Enhanced Treatment Strategy for Disseminated MAC Infection in HIV Patients: A Randomized Controlled Trial

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.

Inclusion criteria

• Age ≥18 years
• HIV infection confirmed
• Disseminated Mycobacterium avium complex (MAC) infection confirmed by positive culture from a sterile site or positive molecular/sequencing-based detection from a sterile site specimen considered clinically significant
• Systemic manifestations consistent with disseminated infection
• Planned initiation of standard antimycobacterial therapy
• Able and willing to provide written informed consent

Exclusion criteria

• Prior effective antimycobacterial treatment for >14 days before enrollment
• Known macrolide resistance, if susceptibility data are available
• Hypersensitivity to macrolides, ethambutol, rifamycins, or fluoroquinolones
• Baseline QTc >500 ms or history of significant cardiac arrhythmia
• Uncorrected hypokalemia or hypomagnesemia
• History of severe adverse reaction to fluoroquinolones, such as tendon rupture or severe neuropathy
• Severe hepatic impairment or severe renal dysfunction precluding study treatment
• Concomitant medications that significantly prolong QT interval and cannot be safely discontinued
• Pregnancy or breastfeeding
• Coexisting infection requiring non-protocol antimycobacterial therapy, such as active tuberculosis
• Any condition that, in the investigator's judgment, would interfere with study participation or interpretation of results