Latent tuberculosis infection (LTBI) is dormant but can progress to life-threatening disease. Exposure to M. tuberculosis results in a dynamic continuum with two common outcomes:1
those who eliminate the infection
those in whom the bacteria infects the lungs. This can initially be a latent (asymptomatic) infection, but can progress to active, potentially life threatening disease, which can sometimes progress to active, potentially life threating disease. This may happen years after the initial latent infection occurs.
Infection eliminated by innate immune response or adaptive immune response
Exposure to airborne bacteria
Asymptomatic Not Contagious TST + / IGRA +
+/- Symptomatic Contagious Usually abnormal CXR
Risk of progression after infection by air-borne bacteria
LTBI affects 26% of the world’s population and represents a significant pool of individuals who could develop active TB disease in the future. Certain populations have a high-risk of LTBI progressing to active TB, and these patients need to be identified and treated. Because active TB is still in the top 10 causes of death worldwide, this large LTBI reservoir also represents a risk of future deaths.2
infected with the bacteria worlwide 2
new cases each year worlwide 2
deaths each year worlwide 2
Additional impact of COVID-19
Disruptions because of COVID-19 may result in additional TB cases and deaths:
The WHO estimates that there is a 50% reduction in TB cases detected and that TB deaths in 2020 will be ~1.85 million worldwide.
A modeling analysis by the Stop TB Partnership estimates that the disruption of TB control programs under a 3-month lockdown and a protracted 10-month restoration of services, the world could see an additional 6.3 million cases of TB between 2020 and 2025 and an additional 1.4 million TB deaths during that same period.
HIGH-RISK LTBI POPULATIONS
Populations at high risk are those patients with LTBI that are critically more vulnerable to disease progression. In the general population, LTBI will progress to active TB for approximately 1 in 10 people over their lifetimes.
However, people that fit into the population groups below have been shown to be at higher risk and their likelihood of disease progression is significantly increased.4
These populations should be identified and treated:
From 16 to 46 times *
People living with HIV
From 16 to 46 times *
TNF-a inhibitors: 10 times *
Advanced kidney disease: 8 times *
Organ transplant: from 70 to 300 times *
Stem cell transplant: 20 times *
Age <2-3 years: >10 times *
age 3-4 years: >3 times *
*For individuals with LTBI: Lifetime risk of developing TB disease compared to those without the risk factor. 4
It is recommended to treat specific high risk subgroups directly (testing for LTBI is not mandatory), including HIV-positive patients and children < 5 years old in close contact with TB infected patients.
Those without HIV-infection in other age groups who are in close contact with a person with active TB infection may be treated directly, based on a clinical judgement of TB exposure and risk balanced against the availability of LTBI testing.
WHY TREAT LTBI?
Ending TB requires treatment of both LTBI and active TB
Treating LTBI is not an option.
The World Health Organization’s END TB strategy aims to eliminate TB by 2050.
The only way to achieve this objective is to treat both active TB and LTBI.
Treat LTBI to neutralise the reservoir of latent TB infection, which is a main source of future active TB disease.5
Develop a strategy to protect your patients
Treat LTBI the right way and lower your patients’ risk of becoming sick from active TB.6
Identify your patients who are most at risk of having LTBI
for LTBI and rule out active TB
Rather than waiting for LTBI to progress to active disease, it is best to identify and treat it at the latent stage.
TREATMENT OPTIONS FOR LTBI
WHO recommended regimens:
Number of day dosing*
6H300mg of isoniazid
9H300mg of isoniazid
3HP900mg of isoniazid + 900mg of rifapentine
3R600 mg of rifampicin
3HR600 mg of rifampicin + 300 mg of isoniazid
1HP600 mg of rifapentine + 300 mg of isoniazid
4R600 mg of rifampicin
4HR600 mg of rifampicin + 300 mg of isoniazid
*1 month = 30days
Patients could benefit from shorter treatments with minimal side-effects.7
The most-common LTBI treatments are long-course regimens (6-9 months), for which most patients don’t finish treatment. This discourages both you and the patient, and it increases the burden of active disease within the community. Treating LTBI lowers the number of drug susceptible-TB patients requiring treatment and also prevents drug resistant-TB by shrinking
the reservoir from which acquired resistance can develop.
Did you know that
- 1 out of 3 patients in South Africa and 1 out of 4 patients in the US refused preventative treatment 11
- From those who refused the treatment:
• 62% out of 100% considered the treatment was too long
• 60% out of 100% didn’t think LTBI was a serious problem
Isoniazid8 (6H) Local observation methods to determine asherence*
6 months 180 doses
Isoniazid9 (9H) Self-administered treatment. Completion rate based on prescriptions filled each month
9 months 270 doses
*Study covering 29 jurisdictions in the US and Puerto Rico with 67,585 contacts; ‘completed treatment’ means taking at least 80% of the doses in a prescribed regimen within 150% of the intended treatment duration, as observed by local methods for monitoring adherence.
Optimise LTBI treatment for improved outcomes
To ensure that the enormous reservoir of LTBI is eliminated, any treatment has to have:
The regimen must have clinically proven effectiveness for the elimination of LTBI
The patient must complete their regimen as prescribed to ensure the proper elimination of LTBI
Well-documented safety profile
The treatment must minimize health risks so as not to deter the patient from starting and completing the regimen
A shorter LTBI treatment duration than standard 6 or 9 month treatment can lead to improved completion rates and better effectiveness for the prevention of active TB cases.
As effective as daily INH
12 doses of 3HP is as clinically effective as 270 doses of daily INH12
3HP is just 12 doses in only 3 months, a shorter regimen than 6 to 9 months INH13
Well-documented safety profile
The safety profile of 3 HP is one that LTBI patients can trust12
Better completion rates than longer regimen
The 3HP treatment regimen is non-inferior to the INH-only regimen(upper limit of the 95% CI of the difference, <0.75%)
Rate difference of progression to TB (intention-to-treat-population)
PREVENT-TB: a randomised, open-label, non-inferiority trial of 3HP given as directly observed therapy compared to 9 months daily INH self administered therapy, in adults and children 12 years and above with LTBI.
3HP treatment for LTBI has demonstrated clinical effectiveness in line with isioniazid (INH):12 doses of 3HP is as effective as 270 doses of dailly INH12
Improved adherence with short LTBI treatment:
3HP is just 12 doses in only 3 months, a shorter regimen than 6 to 9 months INH. Studies have shown improved adherence, including in some subgroups that may be difficult to follow12.13
Rates of treatment completion in subgroups in PREVENT-TB 13
Completion rates(Directly observed therapy)
Children(aged 2 to 17)
Overall Treatment completion in PREVENT-TB 12
Well-documented safety profile:
The safety profile of 3HP is one that LTBI patients can trust.
In PREVENT-TB, the safety, the 3HP treatment regimen had a toxicity profile similar to that of the INH-only group, with lower rates of adverse events, serious adverse events, and hepatotoxicity although a higher rate of possible hypersensitivity reactions was seen.12
N = 4040
N = 3759
Discontinuation for any reason
Discontinuation for adverse event
p = 0.009
Any serious adverse event
Drug related adverse events
Other drug reactions
A wider adoption of 3HP is possible and should be implemented to increase coverage and completion of LTBI treatment11
Shorter regimens could reduce the refusal rates and are associated with higher adherence but these were less known by HCPs than longer regimens.11
Only 1 out of 5 HCPs in South Africa and only 1 out of 2 HCPs in the US, where it is included in national guidelines, knew of 3HP.11
Patient perspective on LTBI
For more in depth information on LTBI
Management of TB infection Continuing Medical Education (CME) opportunity available at: