What is the management approach for Immune Reconstitution Inflammatory Syndrome (IRIS) in patients with Human Immunodeficiency Virus (HIV) who are initiating Antiretroviral Therapy (ART)?

Management of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV Patients on ART

For most patients with mild to moderate IRIS, continue both antiretroviral therapy and antimicrobial treatment for the underlying opportunistic infection, adding NSAIDs for symptomatic relief; reserve corticosteroids (prednisone 0.5-1.0 mg/kg/day for 2-6 weeks with gradual taper) for severe, life-threatening manifestations. 1

Understanding IRIS

IRIS represents a paradoxical worsening of clinical symptoms, signs, or radiologic manifestations occurring when ART restores immune function, resulting in an exaggerated inflammatory response to previously present infectious or non-infectious antigens. 1 This dysregulated host inflammatory response typically develops within 3 to 6 months after initiating ART, though timing varies by underlying pathogen. 1

The overall incidence ranges from 6% to 39% depending on the population studied and burden of opportunistic infections. 1, 2

Major Risk Factors to Identify

• CD4+ count <50 cells/μL at ART initiation significantly increases IRIS risk 1
• Early ART initiation (within 2 weeks) after starting treatment for opportunistic infections 1
• Advanced immunosuppression with disseminated disease and high pathogen burden (e.g., >2 log10 CFU/mL mycobacteremia) 1, 3
• Rapid viral load decline and immune recovery after ART initiation 4

Common IRIS Manifestations by Pathogen

Tuberculosis-IRIS

• Presents with high fevers, worsening respiratory symptoms, enlarging or new lymphadenopathy, expanding CNS lesions, worsening pulmonary infiltrates, new or increasing pleural effusions, or intra-abdominal/retroperitoneal abscesses 1, 3
• For severe TB-IRIS, prednisone 1.25 mg/kg/day significantly reduces hospitalization and surgical intervention needs 1, 3

Cryptococcal-IRIS

• Manifests with increased intracranial pressure and worsening meningeal inflammation 1
• Requires aggressive management of intracranial pressure with serial lumbar punctures to maintain CSF pressure <20 cm H₂O 3

MAC-IRIS

• Presents as paradoxical worsening despite appropriate antimycobacterial therapy with fever, lymphadenitis, or other inflammatory manifestations 1

Core Management Algorithm

Step 1: Assess Severity

• Mild to moderate IRIS: Localized symptoms without organ dysfunction or life-threatening complications
• Severe IRIS: CNS inflammation, respiratory decompensation, hemodynamic instability, or organ failure 3

Step 2: Continue ART and Antimicrobial Therapy

• Do not discontinue ART unless life-threatening complications develop 1
• Maintain optimal antimicrobial therapy for the underlying opportunistic infection 1
• The benefits of treating HIV infection outweigh the risks associated with IRIS 5

Step 3: Initiate Symptomatic Treatment

For mild to moderate IRIS:

• Start NSAIDs such as ibuprofen for symptomatic relief 1
• Monitor closely for progression over the first 3-6 months after ART initiation 1

For severe IRIS:

• Administer prednisone 0.5-1.0 mg/kg/day (or equivalent corticosteroid) for 2-6 weeks with gradual taper 1, 3
• For severe CNS symptoms, consider dexamethasone 3
• For TB-IRIS specifically, prednisone has demonstrated reduced morbidity and hospitalization needs 3

Step 4: Monitor Response

• Track CD4 count recovery and viral load suppression 1
• Watch for new or worsening symptoms within the first 3-6 months after ART initiation 1
• For cryptococcal meningitis, repeat lumbar puncture after 2 weeks of therapy to document CSF sterilization 3

Prevention Strategies

Pre-ART Screening and Treatment

• Screen and treat opportunistic infections before initiating ART when feasible 1
• Ensure adequate antimicrobial therapy is established before introducing ART, particularly for MAC disease 1

Optimizing ART Timing by Infection Type

Tuberculosis without CNS involvement:

• CD4 <50 cells/μL: Start ART within 2 weeks of tuberculosis treatment to reduce mortality, accepting increased IRIS risk 6, 1, 3
• CD4 ≥50 cells/μL: Initiate ART at 2-8 weeks after starting tuberculosis treatment 1, 3

Tuberculous meningitis:

• Initiate high-dose corticosteroids and tuberculosis treatment immediately at diagnosis 6
• Start ART when tuberculous meningitis is under control based on clinical improvement and CSF parameter normalization, within 2-4 weeks 6

Cryptococcal meningitis:

• For patients who can be closely monitored with access to optimal antifungal therapy and aggressive intracranial pressure management, initiate ART 2-4 weeks after starting antifungal therapy 6, 3
• Earlier initiation at 2 weeks for those clinically improved with controlled intracranial pressure and negative CSF cultures 6
• Defer to 4-6 weeks for those not meeting these criteria to reduce IRIS risk 3

Most other opportunistic infections:

• Start ART within 2 weeks of initiating treatment 6

Critical Pitfalls to Avoid

• Do not discontinue ART when IRIS develops unless life-threatening complications occur; the syndrome does not represent ART failure 1, 5
• Do not use glucocorticoids for Kaposi sarcoma-IRIS; they are contraindicated in this specific manifestation 7
• Do not delay ART indefinitely to avoid IRIS; mortality reduction from early ART (especially with CD4 <50 cells/μL and tuberculosis) outweighs IRIS risk 6, 1
• Do not use the most recent CD4 count elevated by ART to determine prophylaxis needs; use the nadir CD4 count 8
• Do not assume negative initial screening rules out future IRIS; repeat testing may be needed as immune function recovers 5

Special Considerations for Severe Immunosuppression

For patients with CD4 <50 cells/μL and multiple opportunistic infections:

• Prioritize stabilization and initiation of antimicrobial therapy for life-threatening infections first 3
• Consider the specific timing recommendations for each opportunistic infection when planning ART initiation 3
• Prepare for potential IRIS by ensuring close monitoring capacity and access to corticosteroids 3
• Monitor for hepatotoxicity when combining multiple antimicrobial agents with ART 3