Latent TB Infection (LTBI)

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

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. Latent TB Infection Latent TB Active TB • 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 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 20-30 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. 3 LTBI Management: The WHO updated the global guidelines 2018 1 2 Diagnose latent TB 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) • OR • 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

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 • 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 • 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)

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 EnglJ 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. Lets FIGHT TB, Leprosy & Lung Disease Together PAMOJA TUNAWEZA For more information contact The NTLD-Program: P.O Box 20781-00202 Nairobi, Kenya, Email: info@ntld.co.ke Website: www.nltp.co.ke@NTLDKenyaNTLDKenya