Table 2.

Range of plausible treatment strategies for pulmonary TB^[a]

Treatment strategy	Strengths	Challenges	Knowledge gaps and unmet needs
One size fits all: New short regimen equally effective in rifampicin resistant and susceptible populations, including asymptomatic sputum positive patients.	Simplest: No DST to initiate treatment. Potential for improved completion rates, outcomes, and maximal impact on incidence reduction.	Even shorter regimens risk overtreating a proportion of patients. Emergence of clinically relevant resistance requiring DST. Shortening to 2 months or less is required to overcome implementation hurdles and improve adherence[b]	Designing regimens to protect from resistance emergence and optimizing PK/PD across all sites of infection.
Stratification by rifampicin resistance status (current SOC)	Simplicity. Minimizes risk of undertreating	DST poorly implemented in low resource settings. Low Rx completion rates. Overtreats a sizable fraction of patients risking side effects and patient well-being. Adds cost.	Improved (faster, cheaper, easier) DST to guide therapy.
1 regimen, varying durations based on patient factors	First step towards minimizing the fraction of overtreated and undertreated patients. Lowest barrier to implementation worldwide; short-term feasibility.	Incremental improvement on current SOC strategy. Can be implemented in high resource settings only35 implementation challenging for community-based DOT. Added complexity of stratification through digital chest X-ray or other tests must be cost effective in low resource settings101,102	Improved (faster, cheaper, easier) biomarkers to guide therapy.
1 regimen, varying doses for drug susceptible and drug resistant and patient factors	Modifies SOC to minimize the fraction of overtreated and undertreated patients. Low barrier to implementation worldwide; short-term feasibility.	Few drugs are eligible for higher-than-standard doses. DST poorly implemented in low resource settings.	Clinical trials to assess the efficacy of modified-dose regimens across disease severity spectrum. Routine implementation of therapeutic drug monitoring and safety monitoring. Accessible, geographically diverse DST/MICs.
Distinct regimens for ETT and HTT disease	Maximizes tradeoff between precision and simplicity. Most effective approach if drugs that shorten treatment in HTT do not shorten treatment in ETT (Figure 2c).	Evidence that ETT and HTT patients need different regimens is lacking. Biomarkers that safely define ETT vs HTT have not been identified yet. Clinical research and trials required, thus not a short-term solution.	Development and validation of a globally accepted – deliverable, scalable, affordable – biomarker which allows patient stratification. Uncovering novel drug mechanisms. Systematic exploration of pharmacodynamic interactions for regimen optimization.
Regimen cycling (different regimens for intensive and continuation phases)	Supported by NHP observations that regimen effectiveness varies over time. Antibiotic cycling is an actively pursued strategy against other bacterial infections.	Lack of data on how, when and where this approach may work. Changing drugs may require additional DST, safety monitoring and cross-regimen drug-drug interaction studies. Potentially complicates compliance and supply chain.	Extensive preclinical and clinical research required to demonstrate value and optimize practice.
Personalized therapy (Figure 3)	Maximizes precision: optimal drug regimen, doses and duration for each patient	Most complex to implement. May require significant technology advances. As regimens become shorter, the benefit to patients and health care systems may bear diminishing returns.	Development and validation of a globally accepted biomarker which allows patient stratification. Digital patient monitoring to assess treatment response and pharmacogenomics to enable stratified care.

^[a]While important and deserving attention, TB meningitis and other disease manifestations require separate regimen optimization.

^[b]The new and successful 4-month regimen for drug susceptible TB (rifapentine-moxifloxacin-isoniazid-pyrazinamide³⁶) is seldom implemented in low resource settings for that reason and due to the lack of a fixed dose combination. DST, drug susceptibility testing; DOT, directly observed therapy; NHP, non-human primate.