstitution Inflammatory Syndrome Has Become Clearer, but More Complex","volume":"228","author":"French","year":"2023","journal-title":"J. Infect. Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jgar.2021.02.017","article-title":"Bedaquiline: Current Status and Future Perspectives","volume":"25","author":"Khoshnood","year":"2021","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1093\/cid\/cix992","article-title":"Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention","volume":"66","author":"Nguyen","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s40267-020-00743-9","article-title":"Pretomanid in Drug-Resistant Tuberculosis: A Profile of Its Use","volume":"36","author":"Shirley","year":"2020","journal-title":"Drugs Ther. Perspect."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Shibeshi, W., Sheth, A.N., Admasu, A., Berha, A.B., Negash, Z., and Yimer, G. (2019). Nephrotoxicity and Ototoxic Symptoms of Injectable Second-Line Anti-Tubercular Drugs among Patients Treated for MDR-TB in Ethiopia: A Retrospective Cohort Study. BMC Pharmacol. Toxicol., 20.","DOI":"10.1186\/s40360-019-0313-y"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"106953","DOI":"10.1016\/j.ijantimicag.2023.106953","article-title":"Pretomanid Resistance: An Update on Emergence, Mechanisms and Relevance for Clinical Practice","volume":"62","author":"Nguyen","year":"2023","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S2213-2600(18)30426-0","article-title":"Efficacy and Safety of Delamanid in Combination with an Optimised Background Regimen for Treatment of Multidrug-Resistant Tuberculosis: A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Phase 3 Trial","volume":"7","author":"Patientia","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.tube.2018.04.008","article-title":"Delamanid: From Discovery to Its Use for Pulmonary Multidrug-Resistant Tuberculosis (MDR-TB)","volume":"111","author":"Liu","year":"2018","journal-title":"Tuberculosis"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.omtm.2019.01.014","article-title":"MTBVAC-Based TB-HIV Vaccine Is Safe, Elicits HIV-T Cell Responses, and Protects against Mycobacterium tuberculosis in Mice","volume":"13","author":"Broset","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.arbres.2023.09.009","article-title":"MTBVAC: A Tuberculosis Vaccine Candidate Advancing Towards Clinical Efficacy Trials in TB Prevention","volume":"59","author":"Martin","year":"2023","journal-title":"Arch. Bronconeumol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Nieuwenhuizen, N.E., Kulkarni, P.S., Shaligram, U., Cotton, M.F., Rentsch, C.A., Eisele, B., Grode, L., and Kaufmann, S.H.E. (2017). The Recombinant Bacille Calmette\u2013Gu\u00e9rin Vaccine VPM1002: Ready for Clinical Efficacy Testing. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01147"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e00439-16","DOI":"10.1128\/CVI.00439-16","article-title":"Safety and Immunogenicity of the Recombinant Mycobacterium Bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa","volume":"24","author":"Loxton","year":"2017","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.trsl.2020.04.008","article-title":"Therapeutic Vaccines for the Treatment of HIV","volume":"223","author":"Chen","year":"2020","journal-title":"Transl. Res."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Bouzeyen, R., and Javid, B. (2022). Therapeutic Vaccines for Tuberculosis: An Overview. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.878471"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"102302","DOI":"10.1016\/j.tube.2022.102302","article-title":"Immunogenicity and Protection against Mycobacterium avium with a Heterologous RNA Prime and Protein Boost Vaccine Regimen","volume":"138","author":"Rais","year":"2023","journal-title":"Tuberculosis"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Jeong, E.-K., Lee, H.-J., and Jung, Y.-J. (2022). Host-Directed Therapies for Tuberculosis. Pathogens, 11.","DOI":"10.3390\/pathogens11111291"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Krug, S., Parveen, S., and Bishai, W.R. (2021). Host-Directed Therapies: Modulating Inflammation to Treat Tuberculosis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.660916"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Ranjbar, S., Jasenosky, L.D., Chow, N., and Goldfeld, A.E. (2012). Regulation of Mycobacterium tuberculosis-dependent HIV-1 transcription reveals a new role for NFAT5 in the toll-like receptor pathway. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002620"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Bryk, R., Mundhra, S., Jiang, X., Wood, M., Pfau, D., Weber, E., Park, S., Zhang, L., Wilson, C., and Van der Westhuyzen, R. (2020). Potentiation of rifampin activity in a mouse model of tuberculosis by activation of host transcription factor EB. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008567"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.21037\/jtd.2020.01.30","article-title":"How Does Metformin Act as a Host-Directed Agent in Tuberculosis Associated with Diabetes Mellitus?","volume":"12","author":"Yew","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1039\/C9MD00057G","article-title":"Drug-Resistance in Mycobacterium tuberculosis: Where We Stand","volume":"10","author":"Mabhula","year":"2019","journal-title":"MedChemComm"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"103955","DOI":"10.1016\/j.drudis.2024.103955","article-title":"Tuberculosis Treatment-Shortening","volume":"29","author":"Singh","year":"2024","journal-title":"Drug Discov. Today"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.jiac.2014.05.010","article-title":"Treatment Outcomes of Refractory MAC Pulmonary Disease Treated with Drugs with Unclear Efficacy","volume":"20","author":"Jo","year":"2014","journal-title":"J. Infect. Chemother."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.chest.2023.11.038","article-title":"Safety and Efficacy of Clofazimine as an Alternative for Rifampicin in Mycobacterium avium Complex Pulmonary Disease Treatment: Outcomes of a Randomized Trial","volume":"165","author":"Zweijpfenning","year":"2024","journal-title":"Chest"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2001348","DOI":"10.1183\/13993003.01348-2020","article-title":"COVID-19, Tuberculosis and Poverty: Preventing a Perfect Storm","volume":"56","author":"Saunders","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Dlatu, N., Longo-Mbenza, B., and Apalata, T. (2023). Models of Integration of TB and HIV Services and Factors Associated with Perceived Quality of TB-HIV Integrated Service Delivery in O. R Tambo District, South Africa. BMC Health Serv. Res., 23.","DOI":"10.1186\/s12913-023-09748-2"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1093\/ofid\/ofy209.011","article-title":"120. A Randomized Double-Blind Trial Assessing the Efficacy of M72\/AS01E Vaccine Against Pulmonary Tuberculosis Disease in Adults with Latent Mycobacterium tuberculosis Infection","volume":"5","author":"Meeren","year":"2018","journal-title":"Open Forum Infect. Dis."},{"key":"ref_100","unstructured":"Bill & Melinda Gates Medical Research Institute (2025, June 16). Bill & Melinda Gates Medical Research Institute Initiates Phase 3 Clinical Trial of Tuberculosis Vaccine Candidate. Available online: https:\/\/www.gatesmri.org\/mri-initiates-phase-3-clinical-trial-tuberculosis-vaccine-candidate\/."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Ahmed, S., Raqib, R., Gu\u00f0mundsson, G.H., Bergman, P., Agerberth, B., and Rekha, R.S. (2020). Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation. Antibiotics, 9.","DOI":"10.3390\/antibiotics9010021"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s00281-015-0532-2","article-title":"HIV-1 Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome","volume":"38","author":"Lai","year":"2016","journal-title":"Semin. Immunopathol."},{"key":"ref_103","first-page":"e68784","article-title":"A Comprehensive Review of HIV-Associated Tuberculosis: Clinical Challenges and Advances in Management","volume":"16","author":"Patel","year":"2024","journal-title":"Cureus"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1097\/QCO.0000000000000704","article-title":"HIV-Associated Tuberculosis: Clinical Challenges and Advances in Management","volume":"34","author":"Mhango","year":"2021","journal-title":"Curr. Opin. Infect. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10325\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:50:35Z","timestamp":1761267035000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,23]]},"references-count":104,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110325"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110325","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,23]]}}}