Background: Disseminated Mycobacterium avium complex (MAC) infection remains a serious opportunistic infection in patients with advanced HIV infection, particularly among those with severe immunosuppression. Despite the widespread use of antiretroviral therapy (ART), disseminated MAC (DMAC) continues to be associated with significant morbidity and mortality. The current standard treatment consists of a macrolide-based triple regimen, including a macrolide, ethambutol, and rifamycin. However, in patients with high mycobacterial burden or profound immunodeficiency, early microbiological response and clinical improvement are often suboptimal, and treatment is complicated by drug interactions and tolerability issues. Objective: This study aims to evaluate whether adding a fluoroquinolone (levofloxacin or moxifloxacin) to the standard triple therapy improves early clinical outcomes in HIV-infected patients with disseminated MAC infection. Methods: This is a prospective, multicenter, randomized, open-label, controlled trial. A total of 124 adult HIV-infected patients with confirmed disseminated MAC infection will be randomly assigned in a 1:1 ratio to receive either standard triple therapy (macrolide, ethambutol, and rifamycin) or an intensified four-drug regimen with the addition of a fluoroquinolone during the initial 8-week intensive phase. Participants will be followed for at least 24 weeks. Outcomes: The primary endpoint is the clinical symptom resolution rate at Day 28. Secondary endpoints include microbiological outcomes (culture or molecular conversion at Days 28, 56, and 84), time to culture conversion, mortality, relapse, and safety outcomes including adverse events and QT interval prolongation. Significance: This study will provide prospective evidence on whether an intensified treatment strategy can improve early clinical response and microbiological clearance in disseminated MAC infection, while maintaining an acceptable safety profile. The findings may help optimize treatment strategies for HIV-associated disseminated MAC infection.
Background and Rationale: Disseminated Mycobacterium avium complex (MAC) infection remains a major opportunistic infection in patients with advanced HIV infection, particularly among those with severe immunosuppression (e.g., CD4 \<50 cells/μL). Although the incidence of disseminated MAC (DMAC) has declined in the era of antiretroviral therapy (ART), it continues to pose a substantial clinical burden due to delayed diagnosis, high mycobacterial load, and frequent co-infections. Clinically, DMAC often presents with systemic symptoms such as fever, weight loss, anemia, and multi-organ involvement, including bone marrow, liver, spleen, and lymph nodes. Current guidelines recommend a macrolide-based triple therapy consisting of a macrolide (azithromycin or clarithromycin), ethambutol, and a rifamycin (typically rifabutin). This regimen has demonstrated efficacy in reducing mortality and preventing macrolide resistance. However, in real-world clinical practice, early microbiological clearance and symptom improvement remain suboptimal, particularly in patients with high disease burden or delayed immune reconstitution. In addition, drug-drug interactions, especially with ART, and tolerability issues may limit treatment effectiveness. Fluoroquinolones have demonstrated in vitro activity against mycobacteria and possess favorable pharmacokinetic properties, including good tissue penetration. Retrospective studies suggest that the addition of a fluoroquinolone to standard regimens may improve outcomes in disseminated MAC infection, but high-quality prospective evidence is lacking. Therefore, an intensified treatment strategy incorporating a fluoroquinolone during the early phase of therapy may enhance bacterial clearance and improve clinical outcomes. Study Objectives: The primary objective of this study is to determine whether adding a fluoroquinolone (levofloxacin or moxifloxacin) to standard triple therapy improves clinical symptom resolution at Day 28 in HIV-infected patients with disseminated MAC infection. Secondary objectives include evaluating microbiological outcomes (culture or molecular conversion), time to culture conversion, mortality, relapse, treatment failure, and safety outcomes, including adverse events and QT interval prolongation. Study Design: This is a prospective, multicenter, randomized, open-label, controlled clinical trial. A total of 124 eligible adult participants with confirmed disseminated MAC infection will be enrolled and randomized in a 1:1 ratio to one of two treatment arms. Control group: Standard triple therapy consisting of a macrolide (azithromycin or clarithromycin), ethambutol, and rifabutin (or an equivalent rifamycin-based regimen according to local practice). Experimental group: Standard triple therapy plus a fluoroquinolone (levofloxacin or moxifloxacin), administered during the initial 8-week intensive phase. The choice of fluoroquinolone will be determined at baseline based on clinical considerations such as renal function and risk of QT interval prolongation, and will remain fixed during the intensive phase unless safety concerns necessitate modification. Treatment and Follow-up: Participants will receive study treatment according to group assignment, with ART initiated or continued as per standard clinical practice, typically within 2 weeks after starting anti-MAC therapy. Patients will be followed for at least 24 weeks, with scheduled visits at baseline and predefined time points (e.g., Days 7, 14, 28, 56, and 84, and Weeks 24 and beyond). Clinical assessments will include symptom evaluation, physical examination, laboratory tests, and safety monitoring. Microbiological assessments will include culture and/or molecular testing from blood or other sterile sites, with emphasis on consistent sampling sources across time points. Outcome Measures: The primary endpoint is the proportion of participants achieving clinical symptom resolution at Day 28, defined by sustained defervescence, improvement in symptom scores, stabilization or gain in body weight, absence of treatment escalation, and survival. Secondary endpoints include: Microbiological conversion rates at Days 28, 56, and 84 Time to culture conversion All-cause and MAC-related mortality Relapse and treatment failure rates Safety outcomes, including adverse events (graded by CTCAE), serious adverse events, and QT interval changes Safety Considerations: Fluoroquinolones are associated with potential adverse effects, including QT interval prolongation, tendon disorders, and central nervous system toxicity. Therefore, baseline and periodic electrocardiogram monitoring will be performed, along with electrolyte assessment and careful evaluation of concomitant medications. Predefined criteria for dose adjustment or discontinuation will be applied to ensure participant safety. Significance: This study aims to generate high-quality prospective evidence on whether an intensified four-drug regimen can improve early clinical and microbiological outcomes in disseminated MAC infection without compromising safety. The results may inform future treatment guidelines and optimize management strategies for HIV-associated disseminated MAC infection.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
124
Standard triple therapy for disseminated MAC infection consisting of a macrolide, ethambutol, and rifabutin, administered according to protocol-defined dosing and duration.
Participants receive standard therapy for disseminated Mycobacterium avium complex infection plus a fluoroquinolone during the initial 8-week intensive phase.
Clinical Symptom Resolution Rate at Day 28
The proportion of participants achieving clinical symptom resolution at Day 28. Clinical symptom resolution is defined as meeting all of the following criteria: 1. absence of fever for at least 48 hours without the use of antipyretics; 2. improvement in systemic symptoms, defined as a ≥50% reduction in total symptom score or all individual symptom scores ≤1; 3. stabilization or increase in body weight compared with baseline; 4. no requirement for escalation or modification of antimycobacterial therapy due to disease progression; 5. survival through Day 28. Participants who do not meet all criteria, require rescue therapy, or die before Day 28 are classified as non-responders.
Time frame: Day 28 (±3 days)
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