Optimizing the cascade of prevention to protect people from tuberculosis

Estimates of the global burden of TB infection (TBI) have traditionally been based on immune reactivity to TB antigens, with the assumption that infection is lifelong. This approach suggests that about one-fourth of the global population—roughly 1.8 billion people—has been infected, with around 1% acquiring the infection within the past two years. However, current diagnostic tests such as IGRAs and TSTs cannot measure bacterial viability or distinguish recent from remote infection. As a result, many individuals receive TB preventive treatment (TPT) despite having little or no risk of disease progression, raising concerns about cost, unnecessary drug exposure, and ethical implications.

Recent research challenges the binary view of TB as either latent or active, instead presenting it as a spectrum from early infection to clinical disease. It also suggests that the assumption of lifelong infection may be flawed—many individuals likely self-clear the infection without treatment. Studies have shown that over 90% of those previously infected may no longer harbor viable mycobacteria. Therefore, identifying those at real risk of disease progression is critical. Breakthroughs in diagnostics that can distinguish persistent from cleared infection or predict progression would significantly improve TPT targeting and cost-effectiveness.

The TB prevention cascade—identifying at-risk individuals, ruling out active TB, testing for infection, providing TPT, and supporting adherence—faces high attrition at each stage, particularly during initial assessment. Fewer than 20% of those eligible for TPT complete the full cascade. While HIV-positive individuals have higher completion rates, coverage among other groups, such as migrants, is much lower. Most studies and interventions to improve this cascade have been conducted in low-burden countries, with limited data from high-burden settings. However, strategies like patient incentives, digital tools, and workforce training have shown promise in improving early steps of the cascade.

Despite progress, TPT coverage remains inadequate. As of 2022, only 52% of people living with HIV had received TPT, falling short of the 90% target. Coverage among household contacts is even lower, with only 4.2 million initiated on TPT between 2018 and 2022—far below the 24 million target. The new 2027 UN goal of reaching 45 million people, including 30 million contacts, will require intensified efforts and investment. Effective delivery models must prioritize contact evaluation, community-based testing, and engagement strategies that increase access and completion.

In terms of treatment regimens, isoniazid preventive therapy (IPT) has been widely used but is limited by long duration and side effects. Shorter rifamycin-based regimens, such as 3HR, 3HP, and 1HP, have improved adherence and safety profiles, though some have higher rates of adverse events or cost barriers. Pediatric-friendly formulations are in development to expand access among children. Ultimately, a pan-TPT regimen—simple, safe, and universally applicable—could revolutionize TB prevention. Innovations like slow-release, single-dose treatments would make mass preventive strategies feasible, much like vaccines or deworming programs, especially in high-burden regions.

Source: Matteelli, A., Churchyard, G., Cirillo, D., den Boon, S., Falzon, D., Hamada, Y., Houben, R.M., Kanchar, A., Kritski, A., Kumar, B. and Miller, C., 2024. Optimizing the cascade of prevention to protect people from tuberculosis: A potential game changer for reducing global tuberculosis incidence. PLOS Global Public Health, 4(7), p.e0003306.