Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) Treatment Trial

Randomized Controlled Trial for Corticosteroids Versus NSAIDs With or Without Adjunctive Atorvastatin for the Treatment for Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome

Tuberculosis is the most common opportunistic infection (OI) in HIV-infected persons worldwide, including in South East Asia. Significant numbers of patients experience tuberculosis-related paradoxical immune reconstitution inflammatory syndrome (TB-IRIS) after ART initiation, yet the optimal treatment of TB-IRIS is unknown. A recent randomized-controlled trial showed the benefit of prednisone over placebo in reduction of days of hospitalization and invasive procedures. The investigators hypothesize that nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as corticosteroids for treatment of non-life threatening TB-IRIS in HIV-infected patients and hypothesize that adjunctive treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (Statins) may improve the outcomes. This is a randomized controlled trial with a 2x2 factorial design to test the relative benefit of corticosteroids, NSAIDS, and Statins for the symptomatic and immunologic control of TB-IRIS.

Inclusion Criteria:

• HIV-1 infection documented by any locally licensed ELISA or rapid HIV test kit.
• Age >18 years
• Paradoxical TB-IRIS diagnosed by case definition (see section 5.2)
• Ability and willingness of the participant or legal guardian/representative to give informed consent. Receiving appropriate ART and anti-TB therapy, as judged by the site investigator

Exclusion Criteria:

• Inability to take oral medication;
• Receiving chemotherapy, immunosuppressant, corticosteroid, NSAID, or statin medications; (ASA is acceptable)
• Cannot or unlikely to attend regular clinic visits;
• Known allergy to NSAIDs, statins or corticosteroids;
• Liver transaminase > 2 times the upper limit of normal within 60 days of enrollment;
• History of myositis/myopathy;
• High Investigator Suspicion of anti-TB treatment failure due to TB-resistance or medication non-adherence;
• Receiving ongoing azole anti-fungal for treatment or secondary prophylaxis of cryptococcosis, histoplasmosis or penicilliosis;
• Serious co-morbidities, co-infections, or laboratory values who should not receive NSAIDs, steroid or statins, as judged by the site investigator;
• Minimal IRIS reaction which is unlikely to require treatment, as judged by the site investigator;
• Pregnancy (a negative urine pregnancy test at screening is required for women of childbearing potential) or breast feeding;
• Receiving a HIV treatment regimen containing a protease inhibitor at study entry.

Exclusion for Randomization A Only

• Life threatening TB-IRIS, as defined by:
• Acute respiratory failure; PaO2 < 60 on room air or;
• Altered mental status or;
• New focal neurological deficit or;
• Compression of the vital organs.
• Persons with uncontrolled diabetes mellitus;
• Impair kidney function, glomerular filtration rate <60 ml/min; within 72 hours of consent
• Uncontrolled congestive heart failure
• History of bleeding disorder;
• Platelet count <100,000/µL;
• History of significant gastrointestinal bleeding or ulceration;
• Prior adjunctive corticosteroid therapy for this TB episode for > 48 hr;
• Pregnancy