Why start Antiretroviral Therapy (ART) as soon as possible in newly diagnosed Human Immunodeficiency Virus (HIV) patients despite the risk of Immune Reconstitution Inflammatory Syndrome (IRIS)?

Why Start ART Immediately Despite IRIS Risk

The benefits of immediate ART initiation—including reduced mortality, faster viral suppression, and prevention of HIV transmission—substantially outweigh the manageable risk of IRIS, which can be monitored and treated while continuing ART. 1, 2

Primary Benefits That Outweigh IRIS Risk

Mortality and Morbidity Reduction

• Immediate ART initiation (same-day to 14 days) improves virologic suppression rates from 75% to 85% at one year, demonstrating clear clinical benefit 1
• Rapid ART start reduces time to viral suppression by more than 50%, with patients achieving HIV RNA <200 copies/mL in median 1.8 months versus 4.3 months with delayed start 3
• Early ART reduces AIDS-related events, non-AIDS-related events, and all-cause mortality 1

Transmission Prevention

• Faster viral suppression directly translates to reduced HIV transmission risk, a critical public health benefit 1
• Same-day ART initiation achieves viral suppression in 79% of patients by week 12,82% by week 24, and 88% by week 48 4

Retention in Care

• Rapid ART programs demonstrate 97% linkage to care and 81% ART initiation rates, compared to lower rates with delayed approaches 1

IRIS: A Manageable Complication

IRIS Can Be Monitored and Treated

• IRIS is not considered ART failure, and ART must be continued during IRIS episodes 5
• The majority of IRIS cases are self-limiting and do not require ART discontinuation 6
• Guidelines explicitly state that "careful monitoring for immune reconstitution inflammatory syndrome is essential" but do not recommend delaying ART 1

IRIS Mortality Is Low Compared to Untreated HIV

• Overall IRIS-associated mortality is low, with poor outcomes primarily limited to CNS involvement (cryptococcal or tubercular meningitis with raised intracranial pressure) or ARDS 6
• The risk of death from untreated HIV and opportunistic infections far exceeds the risk of IRIS-related mortality 1, 6

Prophylactic Strategies Exist

• For tuberculosis-associated IRIS (the most common form), prophylactic prednisone reduces IRIS incidence from 46.7% to 32.5% without increasing severe infections or mortality 7
• This demonstrates that IRIS risk can be actively mitigated while maintaining early ART benefits 7

Timing Recommendations by Clinical Scenario

Most Opportunistic Infections

• Start ART within 2 weeks of OI diagnosis (evidence rating AIa) 1, 2
• This applies to most OIs including PCP, toxoplasmosis, and CMV 2, 8

Tuberculosis

• CD4 <50 cells/μL: Start ART within 2 weeks of TB treatment initiation 1, 2
• CD4 ≥50 cells/μL: Start ART within 2-8 weeks of TB treatment 1, 2
• Even with high IRIS risk, early ART reduces mortality in patients with low CD4 counts 7

Cryptococcal Meningitis (The Exception)

• Delay ART for 4-6 weeks after starting antifungal therapy in high-resource settings with optimal antifungal therapy, frequent monitoring, and aggressive intracranial pressure management 2
• This is the only scenario where IRIS risk justifies delayed ART, due to high mortality from CNS IRIS 1

Malignancy

• Start ART immediately upon HIV and cancer diagnosis 1, 2

Ambulatory Patients Without Active OIs

• Start ART as soon as possible, including same-day start, unless patient has symptoms suggesting an opportunistic infection 1, 2

Critical Pitfalls to Avoid

Do Not Delay ART Waiting for Complete Labs

• Baseline resistance testing, CD4 count, and viral load should be drawn, but ART should not be delayed waiting for results (except HLA-B*5701 if using abacavir) 2
• Treatment can be adjusted later if resistance is detected 1

Do Not Discontinue ART for IRIS

• IRIS is managed by continuing ART and optimizing treatment for the associated condition 6, 5
• Stopping ART during IRIS leads to worse outcomes and is contraindicated 5

Do Not Use Corticosteroids for All IRIS

• While corticosteroids are beneficial for TB-IRIS 7, they are contraindicated in KS-IRIS 5
• Corticosteroids should be reserved for severe IRIS with CNS involvement or ARDS 6

Do Not Assume IRIS Means Treatment Failure

• IRIS represents immune recovery, not virologic failure 9, 6
• Patients should be counseled that inflammation after starting ART may indicate immune system improvement 9

The Risk-Benefit Calculation

The paradigm has shifted from "when is it safe to start ART" to "why would we delay ART" 1, 2. The evidence demonstrates that:

• Immediate ART improves survival and quality of life 1
• IRIS occurs in a minority of patients and is usually manageable 6
• Delaying ART increases mortality from HIV progression and opportunistic infections 1
• The only exception is cryptococcal meningitis, where delayed ART (4-6 weeks) is justified by high CNS IRIS mortality 2

For all other scenarios, the mortality and morbidity benefits of immediate ART initiation clearly outweigh the manageable risk of IRIS 1, 2.