What are the treatment considerations for a patient with isoniazid-resistant tuberculosis (TB), possibly co-infected with Human Immunodeficiency Virus (HIV), and taking medications that interact with the Cytochrome P450 (CYP 450) enzyme system, particularly with regards to the use of CYP 450 enzyme inducer drugs like rifampin?

CYP 450 Enzyme Inducer Drugs in Isoniazid-Resistant TB with HIV Co-infection

For isoniazid-resistant TB in HIV-positive patients on antiretroviral therapy, use rifampin (a potent CYP450 inducer) with pyrazinamide and ethambutol for 6-9 months, but only if the patient is on efavirenz plus two NRTIs, ritonavir plus NRTIs, or dual protease inhibitors (ritonavir/saquinavir); otherwise, substitute rifabutin with appropriate dose adjustments. 1

Treatment Algorithm for Isoniazid-Resistant TB

Step 1: Confirm Resistance Pattern

• Isoniazid-resistant, rifampin-susceptible TB requires a rifamycin-based regimen consisting of rifampin or rifabutin, pyrazinamide, and ethambutol for the entire treatment duration of 6-9 months or 4 months after culture conversion. 1
• Stop isoniazid when high-level resistance is confirmed (>1% of bacilli resistant to 1.0 μg/mL), though some experts continue isoniazid with low-level resistance (resistant to 0.2 μg/mL but not 1.0 μg/mL). 1

Step 2: Assess HIV Status and Antiretroviral Regimen

If HIV-negative or not on antiretroviral therapy:

• Use standard rifampin 10 mg/kg daily (maximum 600 mg) as the preferred rifamycin due to superior efficacy demonstrated in approximately 90 controlled trials. 2, 3

If HIV-positive on antiretroviral therapy, determine compatibility:

Rifampin CAN be used with:

• Efavirenz 600 mg daily + two NRTIs (no dose adjustment needed for rifampin) 1
• Ritonavir + one or more NRTIs 1
• Dual protease inhibitors (ritonavir + saquinavir hard-gel or soft-gel capsule) 1
• Dolutegravir-based ART (increase dolutegravir to 50 mg twice daily when combined with rifampin) 2

Rifampin is CONTRAINDICATED with:

• All other protease inhibitors (except ritonavir or ritonavir/saquinavir combinations) 1
• All NNRTIs except efavirenz in the specific regimen above 1
• Delavirdine 1

Step 3: Choose Rifabutin When Rifampin Cannot Be Used

Rifabutin dose adjustments based on antiretroviral regimen:

• With ritonavir (with or without saquinavir): Reduce rifabutin to 150 mg two or three times per week 1
• With efavirenz: Increase rifabutin to 450-600 mg daily or 600 mg two or three times per week 1
• With indinavir: Increase indinavir from 800 mg every 8 hours to 1,200 mg every 8 hours 1
• With nelfinavir: Consider increasing nelfinavir from 750 mg three times daily to 1,000 mg three times daily 1
• With saquinavir soft-gel capsule + two NRTIs: Use standard rifabutin dose (300 mg daily or two-three times per week) 1

Critical CYP450 Interaction Mechanisms

Rifampin is a potent CYP450 inducer that substantially decreases blood levels of protease inhibitors and NNRTIs, potentially causing antiretroviral treatment failure. 1 The enzyme induction effect persists for at least 2 weeks after rifampin discontinuation, so protease inhibitors or NNRTIs should not be started until 2 weeks after the last rifampin dose. 1

Rifabutin is a less potent CYP450 inducer than rifampin, making it more compatible with antiretroviral therapy when dose-adjusted appropriately. 1 However, ritonavir is the most potent CYP450 inhibitor among protease inhibitors, which increases rifabutin levels and necessitates substantial dose reduction. 1

Isoniazid inhibits CYP2C19 and CYP3A but does not interact with protease inhibitors or NNRTIs, making it safe to use concurrently. 1, 4, 5

Alternative Non-Rifamycin Regimen (When Drug Interactions Are Prohibitive)

If complex antiretroviral combinations make rifamycin use impossible:

• 9-month streptomycin-based regimen: Isoniazid, streptomycin, pyrazinamide, and ethambutol for 2 months, then isoniazid, streptomycin, and pyrazinamide 2-3 times weekly for 7 months. 2
• This approach is suboptimal and generally not recommended for active TB, but may be necessary when drug interactions cannot be managed. 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Starting antiretroviral therapy too early

• For patients not yet on ART, start TB treatment first, then add ART at the end of the 2-month intensive phase or after TB treatment completion to avoid complex drug interactions during the critical TB treatment period. 2

Pitfall 2: Underestimating treatment failure risk

• Treatment of isoniazid-resistant TB with first-line drugs results in failure or relapse in 15% of cases and acquired multidrug resistance in 3.6%, with 96% of acquired resistance being multidrug-resistant. 6
• Use directly observed therapy (DOT) for all HIV-TB co-infected patients to prevent treatment failure and acquired resistance. 2

Pitfall 3: Ignoring other CYP450-metabolized medications

• Rifamycins interact with hormonal contraceptives, dapsone, azole antifungals (ketoconazole, fluconazole, itraconazole), methadone, anticoagulants, corticosteroids, cardiac glycosides, sulfonylureas, diazepam, beta-blockers, anticonvulsants, and theophylline. 1
• Rifabutin has fewer interactions with azole antifungals, anticonvulsants, and methadone compared to rifampin. 2

Pitfall 4: Missing paradoxical reactions

• Close monitoring for TB treatment failure, antiretroviral treatment failure, paradoxical TB reactions, and synergistic drug toxicities is essential. 1, 2

Pitfall 5: Inadequate treatment duration

• Continue treatment for 6-9 months or at least 4 months after culture conversion; extend duration if the patient remains sputum/culture positive or has HIV infection. 1, 3

Monitoring Requirements

• Daily therapy during the intensive phase is preferred, with twice-weekly dosing reserved for the continuation phase after at least 2 weeks (14 doses) of daily therapy. 1, 2
• Rifabutin may be more reliably absorbed than rifampin in patients with advanced HIV disease and appears better tolerated in patients with rifampin-induced hepatotoxicity. 2
• Management should be directed by or conducted in consultation with a physician experienced in treating both TB and HIV. 1