When should antiviral therapy (Antiretroviral Therapy (ART)) be started in an HIV-positive patient with detected Mycobacterium tuberculosis (MTB) infection?

When to Start Antiretroviral Therapy in HIV Patients with Active Tuberculosis

Start antiretroviral therapy (ART) within 2 weeks of initiating tuberculosis treatment for patients with CD4 counts <50 cells/μL, and within 8-12 weeks for those with CD4 counts ≥50 cells/μL, with the critical exception of tuberculous meningitis where ART should be delayed until 2-4 weeks after TB treatment initiation when the meningitis is under control. 1

CD4-Stratified Timing Algorithm

Severe Immunosuppression (CD4 <50 cells/μL)

• Initiate ART within 2 weeks of starting TB treatment 1
• This timing reduces mortality by 56% compared to deferred ART (5.6 vs 12.1 deaths per 100 person-years) 1
• The Cambodian Early vs Late trial demonstrated a 34% mortality reduction with 2-week initiation in patients with median CD4 of 25 cells/μL 1
• The STRIDE and SAPiT trials confirmed significantly lower rates of AIDS-defining conditions and death with immediate (2-week) versus early (8-12 week) ART in this population 1

Moderate Immunosuppression (CD4 50-500 cells/μL)

• Initiate ART within 8-12 weeks of starting TB treatment 1
• Starting at 8 weeks is non-inferior to 2 weeks for mortality in this group 1
• This delayed approach reduces IRIS incidence (20.1 vs 7.7 cases per 100 person-years) without compromising survival 2
• Allows better attribution of drug side effects and improves medication adherence 1

Higher CD4 Counts (>220 cells/μL)

• Initiate ART within 8-12 weeks of starting TB treatment 1
• The TB-HAART trial found no mortality benefit with immediate ART in patients with CD4 >220 cells/μL, confirming safety of co-treatment 1

Critical Exception: Tuberculous Meningitis

For TB meningitis, delay ART initiation until 2-4 weeks after starting TB treatment when the meningitis is under control 1, 3

• High-dose corticosteroids and TB treatment should begin immediately at diagnosis 1
• ART timing depends on clinical improvement and normalization of CSF parameters 1, 3
• Earlier ART in TB meningitis is associated with increased adverse events and higher mortality due to severe IRIS 3
• Wait for evidence of clinical improvement before starting ART 3

Managing IRIS Risk

The increased IRIS risk with earlier ART is substantial but manageable:

• Overall IRIS incidence increases 88% with early ART (risk ratio 1.88) 1
• IRIS rates are 11% with 2-week ART versus 5% with 8-12 week ART 4
• Most IRIS cases are not severe and can be managed symptomatically 1
• For mild IRIS, continue both TB and ART with anti-inflammatory agents like ibuprofen 1
• Severe IRIS may require corticosteroids, but rarely necessitates stopping therapy 1, 5

Practical Implementation Considerations

Always Start TB Treatment First

• Never start ART and TB treatment simultaneously 1
• Initiating 8 drugs concurrently creates impossible-to-evaluate drug interactions and overlapping toxicities 1
• TB treatment should always be established first, then add ART according to the CD4-stratified timeline above 1

For Patients Already on ART

• Continue existing ART regimen when TB is diagnosed 1
• Modify the regimen only if necessary due to drug-drug interactions with rifamycins 1
• Never exclude rifamycins from TB regimen due to ART interactions—adjust ART instead 1

Drug Interaction Management

• Rifabutin has fewer interactions than rifampin and should be substituted when using protease inhibitors or NNRTIs 1
• Integrase inhibitors (bictegravir, dolutegravir) are preferred for new ART due to limited drug interactions 1
• NRTIs and nucleotide RTIs have no significant interactions with rifamycins and require no dose adjustment 1

Monitoring Requirements

• Daily TB therapy is mandatory for all HIV-coinfected patients to prevent rifamycin resistance 1
• More frequent clinical and laboratory monitoring is required compared to HIV-negative TB patients 1
• Monthly assessment for medication adherence and side effects 6
• Close monitoring for IRIS symptoms: fever, worsening respiratory symptoms, lymph node enlargement, expanding CNS lesions 1

Common Pitfalls to Avoid

1. Do not delay ART beyond 8-12 weeks in patients with CD4 <50 cells/μL—this significantly increases mortality 1
2. Do not start ART within 8 weeks in TB meningitis patients—this increases mortality 1
3. Do not omit rifamycins from TB regimen due to ART interactions—this worsens TB outcomes 1
4. Do not use once- or twice-weekly TB regimens in HIV patients with CD4 <100 cells/μL—this promotes rifampin resistance 1