Why is rifabutin (Rifabutin) preferred over rifampin (Rifampin) in patients with tuberculosis (TB) who are also Human Immunodeficiency Virus (HIV)-positive?

Why Rifabutin is Preferred Over Rifampin in TB-HIV Co-infected Patients

Rifabutin is preferred over rifampin in TB patients with HIV because rifampin markedly lowers blood levels of protease inhibitors and NNRTIs through potent CYP450 enzyme induction, making rifampin contraindicated when patients are taking these antiretroviral agents, whereas rifabutin is a less potent enzyme inducer and can be used with appropriate dose adjustments. 1

The Core Pharmacologic Problem

The fundamental issue is drug-drug interactions through the cytochrome P450 system:

• Rifampin is a potent inducer of CYP450 enzymes, which dramatically reduces serum concentrations of protease inhibitors and most NNRTIs, leading to suboptimal antiretroviral therapy and risk of HIV treatment failure 1, 2

• Rifabutin is a weaker CYP450 inducer and, when used with appropriately modified doses, does not cause clinically significant reductions in most protease inhibitors or NNRTIs 1

• The CDC explicitly states that rifampin use with protease inhibitors or NNRTIs is always contraindicated (with limited exceptions for efavirenz and specific ritonavir-based regimens) 1

When Rifabutin Should Be Used

Rifabutin substitution is indicated when HIV-positive patients require:

• Protease inhibitor-based antiretroviral therapy (except ritonavir alone or hard-gel saquinavir) 1
• NNRTI therapy with nevirapine (rifabutin can be used with dose adjustments) 1
• Any antiretroviral regimen where rifampin interactions would compromise HIV viral suppression 3, 4

Critical Dose Adjustments Required

When using rifabutin with antiretrovirals, dose modifications are essential:

• Standard rifabutin dose is 300 mg daily, but this must be reduced to 150 mg daily when combined with protease inhibitors to avoid rifabutin toxicity 1, 2
• Clinical experience from Florida TB hospitals demonstrates successful outcomes using rifabutin 150 mg daily during intensive phase, followed by 300 mg twice weekly during continuation phase 1

Efficacy Evidence: Rifabutin is Non-Inferior

The preference for rifabutin is based on drug interactions, not inferior TB treatment efficacy:

• Three clinical trials demonstrated that 6-month rifabutin-containing regimens (150-300 mg daily) were equally effective and safe as rifampin regimens for TB treatment 1
• One trial in Uganda (the only study including HIV-infected patients) showed 81% sputum conversion at 2 months with rifabutin versus 48% with rifampin, though this difference disappeared after controlling for baseline disease severity 1
• Rifabutin and rifampin have equivalent in vitro antituberculosis activity 1

Important Caveats and Pitfalls

Daily dosing during intensive phase is strongly preferred over intermittent dosing:

• A 2006 study found that intermittent (twice-weekly) rifabutin therapy in HIV patients with CD4 counts <100 cells/mm³ resulted in 12.3% treatment failure/relapse rate with acquired rifamycin resistance 5
• Among patients with CD4 >100 cells/mm³, the failure rate was 0% 5
• Acquired rifampin monoresistance occurred only in patients with CD4 counts <100 cells/mm³ across multiple studies 1
• The CDC recommends daily therapy during the intensive phase, with twice-weekly dosing reserved only for the continuation phase 3

Rifabutin has specific toxicity concerns:

• Uveitis can occur, particularly when rifabutin is combined with clarithromycin or fluconazole, requiring ophthalmologic monitoring 6, 3
• Dose-dependent adverse events increase at 300 mg daily compared to 150 mg daily 1

When Rifampin Can Still Be Used in HIV Patients

Rifampin remains the preferred agent in specific scenarios:

• HIV-negative patients or those not yet on antiretroviral therapy 3, 4
• Patients on efavirenz 600 mg daily plus two NRTIs (rifampin can be used without dose adjustment) 3, 7
• Patients on dolutegravir-based ART (dolutegravir must be increased to 50 mg twice daily when combined with rifampin) 3, 7
• Patients on ritonavir alone plus NRTIs 4

The CDC notes that rifampin is preferred over rifabutin when feasible due to superior efficacy data from approximately 90 controlled clinical trials and faster bacteriologic response 3

Alternative When Neither Rifamycin Can Be Used

If complex drug interactions preclude both rifampin and rifabutin:

• A 9-month streptomycin-based regimen can be considered: isoniazid, streptomycin, pyrazinamide, and ethambutol for 2 months, then isoniazid, streptomycin, and pyrazinamide 2-3 times weekly for 7 months 1, 3
• However, non-rifamycin regimens are associated with higher mortality rates and unacceptably high TB recurrence rates in HIV-infected patients 1

The Bottom Line Algorithm

For HIV-positive TB patients:

1. If not on ART or on efavirenz/dolutegravir-based ART → Use rifampin (with dolutegravir dose adjustment to 50 mg twice daily) 3, 7

2. If on protease inhibitor-based ART → Substitute rifabutin 150 mg daily 1, 2

3. If on nevirapine or other problematic NNRTIs → Substitute rifabutin with dose adjustments 1

4. Always use daily dosing during intensive phase, especially if CD4 <100 cells/mm³ 3, 5

5. Monitor for uveitis if combining rifabutin with macrolides or azoles 3, 6