What is the recommended treatment regimen for Tuberculosis (TB) in a Human Immunodeficiency Virus (HIV)-positive individual?

Treatment of Tuberculosis in HIV-Positive Patients

For HIV-positive patients with active tuberculosis, initiate a 6-month rifabutin-based regimen consisting of isoniazid, rifabutin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifabutin for 4 months, with rifabutin preferred over rifampin due to fewer drug interactions with antiretroviral therapy. 1, 2

Initial Intensive Phase (First 2 Months)

• Administer isoniazid, rifabutin, pyrazinamide, and ethambutol daily for 8 weeks 1, 2
• Alternatively, give daily therapy for at least the first 2 weeks, followed by twice-weekly dosing for 6 weeks to complete the 2-month induction phase 1
• Rifabutin is strongly preferred over rifampin because rifampin is a potent CYP450 inducer that significantly lowers serum concentrations of protease inhibitors and NNRTIs used in antiretroviral therapy 1, 3
• Ethambutol should be included in the initial regimen until drug susceptibility results are available, even in children too young to be monitored for visual acuity 1, 4

Continuation Phase (Months 3-6)

• Continue isoniazid and rifabutin administered daily or twice weekly for 4 months 1, 2
• This completes the standard 6-month treatment course for drug-susceptible tuberculosis 1, 4

Critical Drug Dosing Adjustments with Antiretroviral Therapy

• When rifabutin is used concurrently with indinavir, nelfinavir, or amprenavir, decrease the daily dose of rifabutin from 300 mg to 150 mg 1
• For twice-weekly rifabutin administration, maintain the 300 mg dose even when used with indinavir, nelfinavir, or amprenavir 1
• When rifabutin is used with efavirenz, increase the rifabutin dose from 300 mg to 450 mg for both daily and twice-weekly administration 1
• Three-times-per-week rifabutin administration with antiretroviral therapy has not been studied and cannot be recommended 1

Essential Supportive Therapy

• Administer pyridoxine (vitamin B6) 25-50 mg daily or 50-100 mg twice weekly to all HIV-infected patients receiving isoniazid to reduce the occurrence of peripheral and central nervous system side effects 1, 2, 5

Directly Observed Therapy (DOT)

• Implement directly observed therapy for all HIV-positive TB patients to ensure adherence and prevent the development of drug resistance 1, 2
• DOT is particularly critical in HIV-infected patients given the higher risk of treatment failure and acquired drug resistance 6

Timing of Antiretroviral Therapy Initiation

• Initiate ART in all HIV-infected patients with TB, regardless of CD4 count 2, 7
• For patients with CD4 counts <50 cells/mm³, start ART within 2 weeks of beginning TB treatment 2
• For patients with CD4 counts >50 cells/mm³, start ART within 8 weeks of beginning TB treatment 2
• A staggered approach to initiating therapies is recommended to improve adherence and reduce drug toxicity 2

Alternative Regimens When Rifamycins Cannot Be Used

• If rifamycins are contraindicated or limited due to intolerance or drug interactions, use a 9-month regimen consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol 1
• Initial phase: administer these four drugs daily for 8 weeks (or daily for 2 weeks followed by twice-weekly for 6 weeks) 1
• Continuation phase: isoniazid, streptomycin, and pyrazinamide administered 2-3 times weekly for 7 months 1

Regimen for Patients Not on Antiretroviral Therapy

• For patients not receiving ART or when the decision is made not to combine ART with TB therapy, use the standard 6-month rifampin-based regimen (isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months) 1, 4

Critical Warnings and Contraindications

• Never use three-drug regimens containing only isoniazid, ethambutol, and pyrazinamide (without a rifamycin, aminoglycoside, or capreomycin) for HIV-related TB; if used, minimum duration must be 18 months 1
• Do not interrupt antiretroviral therapy to allow rifampin use, as CDC strongly advises against interruptions of ART 1
• Avoid once-weekly isoniazid-rifapentine in the continuation phase in any patient with HIV infection 5
• Avoid twice-weekly isoniazid-rifampin in patients with CD4+ counts less than 100 cells/mm³ due to high rates of relapse and acquired rifamycin resistance 5, 6

Common Pitfalls to Avoid

• Do not use intermittent (twice-weekly) rifabutin-based therapy in patients with CD4 counts <100 cells/mm³, as this is associated with a 12.3% risk of treatment failure or relapse with acquired rifamycin resistance 6
• Do not switch from rifampin to rifabutin in HIV-negative patients solely to accommodate future PrEP, as this is not evidence-based 3
• Monitor for malabsorption of antituberculosis drugs in patients with advanced HIV disease, as this can lead to treatment failure and emergence of multidrug-resistant TB 2, 8
• Be vigilant for immune reconstitution inflammatory syndrome (IRIS), which can cause paradoxical worsening of TB lesions or appearance of new lesions after initiating ART 2, 8

Special Populations

Pregnant HIV-Positive Women

• Use rifamycin-containing regimens without delay 1
• Pyrazinamide is recommended despite inadequate teratogenicity data in the US, as benefits outweigh potential risks 1
• Streptomycin is absolutely contraindicated due to ototoxicity and potential congenital deafness in the fetus 1, 8

HIV-Positive Children

• Use the same four-drug regimen with appropriately adjusted doses 1, 4
• Include ethambutol at 15 mg/kg even in children too young to be monitored for visual acuity, unless the infecting strain is known to be susceptible to isoniazid and rifampin 1
• For miliary TB, bone/joint TB, or tuberculous meningitis in children, extend treatment to 12 months 4

Drug-Resistant Tuberculosis in HIV Patients

Isoniazid-Resistant TB

• Use rifabutin, pyrazinamide, and ethambutol for 6-9 months or 4 months after culture conversion 1
• Intermittent twice-weekly therapy can be used after at least 2 weeks of daily induction therapy 1

Rifampin-Resistant TB

• Use a 9-month regimen of isoniazid, streptomycin, pyrazinamide, and ethambutol 1
• Initial phase: 2 months of all four drugs 1
• Continuation phase: isoniazid, streptomycin, and pyrazinamide for 7 months 1

Multidrug-Resistant TB (MDR-TB)

• Refer immediately to or consult with physicians experienced in MDR-TB management 1, 2
• Early aggressive treatment with appropriate regimens based on drug-susceptibility patterns markedly decreases mortality 1
• Most MDR-TB regimens include an aminoglycoside (streptomycin, kanamycin, or amikacin) or capreomycin, plus a fluoroquinolone 1
• Treatment duration: 24 months after culture conversion 1
• Always use DOT for MDR-TB patients and take all necessary steps to ensure adherence 1

Monitoring Requirements

• Perform drug susceptibility testing on all initial TB isolates to guide therapy 2, 4
• Monitor liver function tests regularly due to potential hepatotoxicity from multiple medications; HIV/hepatitis C co-infected patients have a 14-fold increased risk 2
• Assess clinical and bacteriologic response with follow-up sputum microscopy and culture at 2 months 3, 2
• Monitor CD4 counts and HIV viral load at least every 3 months 2
• In patients with advanced HIV disease, consider therapeutic drug monitoring to prevent malabsorption-related treatment failure 1