What are the recommended daily doses, treatment duration, monitoring requirements, and contraindications for the HPZM regimen (rifapentine, isoniazid, pyrazinamide, moxifloxacin) in drug‑susceptible pulmonary tuberculosis?

HPZM Regimen for Drug-Susceptible Pulmonary Tuberculosis

The CDC recommends a 4-month daily rifapentine-moxifloxacin regimen (HPZM) for patients aged ≥12 years with body weight ≥40 kg who have drug-susceptible pulmonary tuberculosis, consisting of 8 weeks of rifapentine, isoniazid, pyrazinamide, and moxifloxacin followed by 9 weeks of rifapentine, isoniazid, and moxifloxacin. 1, 2

Daily Doses

Intensive Phase (8 weeks, 56 doses)

• Rifapentine: 1,200 mg daily 1, 2
• Moxifloxacin: 400 mg daily 1, 2
• Isoniazid: 300 mg daily with pyridoxine (vitamin B6) 25-50 mg/day 1, 2
• Pyrazinamide (weight-based): 1, 2
  • 40 to <55 kg: 1,000 mg daily
  • 55 to 75 kg: 1,500 mg daily

  • 75 kg: 2,000 mg daily

Continuation Phase (9 weeks, 63 doses)

• Rifapentine: 1,200 mg daily 1, 2
• Moxifloxacin: 400 mg daily 1, 2
• Isoniazid: 300 mg daily with pyridoxine 25-50 mg/day 1, 2

Administration Requirements

• All medications must be taken with food 1, 2
• 7 days per week dosing with at least 5 of 7 weekly doses under direct observation 1
• Total of 119 doses to complete treatment 1

Treatment Duration

Treatment is considered complete after 119 total doses, independent of cavitation on baseline chest radiograph. 1, 2

• Intensive phase: 56 doses within 70 days of treatment initiation 1
• Continuation phase: 63 doses within 84 days of intensive phase completion 1
• Total duration: Approximately 4-5 months 1

If these timing targets are not met, the patient has interrupted therapy and requires confirmation of continued drug susceptibility before restarting the regimen. 1

Monitoring Requirements

Baseline Evaluations (Required)

• Microbiology: 1
  • Sputum for rapid molecular testing (susceptibility to isoniazid, pyrazinamide, rifampin, and fluoroquinolones)
  • Sputum for AFB smear and culture
  • Phenotypic drug susceptibility testing for rifampin, isoniazid, pyrazinamide, and moxifloxacin
• Imaging: Chest radiograph 1
• Laboratory: 1
  • ALT, AST, bilirubin, alkaline phosphatase
  • Platelet count
  • Creatinine
  • Potassium, calcium, magnesium
  • HIV testing
  • CD4 count and HIV RNA load (if HIV-positive)
  • Hepatitis B and C screening
  • Diabetes screening
  • Pregnancy testing for persons who might become pregnant
• Clinical: Weight and baseline symptoms 1

Monthly Monitoring During Treatment

• Sputum for AFB smear and culture at weeks 4,8,12, and 17 until two consecutive specimens are negative 1
• Weight assessment at each visit to adjust pyrazinamide dosing if needed 1
• Symptom monitoring for tuberculosis improvement (cough, fever, fatigue, night sweats) 1
• Adverse event surveillance for jaundice, dark urine, nausea, vomiting, abdominal pain, diarrhea, anorexia, dizziness, seizures, fever, rash, malaise, neuropathy, arthralgias, tendinopathy, heart palpitations, irregular heartbeat, weakness, or syncope 1
• Adherence assessment at each visit 1

Conditional Laboratory Monitoring

• Liver function tests (ALT, AST, bilirubin, alkaline phosphatase) are required only at baseline unless: 1
  • Abnormalities present at baseline
  • Symptoms of hepatotoxicity develop
  • Patient chronically consumes alcohol
  • Patient takes other hepatotoxic medications
  • Patient has viral hepatitis, history of liver disease, HIV infection, or previous drug-induced liver injury
• Platelet count, creatinine, electrolytes (potassium, calcium, magnesium) should be repeated if abnormal at baseline or if symptoms develop 1
• Repeat drug susceptibility testing if culture remains positive after 8 weeks of treatment 1
• Chest radiograph at week 8 if baseline cultures are negative; end-of-treatment chest radiograph is optional 1

Absolute Contraindications

Do not use this regimen in: 1, 3

• Age <12 years 1, 3
• Body weight <40 kg 1, 3
• Known or suspected drug resistance to isoniazid, rifamycins, fluoroquinolones, or pyrazinamide 1, 3
• Recent anti-tuberculosis drug exposure: >5 doses of isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide, or any fluoroquinolone in the preceding 30 days 1, 3
• Prior tuberculosis treatment: >14 consecutive days of multidrug tuberculosis treatment in the preceding 6 months 1, 3
• HIV-positive with CD4 count <100 cells/μL 1, 3
• HIV-positive on antiretroviral therapy other than efavirenz-based regimens (unless no other drug-drug interactions exist) 1, 3

Situations Requiring Expert Consultation

Consult a tuberculosis specialist before using this regimen in patients with: 1, 3

• Hepatic dysfunction: ALT or AST >3 times upper limit of normal, total bilirubin >2.5 times upper limit of normal, or preexisting advanced liver disease 1, 3
• Renal dysfunction: Serum creatinine >2 times upper limit of normal, renal insufficiency, or end-stage renal disease 1, 3
• Electrolyte abnormalities: Plasma potassium <3.5 mEq/L 1, 3
• Paucibacillary extrapulmonary tuberculosis: Pleural or lymph node tuberculosis 1
• Unable to obtain drug susceptibility testing before treatment initiation 1

Important Clinical Nuances

Cavitary disease is not a contraindication—treatment duration remains 4 months regardless of cavitation on baseline chest radiograph. 1, 3

The regimen may be used in culture-negative pulmonary tuberculosis if clinically suspected to be paucibacillary disease, provided the patient does not fall into excluded groups. 1, 3

HIV-positive patients can use this regimen if CD4 count ≥100 cells/μL and they are receiving or planning efavirenz-based antiretroviral therapy without other drug-drug interactions. 1, 3

Common Pitfalls to Avoid

• Do not assume all patients are eligible—carefully screen for exclusion criteria, particularly recent fluoroquinolone exposure which may select for resistance 1, 3
• Do not skip baseline molecular drug susceptibility testing—rapid identification of resistance mutations to isoniazid, pyrazinamide, rifampin, and fluoroquinolones is essential 1
• Do not use in patients with significant hepatic or renal dysfunction without expert consultation—these patients were excluded from clinical trials 1, 3
• Do not forget pyridoxine supplementation—all patients receiving isoniazid require 25-50 mg/day of vitamin B6 1, 2
• Do not administer without food—all medications must be taken with food 1, 2
• Do not extend treatment based solely on cavitation—duration is independent of radiographic findings 1, 2
• Be aware of real-world tolerability concerns—a recent San Francisco cohort found 50% of patients prematurely discontinued HPMZ due to adverse events (primarily vomiting, elevated transaminases, and rash), highlighting challenges in extrapolating clinical trial results to US practice 4