What is the landmark trial that established the standard treatment regimen for drug-susceptible tuberculosis (TB)?

The British Medical Research Council Trials Established the Standard Treatment for Drug-Susceptible TB

The landmark trial that established the standard treatment regimen for drug-susceptible tuberculosis was the series of controlled trials conducted by the British Medical Research Council (BMRC) between 1946 and 1986, which demonstrated the efficacy of the 6-month short-course chemotherapy regimen. 1

The Evolution of TB Treatment Through Clinical Trials

• The British Medical Research Council conducted a series of controlled trials between 1946 and 1986 that progressively refined TB treatment, ultimately establishing the standard 6-month regimen that revolutionized TB care 1
• These trials demonstrated that an intensive phase of 2 months with rifampin, isoniazid, and pyrazinamide, followed by a continuation phase of 4 months with rifampin and isoniazid could effectively cure most patients 1
• The addition of pyrazinamide to the intensive phase was a critical innovation that allowed treatment duration to be shortened from 9 months to 6 months 1

The Standard 6-Month Regimen Components

• The established standard regimen consists of:
  • Initial phase (first 2 months): daily rifampin, isoniazid, pyrazinamide, and ethambutol 1
  • Continuation phase (next 4 months): daily rifampin and isoniazid 1
• Ethambutol can be omitted in the initial phase for patients with a low risk of isoniazid resistance 1, 2
• The recommended dosages are:
  • Isoniazid: 5 mg/kg (up to 300 mg daily) 1, 3
  • Rifampin: 10 mg/kg (<50 kg: 450 mg; >50 kg: 600 mg) 1, 2
  • Pyrazinamide: 35 mg/kg (<50 kg: 1.5 g; >50 kg: 2.0 g) 1, 4
  • Ethambutol: 15 mg/kg 1, 4

Key Clinical Trials Supporting the Standard Regimen

• The 1978 controlled trial by the American Review of Respiratory Disease compared four short-course regimens and found that those containing rifampin, isoniazid, and pyrazinamide had low relapse rates 5
• A 1982 Hong Kong Chest Service/British Medical Research Council trial demonstrated that regimens containing pyrazinamide had significantly lower relapse rates (1-2%) compared to those without pyrazinamide (8%) 6
• A 2004 international multicenter randomized trial in The Lancet confirmed the superiority of the 6-month regimen (2EHRZ/4HR) over 8-month regimens, with significantly lower rates of unfavorable outcomes (5% vs 10-14%) 7

Recent Advances and Alternative Regimens

• In 2022, the WHO conditionally recommended a 4-month regimen using rifapentine, isoniazid, pyrazinamide, and moxifloxacin for eligible patients aged 12 years and older with pulmonary DS-TB 1
• The Study 31/A5349 trial demonstrated that this 4-month regimen with rifapentine (a longer half-life rifamycin) and moxifloxacin was non-inferior to the standard 6-month regimen 1
• The RIFAQUIN trial studied another alternative 6-month regimen where daily isoniazid was replaced by daily moxifloxacin for the first 2 months, followed by once-weekly doses of moxifloxacin and rifapentine for 4 months 1

Special Considerations in TB Treatment

• For TB meningitis and CNS tuberculosis, treatment should be extended to 12 months total (2 months HRZE followed by 10 months HR) 1, 2
• If pyrazinamide cannot be included in the initial regimen, treatment duration should be extended to 9 months total 2
• For patients with isoniazid-resistant TB, a regimen of rifampin, ethambutol, and pyrazinamide for 6 months with the addition of a fluoroquinolone is suggested 1, 8

Common Pitfalls and Caveats

• Ethambutol should be used with caution in children whose visual acuity cannot be monitored 1, 4
• Rifampin interacts with many medications, including oral contraceptives, anticoagulants, and antiretroviral drugs, requiring careful medication review 2
• In cases of suspected drug resistance, pyrazinamide and ethambutol should be continued until full susceptibility is confirmed, even beyond 2 months 1, 4
• For HIV co-infected patients, the same basic regimen is used, but with important considerations regarding drug interactions between rifamycins and antiretroviral agents 4, 3

The British Medical Research Council trials represent a watershed moment in TB treatment, establishing a regimen that dramatically improved outcomes and shortened treatment duration from 18-24 months to just 6 months, significantly improving patient adherence and treatment success rates worldwide.