Latent Tuberculosis Infection Georges KHAYAT Associate Professor, Faculté de Médecine, Université Saint Joseph

It is defined as a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifested active TB It is defined as infection with M. tuberculosis manifested by a positive TST or IGRA result, but without evidence of active TB disease including symptoms, progressive radiographic changes or microbiological evidence of replicating organisms The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. LTBI 24/03/2016 LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis ? A TBNET consensus statement. U. Mack & co. for the TBNET. Eur Respir J 2009; 33: 956–973 What is LTBI?

LTBI could reactivate in active tuberculosis : the lifetime risk is estimated between 5–10%, most of them within the first five years after initial infection. The risk depends on several factors : the most important one being the immunological status of the host. Treatment can prevent reactivation TB … but LTBI 24/03/2016 Potential benefit of treatment Risk of drug-related adverse events

The benefits are greater than the harms for infected individuals in population groups in which the risk of progression to active disease significantly exceeds that for the general population. Management of LTBI requires : Identifying and testing individuals who should be tested Delivering effective, safe and complete treatment with no or minimal risk of adverse events Ensuring monitoring and evaluation of the process Population-wide mass LTBI testing and treatment are not feasible because Imperfect tests Risk of serious and fatal side-effects High cost LTBI 24/03/2016

Household and close contacts when the index case : Has sputum smear-positive pulmonary TB Has multi-drug-resistant TB (MDR or XDR (proven or suspected) Is a PLHIV or Is a child <5 years of age. LTBI 24/03/2016 Guidelines on the management of latent tuberculosis infection. © World Health Organization 2015 In low and middle income countries Contact Investigation Is recommended Contact Investigation Is suggested Household and close contacts of all other index cases with pulmonary tuberculosis

LTBI 24/03/2016 Philos Trans R Soc Lond B Biol Sci.Philos Trans R Soc Lond B Biol Sci May 12;369(1645): The ongoing challenge of latent tuberculosis. Esmail H 1, Barry CE 3rd, Young DB, Wilkinson RJ.Esmail HBarry CE 3rdYoung DBWilkinson RJ

LTBI 24/03/2016 Philos Trans R Soc Lond B Biol Sci.Philos Trans R Soc Lond B Biol Sci May 12;369(1645): The ongoing challenge of latent tuberculosis. Esmail H 1, Barry CE 3rd, Young DB, Wilkinson RJ.Esmail HBarry CE 3rdYoung DBWilkinson RJ

LTBI 24/03/2016 Guidelines on the management of latent tuberculosis infection. © World Health Organization 2015 In high-income or upper middle-income countries

People living with HIV Adult and child contacts of pulmonary TB cases Patients initiating anti-tumour necrosis factor (TNF) treatment Patients receiving dialysis Patients preparing for organ or haematologic transplantation Patients with silicosis Either (IGRA) or Mantoux tuberculin skin test (TST) LTBI 24/03/2016 Guidelines on the management of latent tuberculosis infection. © World Health Organization 2015 In high-income or upper middle-income countries should be performed Systematic testing and treatment of LTBI should be performed (clear evidence of benefit)

Prisoners Health-care workers Immigrants from high TB burden countries Homeless persons Illicit drug users LTBI 24/03/2016 Guidelines on the management of latent tuberculosis infection. © World Health Organization 2015 In high-income or upper middle-income countries Systematic testing and treatment of LTBI should be considered (the benefits may outweigh the harms) Systematic testing and treatment of LTBI should not be done (the benefits do not outweigh the risks) Diabetic patients People with harmful alcohol use Tobacco smokers Underweight Either IGRA or TST should be used to test for LTBI

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There was insufficient data to provide evidence on predictive utility of the tests among specific high-risk subpopulations or groups.

LTBI 24/03/2016 PHILIP LOBUE AND DICK MENZIES. Respirology (2010) 15, 603–622 Treatment of latent tuberculosis infection: An update. How to treat LTBI?

LTBI 24/03/2016 PHILIP LOBUE AND DICK MENZIES. Respirology (2010) 15, 603–622 Treatment of latent tuberculosis infection: An update. How to treat LTBI? 6-month isoniazid 9-month isoniazid 3–4 months isoniazid plus rifampicin 3–4 months rifampicin alone

LTBI 24/03/2016 Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection MMWR / December 9, 2011 / Vol. 60 / No. 48 The current standard regimen of Isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion.

LTBI 24/03/2016 Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection MMWR / December 9, 2011 / Vol. 60 / No. 48 The current standard regimen of Isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion.

LTBI 24/03/2016 Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection MMWR / December 9, 2011 / Vol. 60 / No. 48 The current standard regimen of Isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion. Open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis.

Persons with LTBI at high risk for progression to active disease: > 12 years of age + Close contact with TB (culture-confirmed) within 2 y before enrollment & have had a positive result on a tuberculin skin test + Conversion to positive results on a tuberculin skin test + HIV infection with a positive tuberculin skin test or have had close contact with a patient with tuberculosis regardless of test results + Positive TST with fibrotic changes on chest radiography (previously untreated TB) Expanded to include children between the ages of 2 and 11 years LTBI 24/03/2016 INCLUSION

Tuberculosis : Sure or suspected Resistance to isoniazid or rifampin in the source case Rifamycin or isoniazid taken during the previous 2 years Previous completion of treatment for TB or LTBI in HIV-seronegative persons Sensitivity or intolerance to isoniazid or rifamycin ASAT level five times the upper limit of normal Pregnancy or lactation HIV therapy within 90 days after enrollment Weight < 10.0 kg LTBI 24/03/2016 EXCLUSION

LTBI 24/03/2016 Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection MMWR / December 9, 2011 / Vol. 60 / No. 48

LTBI 24/03/2016 Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection MMWR / December 9, 2011 / Vol. 60 / No. 48 ADVERSE EVENTS

LTBI 24/03/2016 Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection MMWR / December 9, 2011 / Vol. 60 / No. 48 ADVERSE EVENTS Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P= 0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001).

LTBI 24/03/2016 The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment- completion rate. Adverse events do not appear to be a problem but long-term safety monitoring will be important. A 3-month course of once-weekly rifapentine plus isoniazid represents an advance in the treatment of latent M. tuberculosis infection

We need to improve the identification of those who are most likely to reactivate with more predictive diagnostic tests We need drugs that target and rapidly sterilize persistent bacilli for decreasing treatment duration LTBI 24/03/2016