Latent tuberculosis infection prevention means identifying people who carry Mycobacterium tuberculosis without symptoms and treating them before they progress to active disease. About one quarter of the global population, roughly two billion people, is infected, and 5 percent to 10 percent will develop active TB within two to five years. Screening plus preventive treatment is the key to breaking transmission.

Why latent TB infection matters

Tuberculosis remains a serious global public health threat despite being preventable and curable. Latent tuberculosis infection prevention plays a key role in cutting this burden. In 2024, a global health authority reported 10.7 million new TB cases worldwide, an incidence of 131 per 100,000 people, with new confirmed cases accounting for 87 percent of total incidence. TB deaths reached 1.23 million in 2024, down only slightly from 1.3 million in 2022. One country accounts for 6.8 percent of the global TB burden and ranks fourth among 30 high-burden nations.

Latent tuberculosis infection is not a static state. It is the main source of active tuberculosis: 80 percent to 90 percent of new active pulmonary TB patients come from the previously infected latent population. Within two to five years of infection, 5 percent to 10 percent of people with latent TB progress to active disease. Without active screening, these individuals often go unrecognized and become hidden sources of transmission.

Even without any new infections, models project that the existing latent infection pool alone could sustain a TB incidence of 16.5 per 100,000 in 2025 and 8.3 per 100,000 in 2050. This makes latent TB infection identification and management a critical component of the global strategy to end the TB epidemic.

Diagnostic approaches: TST, IGRA, and TBST

There is no gold standard test for latent TB infection. Latent tuberculosis infection prevention starts with accurate diagnosis, which relies on detecting the host's cellular immune response to TB antigens. The three main tools are the tuberculin skin test (TST, also called TST skin test), interferon-gamma release assay (IGRA, or IGRA testing), and the newer TB-specific antigen skin test (TBST, also called C-TST or EC test, or TBST EC test).

Feature	TST	IGRA	TBST / EC test
Antigen basis	PPD tuberculin	ESAT-6, CFP-10, TB7.7 peptide antigens	Recombinant EC fusion protein (ESAT-6 plus CFP-10)
Affected by BCG vaccination	Yes	No	No
Affected by non-TB mycobacteria	Yes	Not stated	Not stated
Result reading	Manual, subjective	Standardized quantitative	Skin test reading
Return visit required	Yes	Not required	Not required
False-negative risk	Higher in immunocompromised people	Not stated	Not stated
Laboratory requirement	Low	High	Lower than IGRA
Cost	Low	High	Lower than IGRA
Applicable age	Not stated	Not stated	Infants over 6 months, adolescents, adults under 65

TST is inexpensive and widely used but has clear limitations. Reading depends on manual observation and requires the patient to return within a set time, adding operational complexity and missed-diagnosis risk. Immunocompromised individuals often get false-negative results. Cross-reaction with BCG vaccination history and non-tuberculous mycobacteria can produce false positives, inflating the apparent latent TB infection rate.

IGRA stimulates peripheral blood T cells with TB-specific antigens and measures gamma-interferon levels. Compared with TST, IGRA is not affected by BCG vaccination, gives standardized quantitative results, and shows high specificity in low-burden areas. Its drawbacks are the need for laboratory equipment, trained technicians, and specialized reagents, which makes universal screening difficult in low-resource settings.

TBST uses a recombinant TB fusion protein (EC) containing ESAT-6 and CFP-10, both absent from BCG. It offers high specificity at a lower cost than IGRA. A national drug regulator has approved the EC diagnostic reagent, and it is now in clinical use for people from infants over 6 months to adults under 65.

Combined screening: the two-step TST plus TBST method

Because each test has strengths and weaknesses, combining methods improves accuracy. A proposed two-step approach injects PPD and EC into the left and right forearms respectively, five minutes apart, then reads the skin reactions.

TST result	TBST result	Interpretation	Action
Negative	Negative	Not infected (no BCG response or no response after BCG)	Consider adult BCG vaccination
Positive	Negative	Likely BCG vaccination response or non-TB mycobacteria influence; M. tuberculosis infection not confirmed	Confirm with IGRA
Positive	Positive	M. tuberculosis infection indicated	If chest X-ray normal: latent TB infection, start preventive treatment. If chest X-ray abnormal: rule out active TB

For high-risk populations, TST combined with IGRA is recommended for confirmation. Immunocompromised people, such as those with chronic underlying conditions or on immunosuppressive therapy, may have false-negative TST results and should be verified with IGRA. Verifying TST-positive people with IGRA on the same day as the reading improves accuracy. A systematic review confirmed that IGRA has some predictive value for assessing the risk of latent TB infection progressing to active disease.

In high-income countries, combined screening for high-risk groups may be cost-effective. In low- and middle-income countries, resource constraints make combined TST and IGRA testing burdensome, and more health-economic evidence on different test combinations may be needed. Screening strategies should be tailored by population infection risk to balance cost control with specificity and accuracy.

Predictive markers for progression to active disease

Existing screening methods can tell whether a person is infected, but not whether they will progress to active TB or how high their risk is. Better forward-looking detection tools are needed for early identification and dynamic prediction.

Several prospective cohort studies show that dynamic immune and molecular testing can effectively predict progression risk. In immune-cell research, one prospective cohort found that people with latent TB infection and TST of 14 mm or more had a higher proportion of peripheral blood monocytes, significantly associated with active TB risk; monocyte dynamics may serve as a reference for judging intervention timing.

In omics and molecular biomarkers, RNA expression studies have identified multiple TB progression genes and scoring models. A three-gene TB score model built on GBP1, STAT1, and TAP1 achieved 86 percent sensitivity and 84 percent specificity for diagnosing progression from latent TB infection to active TB, with a 99.3 percent negative predictive value for active TB. Differential expression of microRNA is closely associated with latent TB infection occurrence and reactivation, offering potential for early diagnosis.

Studies on TB antigens, antibodies, and immune-cell phenotypes have also advanced. DosR regulon-encoded Rv gene series can effectively distinguish latent TB infection from active TB. Membrane-associated antigen IgM antibody, alpha-crystallin IgA antibody, specific T-cell proliferation, and TNF-alpha effector T cells and effector memory phenotype are all closely linked to progression in immunocompetent adults.

These methods are meaningful for infection-status and risk assessment but remain at the experimental stage. Cost and benefit do not yet match, and they cannot be broadly applied to TB infection detection. Future challenges include validating test accuracy across different populations and verifying the economic impact of their application.

Who should be screened: recommended populations

Whether latent TB infection progresses to active disease depends on many factors, with immune impairment being the most important. People with HIV face 12 to 16 times the risk of active TB compared with the general population, and TB is a leading cause of hospitalization and in-hospital death among people with HIV worldwide, a pattern known as HIV tuberculosis coinfection. About 7 percent to 10 percent progress to active TB each year. In 2022, roughly one third of AIDS-related deaths were due to TB; among the 1.23 million estimated global TB deaths in 2024, about 150,000 were HIV-positive people.

Clear risk factors for active TB include age, rural residence, low body mass index, diabetes, close contact with pulmonary TB, silicosis, and prior TB history.

Global treatment guidelines recommend preventive treatment for the following groups:

• People with HIV: adults, adolescents, pregnant people, and those previously treated for TB, regardless of immunosuppression level (strong recommendation); HIV-positive infants exposed to TB patients (strong); HIV-positive children aged 12 months and older living in high-transmission settings, regardless of exposure (strong); children who successfully completed TB treatment (conditional).

• Household contacts of people with bacteriologically confirmed pulmonary TB: children aged 3 to 5 years.

• People starting anti-TNF therapy, receiving dialysis, preparing for organ or blood transplant, or living with silicosis: systematic TB infection testing and treatment.

• Other groups to consider: prisoners, healthcare workers, immigrants from high-burden countries, homeless people, and people who use drugs.

Preventive treatment regimens

The global health authority recommends 6H (isoniazid preventive therapy for six months) as the standard regimen for latent TB infection treatment, a cornerstone of latent tuberculosis infection prevention. In areas with moderate TB prevalence, the 6H regimen significantly reduces TB incidence, although TB preventive treatment adherence to six months of isoniazid remains suboptimal in many regions.

The 2023 global health authority guideline update proposes the following regimens: 3HP (isoniazid plus rifapentine, once weekly, for three months), 3HR (isoniazid plus rifampicin, for three months), and 4R (rifampicin preventive treatment alone, for four months). These are all forms of tuberculosis preventive treatment.

For people with HIV, isoniazid-containing regimens are recommended because no evidence shows that rifampicin alone works for HIV-positive people. The 4R regimen is more often recommended for HIV-negative adults and children of all ages. Non-inferiority research found that 4R is as effective as 6H for preventing TB, with a lower discontinuation rate due to adverse reactions and a higher treatment completion rate.

For drug-resistant TB, people exposed to drug resistant tuberculosis, including multidrug-resistant or rifampicin-resistant TB patients, should receive six months of levofloxacin as preventive treatment. For contacts exposed to rifampicin-resistant TB, isoniazid preventive treatment for at least six months, extendable to nine months, is recommended. For contacts of isoniazid-resistant TB patients, rifampicin treatment for at least six months is an option.

Rifamycins interact with many drugs, including azole antifungals, warfarin, oral contraceptives, and anti-HIV reverse transcriptase inhibitors. These combinations are best avoided whenever possible, or adjusted using pharmacokinetic principles; rifabutin is an alternative.

Adverse reactions and drug interactions

Anti-TB drugs carry multiple adverse reactions. The most common, in order, are gastrointestinal symptoms, elevated liver enzymes, rash, and neuritis. Rare but serious events include severe bone marrow suppression and hypersensitivity from rifampicin. Drugs used for preventive treatment are generally safe and well tolerated, but serious adverse events vary by individual and require close monitoring.

Risk factors for adverse reactions include age over 60, female sex, treatment regimen, alcoholism, anemia, HIV coinfection, and deficiencies in sodium, iron, or albumin. When treating these groups, close monitoring of liver function, neurological symptoms, and neutrophil levels is advised as part of adverse reaction monitoring.

Rifampicin is a major inducer of CYP3A4 and P-glycoprotein, which can lower concentrations of drugs metabolized by CYP3A4 and/or transported by P-glycoprotein. For example, dolutegravir may require dose increases when co-administered with rifampicin-based regimens.

New drugs and vaccines under development

To address adverse reactions and rifampicin drug interactions, researchers are developing new drugs and formulations that could replace rifampicin. Nanoparticles, microspheres, and liposomes are among the newer delivery systems being explored, with potential to improve acceptability among people receiving preventive treatment. These products remain in the research and development stage.

BCG remains the most important primary-prevention measure and the only approved TB vaccine, but its effectiveness wanes over time. New TB vaccine development is advancing across multiple types: whole-cell attenuated live vaccines, whole-cell inactivated vaccines, protein subunit vaccines, and viral vector vaccines. Immunization strategies fall into three categories: priming vaccines (mainly for primary prevention, such as recombinant BCG VPM1002), boosting vaccines (mainly post-exposure preventive vaccines using subunit antigens with adjuvants and attenuated viral vectors), and therapeutic vaccines (for people already infected or at risk of recurrence).

Mycobacterium vaccae (MV), an inactivated whole-cell vaccine, enhances immune function by regulating peripheral blood T cells and cytokine secretion. It is approved in China as an adjunctive therapeutic vaccine for TB patients, and its effectiveness in latent TB infection preventive treatment has been confirmed by multiple studies. RUTI, a new TB vaccine with the most research to date, induces spleen-specific T-cell immunity and increases interferon-secreting cells, with good response in lung tissue. It shows promise in latent TB infection, especially among people with HIV coinfection, although the global health authority has not yet included therapeutic vaccines in the LTBI treatment strategy.

Older adults and diabetes: special considerations

Older people have weakened immunity and more underlying diseases, so latent TB infection reactivation risk and active TB progression risk are higher than in the general adult population. Once active TB develops, older adults often have more severe symptoms, faster spread, harder treatment, longer courses, and more adverse reactions. Yet preventive treatment for older adults with latent TB infection, also described as latent TB in older adults, is not yet included in national guidelines, mainly because of safety concerns (liver and kidney decline, polypharmacy, drug interactions, adverse reactions) and a lack of local health-economic evidence for large-scale screening and treatment. A domestic study found that latent TB infection rates rise with age, and preventive treatment in older adults could reduce incidence by 84 percent and mortality by 92 percent. The global health authority does not use age as an exclusion criterion; age serves only as a risk-stratification and adverse-reaction assessment factor. The recommended strategy is stratified assessment and cautious recommendation: prioritize low-risk subgroups with good tolerance, and actively promote real-world safety cohort studies. Older adults with high IGRA quantitative levels, long-term glucocorticoid use, nursing-home residence, and acceptable liver and kidney function should be considered for preventive treatment with strict monitoring for liver and kidney injury and neurotoxicity.

The global health authority position on preventive treatment for people with diabetes is in transition. The 2024 guideline withdrew the 2020 clause that explicitly recommended against it, leaning toward "insufficient evidence, pending evaluation." Studies show a 22.43 percent latent TB infection detection rate in people with diabetes, higher than the general population in most regions, and diabetes is a confirmed risk factor for progression to active TB, a key diabetes tuberculosis risk. However, extending from higher infection rates to universal screening and treatment faces multiple evidence gaps. Few studies confirm the link between annual reactivation rates and diabetes; safety data are scarce, with a prior randomized trial stopped early due to serious liver toxicity; and local health-economic models disagree, with universal screening showing limited benefit. The recommended approach aligns with the global health authority's cautious stance: move from "universal inclusion" to "precision pilots," prioritizing high-TB-prevalence areas and subgroups with poor glycemic control or long disease duration, while advancing local safety and cost-effectiveness prospective cohort studies.

Latent tuberculosis infection prevention: practical recommendations

• Build a broad, well-structured active screening system for latent TB infection to achieve systematic testing and dynamic monitoring of key populations, including TB contact screening, a foundation of latent tuberculosis infection prevention.

• Use standardized screening for close contacts of active TB patients to improve latent TB infection identification efficiency.

• Apply precise preventive treatment to people with recent infection and other high-risk latent TB infection populations to block transmission chains and reduce incidence.

• Tailor diagnostic test combinations to population infection risk, balancing cost with accuracy and specificity.

• Prioritize isoniazid-containing regimens for people with HIV; consider 4R for HIV-negative adults and children.

• Monitor liver function, neurological symptoms, and neutrophil levels closely, especially in people over 60, women, and those with comorbidities.

• Avoid rifamycin regimens with interacting drugs such as azole antifungals, warfarin, oral contraceptives, and anti-HIV drugs; use rifabutin when needed.

• For older adults and people with diabetes, use stratified, risk-based decisions rather than blanket inclusion.

Limitations

This review synthesizes the latest evidence and authoritative guidelines, but two evidence gaps limit translation into clinical practice. First, new biomarkers such as gene-expression profiles, DosR-related antigens, and microRNA lack prospective external validation in western and central high-burden regions. Second, real-world safety and local cost-effectiveness evidence for preventive treatment in older adults and people with diabetes is still relatively scarce, directly constraining cautious guideline decisions. Future research should prioritize prospective validation of new biomarkers in key Chinese populations and establish safety monitoring cohorts for high-risk subgroups.

Bottom line

Latent tuberculosis infection is the hidden reservoir driving the TB epidemic. Latent tuberculosis infection prevention depends on systematic screening, precise preventive treatment, and risk-stratified management of older adults and people with diabetes to end TB. Progress in diagnostics, shorter regimens, and new vaccines will determine how fast transmission can be blocked.

FAQ

What is latent tuberculosis infection?

Latent tuberculosis infection is a state in which a person carries Mycobacterium tuberculosis in the body without showing any clinical symptoms of active tuberculosis. The bacteria remain under control by the immune system but can reactivate later.

How many people worldwide have latent tuberculosis infection?

About one quarter of the global population, roughly two billion people, is infected with Mycobacterium tuberculosis, and latent tuberculosis infection makes up an important part of this total.

What is the risk of latent TB progressing to active TB?

Within two to five years of infection, 5 percent to 10 percent of people with latent tuberculosis infection will progress to active tuberculosis. Among new active pulmonary TB patients, 80 percent to 90 percent come from the previously infected latent population.

What tests are used to diagnose latent TB infection?

The main tests are the tuberculin skin test, interferon-gamma release assay, and the TB-specific antigen skin test. Each has strengths and weaknesses, and no single test is a gold standard.

Is the TB skin test affected by BCG vaccination?

Yes. The tuberculin skin test can produce false positives due to cross-reaction with BCG vaccination history and non-tuberculous mycobacteria. The newer TB-specific antigen skin test and interferon-gamma release assay are not affected by BCG vaccination.

Who should receive preventive treatment for latent TB?

Recommended groups include people with HIV, household contacts of confirmed pulmonary TB patients (especially children aged 3 to 5 years), people starting anti-TNF therapy, people on dialysis, people preparing for transplant, people with silicosis, prisoners, healthcare workers, immigrants from high-burden countries, homeless people, and people who use drugs.

What is the standard preventive treatment regimen?

The global health authority recommends isoniazid for six months (6H) as the standard regimen. Updated options include isoniazid plus rifapentine weekly for three months (3HP), isoniazid plus rifampicin for three months (3HR), or rifampicin alone for four months (4R).

Is preventive treatment safe for older adults?

Preventive treatment is not yet included in national guidelines for older adults, mainly due to safety concerns and a lack of local cost-effectiveness evidence. A stratified, cautious approach is recommended, prioritizing low-risk older adults with good tolerance.

What adverse reactions can preventive treatment cause?

The most common adverse reactions are gastrointestinal symptoms, elevated liver enzymes, rash, and neuritis. Rare but serious events include severe bone marrow suppression and hypersensitivity from rifampicin.

Can people with diabetes receive latent TB preventive treatment?

The global health authority's position is shifting from "not recommended" toward "insufficient evidence, pending evaluation." Precision pilots in high-prevalence areas and subgroups with poor glycemic control are recommended rather than universal screening.