In an HIV‑positive adult with active tuberculosis, what is the recommended first‑line antitubercular regimen, the compatible antiretroviral therapy, and the timing of ART initiation based on CD4 count?

Antitubercular Therapy in HIV

First-Line Antitubercular Regimen

HIV-positive adults with active tuberculosis should receive the same standard 6-month regimen as HIV-negative patients: 2 months of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB), followed by 4 months of INH and RIF. 1

Critical Dosing Frequency Requirements

• Daily therapy is mandatory throughout both the intensive and continuation phases for all HIV-infected patients to prevent relapse and rifamycin resistance. 1
• Three-times-weekly therapy in the continuation phase may be considered only if the patient is receiving antiretroviral therapy (ART) concurrently. 1
• Never use twice-weekly therapy in patients with CD4 counts <100 cells/μL due to unacceptably high rates of relapse and acquired rifamycin resistance. 1
• Never use once-weekly isoniazid-rifapentine in any HIV-infected patient regardless of CD4 count. 1

Duration Modifications Based on ART Status

• For HIV-infected patients receiving ART during TB treatment: use the standard 6-month regimen (2 months intensive phase + 4 months continuation phase). 1
• For HIV-infected patients NOT receiving ART during TB treatment: extend the continuation phase to 7 months (total 9 months of treatment). 1
• If cultures remain positive after 2 months of therapy, strongly consider extending treatment to 9 months total regardless of ART status. 1

Antiretroviral Therapy Integration

Timing of ART Initiation by CD4 Count

All HIV-infected patients with tuberculosis must receive ART during antituberculosis treatment—the timing depends strictly on CD4 count: 1

• CD4 count <50 cells/μL: Start ART within 2 weeks of beginning TB treatment. 1

  • This reduces mortality by 34% compared to delayed initiation. 1
  • Accept the higher risk of immune reconstitution inflammatory syndrome (IRIS) because mortality benefit outweighs this risk. 1

• CD4 count 50-220 cells/μL: Start ART at 8-12 weeks after beginning TB treatment. 1

  • Starting at 2 weeks provides no additional mortality benefit in this group compared to 8 weeks. 1
  • Delaying to 8-12 weeks reduces IRIS risk without compromising survival. 1

• CD4 count >220 cells/μL: Start ART by 8-12 weeks after beginning TB treatment. 1

  • Immediate ART initiation showed no mortality benefit in this population. 1

Exception: Tuberculous Meningitis

• Do not initiate ART during the first 8 weeks of antituberculosis therapy in patients with tuberculous meningitis, regardless of CD4 count. 1

Compatible Antiretroviral Regimens

Rifamycin-ART Drug Interactions

Rifampin induces cytochrome P450 enzymes and significantly reduces levels of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 1

Preferred approach: Use rifabutin (150-300 mg daily) instead of rifampin when protease inhibitors or NNRTIs are required. 1, 2

• Rifabutin has less enzyme induction than rifampin and maintains better compatibility with antiretrovirals. 1
• Rifabutin-based regimens are equally efficacious to rifampin-based regimens for TB treatment. 1

Alternative approach: Use integrase strand transfer inhibitors (INSTIs) with rifampin, as these have fewer drug interactions. 1

Therapeutic Drug Monitoring

• Consider therapeutic drug monitoring for rifabutin when used with antiretrovirals, as dose adjustments may be needed. 1
• Monitor for rifabutin toxicity (uveitis, neutropenia) when combined with protease inhibitors. 1

Essential Adjunctive Therapy

All HIV-infected patients with active tuberculosis must receive co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis to reduce mortality and morbidity from opportunistic infections. 1

• WHO recommends co-trimoxazole for all HIV-TB coinfected patients regardless of CD4 count. 1
• In high-income countries, co-trimoxazole is primarily used when CD4 counts are <200 cells/μL. 1

Baseline Testing Requirements

Before initiating treatment, obtain: 2, 3

• HIV testing with counseling (if status unknown)
• CD4+ T-cell count
• Hepatitis B surface antigen (HBsAg) and hepatitis C testing
• Baseline liver function tests, complete blood count, serum creatinine
• Three sputum specimens for AFB smear, culture, and drug susceptibility testing
• Chest radiography

Critical Monitoring During Treatment

• Collect sputum specimens monthly until two consecutive specimens are culture-negative. 4
• Monitor for IRIS, which occurs more commonly with earlier ART initiation and CD4 counts <50 cells/μL. 1
• Monitor liver function tests closely given the hepatotoxic potential of INH, RIF, and PZA, especially in patients with baseline liver disease or hepatitis B/C coinfection. 5

Common Pitfalls to Avoid

• Never add a single drug to a failing regimen—this promotes resistance. 6
• Never use intermittent (twice-weekly) therapy in patients with advanced immunosuppression (CD4 <100 cells/μL). 1
• Never delay ART beyond 2 weeks in patients with CD4 counts <50 cells/μL—mortality increases significantly. 1
• Never use rifampin with protease inhibitors without dose adjustments or switching to rifabutin. 1
• Ensure directly observed therapy (DOT) for all HIV-TB coinfected patients to maximize adherence. 1