HIV-infection/Aids, Immune Reconstitution Inflammatory Syndrome, Immune Reconstitution Syndrome, Tuberculosis
Conditions
Keywords
TB, AIDS, HIV, IRIS, immune reconstitution inflammatory syndrome, anti-inflammatory, treatment
Brief summary
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.
Interventions
DRUGDexamethasone
Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
DRUGAtorvastatin
Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)
DRUGNaproxen
Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
DRUGPlacebo
Atorvastatin placebo
Sponsors
Pfizer
Minnesota Medical Foundation
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Days of hospitalization combined with outpatient therapeutic procedures | 56 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 | — |
| CD4 count change | 28 days | — |
| Study medicine discontinuation | 28 days | (e.g. switching to open-label medication) |
Countries
Thailand
Outcome results
None listed