Why is the new tuberculosis (TB) regimen referred to as a conditional regimen?

Why New TB Regimens Are Called "Conditional Regimens"

New tuberculosis regimens are designated as "conditional recommendations" because they are based on very low certainty of evidence, meaning the balance between benefits and harms is uncertain, and the recommendations may change as more robust data becomes available. 1

Understanding Conditional vs. Strong Recommendations

The grading system used by WHO and other guideline bodies distinguishes between:

• Strong recommendations are made when there is moderate to high certainty in the evidence, indicating clear benefits that outweigh harms 1
• Conditional recommendations are made when the certainty of evidence is very low, suggesting that different choices will be appropriate for different patients and clinical situations 1

Specific Examples of Conditional TB Regimens

Shorter All-Oral Bedaquiline-Containing Regimen (9-12 months)

• This regimen received a conditional recommendation with very low certainty in the evidence because the data supporting it came from limited observational studies rather than large randomized controlled trials 1
• The recommendation applies only to highly selected patients: those with confirmed MDR/RR-TB, no prior exposure to second-line drugs for >1 month, confirmed fluoroquinolone susceptibility, and no extensive disease 1

BPaL and BPaLM Regimens

• These newer 6-month regimens for MDR-TB were graded as conditional recommendations with very low certainty when first introduced 1
• The evidence base was insufficient to make strong recommendations, despite promising early results 1

Longer MDR-TB Regimens

• The recommendation to include at least four effective drugs in the intensive phase is conditional with very low certainty in the estimates of effect 1
• Individual drug selections within these regimens often carry conditional recommendations: clofazimine, cycloserine/terizidone, ethambutol, and delamanid all have conditional recommendations 1

Isoniazid-Resistant TB Regimen

• The 6-month regimen of rifampin, ethambutol, pyrazinamide, and levofloxacin for Hr-TB is a conditional recommendation with very low certainty 1

Why the Evidence Certainty Is Very Low

Several factors contribute to the low certainty of evidence:

• Limited randomized controlled trial data - Many newer regimens are supported primarily by observational cohort studies rather than RCTs 1
• Small sample sizes - The number of patients studied is often insufficient to detect rare but serious adverse events 1
• Heterogeneous populations - Patients with drug-resistant TB have varying resistance patterns, comorbidities, and prior treatment exposures 1
• Short follow-up periods - Long-term relapse rates may not be fully captured in available studies 1
• Lack of head-to-head comparisons - Direct comparisons between newer regimens and established alternatives are often absent 1

Clinical Implications of Conditional Recommendations

When a regimen carries a conditional recommendation:

• Shared decision-making is essential - Clinicians must discuss the uncertain balance of benefits and harms with patients 1
• Individual patient factors heavily influence the choice - Drug susceptibility testing results, treatment history, disease extent, and comorbidities all affect whether the regimen is appropriate 1
• Close monitoring is mandatory - Given the uncertainty, careful assessment of clinical and bacteriologic response is critical 1
• Alternative regimens should be considered - If the patient doesn't meet the specific eligibility criteria, other treatment options may be more appropriate 1

Critical Pitfalls to Avoid

• Do not apply conditional regimens broadly - These recommendations are intended for specific patient populations that meet strict eligibility criteria 1
• Do not ignore drug susceptibility testing - Conditional regimens often require confirmed susceptibility to key drugs; using them without DST results risks treatment failure 1
• Do not assume equivalence to strong recommendations - Conditional recommendations require more individualized assessment and may not be suitable for all patients with the same diagnosis 1
• Do not neglect to document the rationale - When using a conditional regimen, clearly document why it was chosen over alternatives 1

The conditional nature of these recommendations reflects the evolving evidence base in TB treatment and emphasizes the need for ongoing research to strengthen future guidelines 1.