What is the recommended treatment regimen for a patient with active tuberculosis (TB), considering potential comorbidities such as Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS)?

Treatment of Active Tuberculosis

The standard treatment for active tuberculosis is a 6-month regimen consisting of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for the first 2 months (intensive phase), followed by INH and RIF for 4 months (continuation phase). 1, 2, 3, 4

Initial Four-Drug Regimen (Intensive Phase: 2 Months)

Start all patients on four drugs unless drug susceptibility is already confirmed and isoniazid resistance is <4% in your community. 1, 2

Standard Dosing

• Isoniazid: 5 mg/kg (max 300 mg) daily or 15 mg/kg (max 900 mg) three times weekly 2, 3
• Rifampin: 10 mg/kg (max 600 mg) daily or three times weekly 2, 3
• Pyrazinamide: 25 mg/kg daily or 50-70 mg/kg three times weekly 2, 3
• Ethambutol: 15-25 mg/kg daily or 30 mg/kg three times weekly 2, 3

The fourth drug (ethambutol) prevents emergence of resistance while awaiting drug susceptibility results and can be discontinued once susceptibility to INH and RIF is confirmed. 2, 3

Continuation Phase (4 Months)

Continue INH and RIF for an additional 4 months after completing the intensive phase. 1, 2

• Isoniazid: 5 mg/kg (max 300 mg) daily or 15 mg/kg (max 900 mg) three times weekly 2, 3
• Rifampin: 10 mg/kg (max 600 mg) daily or three times weekly 2, 3

Special Considerations for HIV/AIDS Co-infection

HIV-infected patients require the same 6-month regimen with critical modifications based on CD4 count and antiretroviral therapy. 1

CD4 Count-Based Adjustments

• CD4 <100 cells/μL: Use daily or three times weekly dosing only—never twice weekly due to high relapse rates and acquired rifamycin resistance 1
• CD4 >100 cells/μL: Standard regimens acceptable 1
• Consider extending treatment to 9 months for HIV-infected patients, especially those with CD4 <100 cells/μL, cavitation, or positive cultures at 2 months 1, 2

Rifamycin Selection with Antiretroviral Therapy

Rifabutin should replace rifampin in patients taking protease inhibitors or NNRTIs to avoid critical drug interactions that cause treatment failure. 1, 2, 5

• Rifampin induces CYP450 enzymes and dramatically reduces antiretroviral drug levels 1
• Rifabutin has fewer problematic interactions but requires dose adjustments 1
• Never use rifampin with protease inhibitors or NNRTIs without switching to rifabutin 2

Timing of ART Initiation

• CD4 <50 cells/μL: Start ART within 2 weeks of TB treatment 5
• CD4 >50 cells/μL: Start ART within 8 weeks of TB treatment 5

Immune Reconstitution Inflammatory Syndrome (IRIS)

HIV-infected patients may experience paradoxical worsening (IRIS) after starting ART, manifesting as fevers, lymphadenopathy, expanding CNS lesions, or worsening chest radiographs. 1

• Rule out treatment failure before diagnosing IRIS 1
• NSAIDs for symptomatic relief 1
• Prednisone 1-2 mg/kg/day for 1-2 weeks for severe reactions 1, 5

Directly Observed Therapy (DOT)

All patients should receive directly observed therapy, which is especially critical for HIV-infected patients and those at risk for non-adherence. 1, 5, 3

Extrapulmonary Tuberculosis

Use the standard 6-month regimen for most extrapulmonary sites. 1

Extended Duration Sites

• Tuberculous meningitis: 9-12 months total (add corticosteroids to prevent neurological sequelae) 1, 2
• Miliary TB, bone/joint TB in children: 12 months 1, 2
• Consider 9 months for disseminated disease 1

Drug-Induced Hepatotoxicity Management

Drug-induced hepatitis is defined as AST >3× upper limit of normal with symptoms OR >5× upper limit of normal without symptoms. 1

Immediate Actions

• Stop INH, RIF, and PZA immediately 1
• Check hepatitis A, B, C serologies if not done at baseline 1
• Assess for other hepatotoxins (especially alcohol) 1

Bridging Therapy

Use two or more non-hepatotoxic drugs (EMB, streptomycin, amikacin/kanamycin, capreomycin, or fluoroquinolones like levofloxacin/moxifloxacin) until AST normalizes. 1, 6

Sequential Drug Reintroduction

Once AST <2× upper limit of normal and symptoms improve significantly, restart first-line drugs sequentially: 1, 6

1. Reintroduce INH first
2. Then RIF
3. Finally PZA
4. Monitor AST, bilirubin, and symptoms closely with each addition 1, 6

Special Populations

Pregnancy

• Use INH, RIF, and EMB (avoid streptomycin due to congenital deafness risk) 1, 3
• Pyrazinamide is not routinely recommended due to inadequate teratogenicity data 1, 3
• Extend treatment duration as needed since the 6-month regimen cannot be used without PZA 1

Children

• Use the same regimens as adults with adjusted doses 1
• Avoid EMB in children <6 years whose visual acuity cannot be monitored; substitute streptomycin 1
• Consider EMB if resistance to other drugs is suspected or demonstrated 1
• Infants and young children require prompt treatment due to high dissemination risk 1

Renal Insufficiency

• Adjust dosing for EMB, PZA, and cycloserine based on creatinine clearance 1
• Administer all drugs after hemodialysis to facilitate DOT and avoid premature drug removal 1
• Monitor serum drug concentrations for cycloserine and EMB 1

Multidrug-Resistant TB (MDR-TB)

For suspected or confirmed MDR-TB (resistance to at least INH and RIF), start 5-6 drug regimens including at least three drugs to which the strain is likely susceptible. 1

• Consult an expert in MDR-TB treatment immediately 1, 5
• Base final regimen on drug susceptibility testing results 1
• Never add a single drug to a failing regimen—this creates acquired resistance 2, 7

Monitoring Requirements

Baseline Testing

• HIV testing for all TB patients 1
• Drug susceptibility testing on all initial isolates 1, 3
• Baseline AST/ALT, bilirubin, CBC 6
• Hepatitis A, B, C serologies 1

During Treatment

• Sputum microscopy and culture at 2 months to assess response 5
• Liver function tests at 2 weeks, then every 2 weeks if stable 6
• CBC weekly for first month, then every 2 weeks during intensive phase (especially important with HIV co-infection) 6
• HIV viral load and CD4 count every 3 months in HIV-infected patients 5

Critical Pitfalls to Avoid

• Never use standard corticosteroid doses with rifampin—increase doses 2-3× baseline to compensate for CYP450 induction 6
• Never use once-weekly INH-rifapentine continuation phase in HIV-infected patients due to unacceptably high relapse rates 1
• Never delay TB treatment to accommodate other medications—TB treatment is the immediate mortality reduction priority 2
• Never omit ethambutol in the initial phase unless drug susceptibility is confirmed and isoniazid resistance is <4% in the community 2
• Never use rifampin with protease inhibitors or NNRTIs without expert consultation and likely switch to rifabutin 1, 2
• Never use twice-weekly regimens in HIV patients with CD4 <100 cells/μL 1