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

• Change in Clinical Symptom Score at Day 7, as measured by the 10-point visual analog scale to quantify symptom severity. [ Time Frame: Day 7 ] [ Designated as safety issue: No ]
• Change in serum C-reactive protein at Day 7 [ Time Frame: Day 7 ] [ Designated as safety issue: No ]

• Days of hospitalization combined with outpatient therapeutic procedures [ Time Frame: 56 days ] [ Designated as safety issue: No ]
• Study medicine discontinuation [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  (e.g. switching to open-label medication)
• Karnofsky Performance Status Scale at day 7 and 28; [ Time Frame: Day 7 and Day 28 ] [ Designated as safety issue: No ]
• Incidence of Adverse Events [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
  DAIDS Grading Scale 3-5 events
• Radiologic improvement at 2 weeks; [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• Mortality [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
• CD4 count change [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
• Recurrence of IRIS manifestations within the 8 week study period [ Time Frame: 56 days ] [ Designated as safety issue: No ]
• ART or TB therapy discontinuation [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
• Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28 [ Time Frame: Day 28 ] [ Designated as safety issue: Yes ]

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.

• Immune Reconstitution Inflammatory Syndrome
• Immune Reconstitution Syndrome
• Tuberculosis
• HIV-infection/Aids

• Drug: Dexamethasone
  Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
  Other Name: decadron
• Drug: Atorvastatin
  Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)
  Other Name: Lipitor
• Drug: Naproxen
  Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
  Other Names:

  • naproxen sodium
  • Aleve
  • Anaprox
  • Antalgin
  • Feminax Ultra
  • Flanax
  • Inza
  • Midol Extended Relief
  • Nalgesin
  • Naposin
  • Naprelan
  • Naprogesic
  • Naprosyn
  • Narocin
  • Proxen
  • Synflex
  • Xenobid
• Drug: Placebo
  Atorvastatin placebo

• Experimental: Steroid+Statin
  1. Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week;
  2. Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration)
  Interventions:

  • Drug: Dexamethasone
  • Drug: Atorvastatin
• Active Comparator: NSAID+Statin
  1. Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week;
  2. Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration)
  Interventions:

  • Drug: Atorvastatin
  • Drug: Naproxen
• Active Comparator: Steroid+Placebo
  1. Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week;
  2. Placebo
  Interventions:

  • Drug: Dexamethasone
  • Drug: Placebo
• Active Comparator: NSAID+Placebo
  1. Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week;
  2. Placebo
  Interventions:

  • Drug: Naproxen
  • Drug: Placebo

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, GFR <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

• Pfizer
• Minnesota Medical Foundation