Disseminated Nontuberculous Mycobacteria Infection in Human Immunodeficiency Virus-Infected Patients
Nontuberculous mycobacteria (NTM) infections can affect both immunocompetent and immunocompromised individuals. However, disseminated NTM infections predominantly occur in immunocompromised patients, such as those using long-term immunosuppressants or individuals with human immunodeficiency virus (HIV) infection, particularly when their CD4+ T lymphocyte count falls below 50 cells/mm³. Disseminated NTM infection is recognized as a fatal AIDS-defining opportunistic infection, associated with high mortality in this population.
The incidence of disseminated Mycobacterium avium complex (MAC) disease ranges from 20% to 40% in HIV-infected patients with advanced immunosuppression who are not receiving effective antiretroviral treatment (ART) or chemoprophylaxis. In the era of ART, a study conducted in the United States identified 37 cases of disseminated nontuberculous mycobacteria (DNTM) among 7,349 patients, with a median annual incidence of 110 cases per 100,000 HIV person-years. The highest incidence was observed in patients with a CD4+ T lymphocyte count below 50 cells/mm³, reaching 5,300 cases per 100,000 person-years between 2007 and 2012. Overall, the prevalence of any NTM species in people living with HIV was 49%.
The risk factors for susceptibility to DNTM infection remain largely unknown. Research indicates that natural immunity to mycobacteria relies on the interleukin-12 and interferon-gamma (IFN-γ) pathway, which connects myeloid cells (monocytes, macrophages, and dendritic cells) to lymphoid cells (T cells and natural killer cells). At least seven autosomal mutations (in interleukin 12B, interleukin 12 receptor subunit beta 1, interferon-stimulated gene 15 [ISG15], interferon gamma receptor 1, interferon gamma receptor 2, signal transducer and activator of transcription 1, and interferon regulatory factor 8) and two X-linked mutations (in inhibitor of nuclear factor kappa B kinase regulatory subunit gamma and cytochrome B-245 beta chain) have been reported to confer susceptibility to DNTM infection. These genetic defects, often presenting in childhood, can lead to disseminated infections.
DNTM infection is considered an AIDS-defining condition, and its treatment involves optimizing immune function and prolonged use of species-specific antimycobacterial drugs. Treatment is often complicated by the intrinsic or acquired drug resistance of NTM and the adverse effects of drug combinations, leading to frequent treatment failures.
Despite the complex pathogenesis and challenging treatment, there is considerable room for therapeutic improvement in DNTM. The treatment of AIDS with DNTM infection involves a combination of ART and long-term use of specific antibiotics. According to the updated Department of Health and Human Services guidelines, ART should be initiated as soon as possible after the diagnosis of MAC disease, preferably concurrently with the start of ART in patients with HIV and disseminated Mycobacterium avium complex (DMAC) disease who have not yet begun effective ART. Early ART initiation can reduce the risk of AIDS-defining opportunistic infections and improve the response to antimycobacterial therapy in the setting of advanced immunosuppression. For patients already on ART, treatment should be continued, with adjustments made for any drug interactions between antiretrovirals and antimicrobials. Unless ART leads to immune reconstitution, people living with HIV will require continuous antimycobacterial treatment.
Innovative approaches to treatment are being explored. Auster et al. developed a protocol that accelerates the growth kinetics of therapeutic assays in short-term in vitro quantitative assays. This protocol optimizes the growth and characterization of M. avium and M. intracellulare independently and in combination for the systematic development of therapeutic drug testing. Sharma et al. designed a duplex polymerase chain reaction based on the sequence variation between the genes encoding catalase-peroxidase (KatG) of MAC and Mycobacterium tuberculosis (MTB). This method facilitates quick differential diagnosis of DMAC and MTB infections in HIV patients, which is crucial for informing urgent treatment decisions.
Bonfield et al. utilized in vitro and in vivo models of chronic NTM infection to evaluate the potential therapeutic use of human marrow-derived mesenchymal stem cells (hMSCs). They identified donor-specific hMSCs with potency against M. avium and M. intracellulare, demonstrating that hMSCs are antimicrobial and anti-inflammatory in vitro and in the context of an in vivo sustained infection of either M. avium or M. intracellulare. Sharma et al. found that trehalose significantly reduced HIV antibody and HIV antigen (HIV-p24) levels in ex vivo-infected peripheral blood mononuclear cells (PBMCs) or PBMCs from treatment-naive HIV patients and controlled mycobacterial survival within MTB-infected animals.
A study showed that lymphocytes from patients with MAC-lung disease (MAC-LD) had attenuated function regarding IFN-γ production and increased apoptosis status, associated with an increase in the expression of the programmed cell death protein-1 (PD-1) pathway. By partially blocking PD-1 and its ligands, IFN-γ secretion increased, and apoptosis status improved. Targeted regulation of the PD-1 pathway may have therapeutic potential for MAC-LD, especially for patients who fail current medical treatment. The effect of this novel therapeutic method in DNTM infection still needs to be identified.
Host-directed therapeutic (HDT) strategies offer several major advantages compared with conventional antibiotics. HDTs can be effective against drug-resistant bacteria, drug-susceptible bacteria, and potentially dormant mycobacteria. They are unlikely to result in bacterial drug resistance and can synergize with antibiotics or shorten the duration of antibiotic treatment by targeting different pathways. A review summarized the evidence supporting specific adjunctive HDTs for MAC, focusing on the repurposing of existing immune-modulatory agents targeting various cellular pathways. These HDT agents include mammalian target of rapamycin inhibitors, anti-PD-1/programmed cell death-ligand 1 therapy, heme oxygenase inhibition, IFN-γ therapy, suppressing excessive tumor necrosis factor (TNF)-α activation (anti-TNF antibodies), broad suppression of inflammation (non-steroidal anti-inflammatory drugs and corticosteroids), targeting lipid metabolism and inducing autophagy (statins), activation of adenosine monophosphate-activated protein kinase and potentiation of macrophage effector function (metformin), immunomodulation and antimicrobial properties (clavanin-MO), and potentiation of macrophage effector function and antimicrobial activity (thioridazine). HDTs against MAC represent a promising but underexplored avenue of research, with potential to improve microbiological and clinical outcomes.
Several new drugs have shown effectiveness in treating nontuberculosis, such as oxazolidinone (linezolid and tedizolid), inhaled nitric oxide, and liposomal amikacin for inhalation, bedaquiline, clofazimine, and β-lactams in combination with β-lactamase inhibitor avibactam. Inhaled drugs could reduce toxicity and improve the efficacy of anti-DNTM. Clofazimine was synergistic with amikacin against M. avium and Mycobacterium abscessus and significantly prevented the regrowth of nontuberculosis strains after exposure to clarithromycin and amikacin. Novel treatments are research priorities.
Recently, a subunit vaccine ID91 (a recombinant fusion protein) combined with GLA-SE (glucopyranosyl lipid adjuvant, a toll-like receptor 4 agonist formulated) indicated protection against M. avium in a mouse model. Vaccines are worthy of consideration in this area.
doi.org/10.1097/CM9.0000000000001820
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