1. Latent TB Infection (LTBI)
KPA Annual Scientific Conference, Mombasa
Dr Teresiah Njoroge

2. Presentation Outline Natural history of Tuberculosis
Definition of LTBI
LTBI Management: The WHO updated Guidelines 2018
Diagnosis of LTBI
Treatment of LTBI
Prevention of Latent TB in MDRTB Contacts
Management of LTBI in Kenya
Practical Considerations

3. Natural History of TB Infection
Studies have shown that, on average, 5–10% of those infected will develop active TB disease in their lives, usually within the first 5 years after initial infection
The risk for active TB disease after infection depends on several factors, the most important being immunological status
Prevention of active TB disease by treatment of LTBI is a critical component of the WHO End TB Strategy
The potential benefit of treatment should, however, be carefully balanced against the risk for drug-related adverse events

4. LTBI
Latent tuberculosis infection (LTBI) is defined as a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB
No “gold standard” test for LTBI
Global burden is not known with certainty; however, up to one third of the world’s population is estimated to be infected
On average, 5–10% of those infected will develop active TB disease usually within the first 5 years after initial infection
The risk for active TB disease after infection depends on several factors, the most important being immunological status

5. TB lives but does not grow in body
Does not cause symptoms
Is not contagious
Can advance to active TB disease
TB is active and grows in body
Causes symptoms and ill feeling
Is contagious
Can cause death if not treated
Latent TB
Active TB
Latent TB Infection
Latent TB Infection (LTBI) is defined as a positive test of TB infection without evidence of clinically active TB
1.7 billion people are infected with LTBI globally
People living with HIV are times more likely to develop active TB disease than people without HIV
Household contacts of TB patients have an increased risk of developing TB, especially children under 5

6. LTBI Management: The WHO updated the global guidelines 2018
Diagnose latent TB 3
Identify population at risk in country & exclude active TB among contacts
Treat for an appropriate time
Interferon-gamma release assays (IGRA) OR
Mantoux tuberculin skin test(TST)
Assume LTBI based on exposure or a weak immune system due to HIV in high burden settings (after excluding active TB)
Isoniazid therapy for 6 months
Rifapentine +INH for 12 weekly doses
Rifampicin + INH for 3 months daily doses
INH 36+ months for adults and adolescent PLHIV in high incidence settings
Systematic screening and treatment in high risk populations (adults & children living with HIV)
Testing for TB contacts & treating children (at least children <5years old)
Testing for TB and treating other risk groups (prisoners, HCW, immigrants, homeless, drug users, diabetics)
LTBI treatment prevents progression from latent TB to active TB
Source: WHO Latent TB Guidelines 2018

7. Identification of populations for testing and treatment of LTBI
People living with HIV
HIV-negative household contacts of a person with pulmonary TB
Other HIV-negative at-risk groups
Patients initiating anti-TNF treatment
Patients receiving dialysis
Patients preparing for an organ or haematological transplant and patients with silicosis should be systematically tested and treated for LTBI
In countries with a low TB incidence- for prisoners, health workers, immigrants, homeless people and people who use illicit drugs
NB-Systematic testing for LTBI is not recommended for people with diabetes, people with harmful alcohol use, tobacco smokers and underweight people unless they are already included in the above recommendations

8. Infants and children living with HIV
Infants aged < 12 months living with HIV who are contacts of TB should receive 6 months of IPT if the investigation shows no TB disease
Children aged ≥ 12 months living with HIV who have no contact with a case of TB should be offered 6 months of IPT if they live in a setting with a high prevalence of TB
All children living with HIV who have successfully completed treatment for TB disease may receive isoniazid for an additional 6 months

9. HIV-negative household contacts of a person with pulmonary TB
Children aged < 5 who are found not to have active TB on an appropriate clinical evaluation or according to national guidelines should be given TB preventive treatment
New WHO Recommendation
Countries with high TB burden- children aged ≥ 5 years, adolescents and adults who are found not to have active TB by an appropriate clinical evaluation or according to national guidelines may be given TB preventive treatment
In settings with high TB incidence and transmission, adults and adolescents living with HIV who have an
unknown or a positive TST and are unlikely to have active TB disease should receive at least 36 months of
IPT, regardless of whether they are receiving ART. IPT should also be given irrespective of the degree of
immunosuppression, history of previous TB treatment and pregnancy.

10. Diagnosis of Latent Tuberculosis Infection
No gold standard method for diagnosing LTBI
Tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be used to test for LTBI
It requires a competent immune response in order to identify people infected with TB and are imperfect tests for measuring progression to active disease
PLHIV who have a positive test for LTBI benefit more from preventive treatment than those who have a negative LTBI test
LTBI testing can be used, where feasible, to identify such individuals
LTBI testing by TST or IGRA is NOT a requirement for initiating preventive treatment in people living with HIV or child household contacts aged < 5 years

11. Diagnosis-2
WHO conclusion: No strong evidence that one test should be preferred over the other
TST may require significantly fewer resources than IGRA and may be more familiar to HCWs
However, recurrent global shortages and stock-outs of TST reduce its use in scaling up programmatic management of LTBI
WHO strongly recommended the two tests as equivalent options, with relatively similar advantages and disadvantages

12. Treatment options for LTBI
Isoniazid monotherapy for 6 months for adults and children in countries with high and low TB incidence
Rifampicin plus isoniazid daily for 3 months for children and adolescents aged < 15 years in countries with a high TB incidence
Rifapentine and isoniazid weekly for 3 months for both adults and children in countries with a high TB incidence 6H
3RH
3HP

13. Comparing options for LTBI treatment
3RH:
Availability of child-friendly formulation (same FDC as for continuation phase treatment – RH 75/50mg)
Suitable for children up to 25kg
Older children can use adult FDCs
Better adherence (shorter regimen)
Do not give to patients on PI or NVP based ART
Low cost (FDC)
3HP:
Very promising future regimen
1 month daily treatment option (1HP) being evaluated in PLHIV
Better adherence (shorter regimen)
No FDC nor child-friendly formulation available yet
No evidence for use in children <2 years
Do not give to patients on PI or NVP based ART
Safe to use in PLHIV on EFV and RAL
Ongoing studies use with DTG (so far no interactions)
High cost (RPT tabs)
6 H
Poor adherence/completion rates with longer regimen
Higher rates of hepatotoxity than other regimens
Still regimen of choice for CLHIV on ART
Lowest cost (uncoated tab), high cost dispersible tab

14. Treatment option…
Rifampicin- and rifapentine-containing regimens should be prescribed with caution to people living with HIV who are on ART because of potential drug–drug interactions.
These regimens should not be administered to people receiving protease inhibitors or nevirapine
IPT should also be given irrespective of the degree of immunosuppression, history of previous TB treatment and pregnancy

15. Rationale for the recommendations
The selection of treatment options should consider the characteristics of the clients to ensure that it is not only initiated but also completed
WHO agrees that the benefits of all the treatment options outweigh the potential harm
All the treatment options can be self-administered
The benefits of 3 months’ daily rifampicin plus isoniazid for infants and children < 15 years outweighs the harm, given its safety profile, high rate of completion as compared to INH monotherapy and the availability of child-friendly, fixed-dose combinations of rifampicin and isoniazid

16. References
Getahun H, Matteelli A, Chaisson RE, Raviglione M. Latent Mycobacterium tuberculosis infection. N Engl J Med. 2015;372(22):2127–35
Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003;163(9):1009–21
Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol. 1974;99(2):131–8

17. FIGHT TB, Leprosy & Lung Disease
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