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

• Dexamethasone (Drug), also known as decadron: Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
• Atorvastatin (Drug), also known as Lipitor: Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)
• Naproxen (Drug), also known as naproxen sodium, Aleve, Anaprox, Antalgin, Feminax Ultra, Flanax, Inza, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Proxen, Synflex, Xenobid: Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
• Placebo (Drug): Atorvastatin placebo

Primary outcomes

• Change in Clinical Symptom Score at Day 7, as measured by the 10-point visual analog scale to quantify symptom severity. [Day 7]
• Change in serum C-reactive protein at Day 7 [Day 7]

Secondary outcomes

• Days of hospitalization combined with outpatient therapeutic procedures [56 days]
• Study medicine discontinuation [28 days]: (e.g. switching to open-label medication)
• Karnofsky Performance Status Scale at day 7 and 28; [Day 7 and Day 28]
• Incidence of Adverse Events [56 days]: DAIDS Grading Scale 3-5 events
• Radiologic improvement at 2 weeks; [14 days]
• Mortality [56 days]
• CD4 count change [28 days]
• Recurrence of IRIS manifestations within the 8 week study period [56 days]
• ART or TB therapy discontinuation [56 days]
• Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28 [Day 28]

Sex: All, ages: 18 Years to any

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

• Sasisopin Kiertiburanakul, MD, MHS, Principal investigator, Mahidol University
• David R Boulware, MD, MPH, Study chair, University of Minnesota
• Ubonvan Jongwutiwes, MD, Study director, Memorial Sloan Kettering Cancer Center