Diagnosis & Management ofLatent TB Infection

Prof. Ashok Rattan, MD, MAMS, INSA DFG, WHO Lab Director

Academics, Industry: Research, Diagnosis, Public Health, Academics

Adviser: Laboratory Operations, Pathkind Labs.

A disease of great antiquity

• Fossil bones 8000 BC show evidence

• Egyptian mummies: Spinal caries 2400 BC

• 1500 BC mention of consumption in India

• Hippocrates 460 – 370 BC recognized phthisis (felt it was heredity)

Tuberculosis, Phthisis

Robert Koch24th March 1882

Physiologist Society of Berlin

• Bacteria isolated from tubercular patients

Injected into

• 94 guinea pigs

• 70 rabbits

• 9 cats

• 44 mice

Caused a similar disease in all these animals

Towards TB elimination: END TB STRATEGYPriority action area

1. Ensure political commitment, funding and stewardship for planning and essential services of high quality.

2. Address the most vulnerable and hard-to-reach groups.

3. Address special needs of migrants and cross-border issues.

4. Undertake screening for active TB and LTBI in TB contacts and selected high-risk groups, and provide appropriate treatment.

5. Optimize the prevention and care of drug-resistant TB.

6. Ensure continued surveillance, programme monitoring and evaluation and case based-data management.

7. Invest in research and new tools.

8. Support global TB prevention, care and control.4

Two strategies to eliminate TB

A. Early & rapid diagnosis of all persons with active TB & institution of effective therapy.1. Reduce transmission

2. Cure patients

Only 50% of all cases globally are currently diagnosed & treated.

Every open case infects approx. 10 cases/year

Significant transmission of infections occurs before diagnosis is made

BackgroundTowards TB elimination in EU/EEA •With current mean annual change in the TB notification rate (- 6%), the EU/EEA will achieve TB elimination by 2092.

•To reach elimination by 2050, TB rates need to decline by -12% annually.

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Decline needed to reach TB elimination by 2050 Current mean annual decline

B. Treatment of LTBI• In 1950s clinicians that INH monotherapy in LTBI prevented subsequent

development of active TB in upto 90%

• Subsequently more than 20 RCT involving more than 100,000 participants in over a dozen countries demonstrated efficacy.

• Eastern Europe, 28,000 TST positive; 7,000 each group

IUATB Committee on Prophylaxis

Bull WHO 1982; 60: 555-64

LTBI treatment duration Active TB in next 5 yearswhen compared to placebo

3 Months INH 31% reduction

6 Months INH 69% reduction

12 Months INH 93% reduction

Latent TB Infection (LTBI)

• LTBI is defined as a state of persistent immune response to stimulation by M. tubercuslosis antigens without evidence of clinically manifested active TB

• A direct measurement tool for M. tuberculosis infection in humans is currently unavailable.

• The vast majority of infected persons have no signs and symptoms of TB, but are at risk for developing active TB disease.

• Diagnosis & Treatment of LTBI at present is not a priority of RNTCP

Diagnosis of latent TB infection (LTBI)

• There is no diagnostic gold standard for LTBI

• Existing tests are immunological tests that provide indirect evidence of sensitization of the host to TB antigens

• A. Tuberculin Skin Test (TST) using PPD

• B. Interferon Gamma Release Assays (IGRA) using TB specific antigens• Early Secreted Antigenic Target (ESAT 6)

• Culture filtrate protein (CFT 10)

• TB 7.7

• Quantiferon TB Gold In Tube

• T Spot

Diagnosis of LTBI in high prevalence countries

ESAT 6 & CFP 10 Specific antigens (RD 1 region) of M. tuberculosis[can not differentiate between LTBI and Active TB]

WHO recommends that in high burden countries IGRA shouldnot replace TST

Seven key questions:

1. Which population would benefit most from LTBI diagnosis & treatment ?

2. Which is the most appropriate algorithm to identify individuals to be treated for LTBI ?

3. What is the best treatment option for LTBI ?

4. What is the best way to monitor and manage hepatic toxicity ?

5. What interventions are effective to improve initiation, adherence & completion of LTBI treatment ?

6. Should preventive therapy be recommended by contacts of patients with MDR TB ?

7. Is the treatment and management of LTBI cost effective ?

8. Should treatment for LTBI be offered in India: Pros & cons

1. Identification of at risk populations for LTBI testing and treatment ?

• Evidence evaluated• Three types of evidences evaluated

• Prevalence of LTBI: in different risk groups 276 studies

• Risk of progression to active TB in persons with LTBI: 8 studies

• Increased incidence of active TB in different high risk groups vs normal population

High Risk factors for development of active TB• HIV +ve cases: 10 to 100 times higher risk of LTBI reactivation

• A meta analysis indicated that treatment of TST +ve reduced risk of overt TB• No evidence of efficacy amongst TST negative HIV +ve patients

• Transplantation with immunosuppressant use:• From Spain :kidney, liver & heart transplant had 20 times higher risk• Sakhuja et al: 11.8% TB after kidney transplant, 70 times higher

• Silicosis: 25 to 30% of silicosis develop TB, relative risk is 2.8 times

• Close contacts with pulmonary TB: reactivation rate is 15 times greater for those recently infected (<2 years)

• TNF α antagonists : etanercept, adalimumab, infliximab, golimumab, certolizumab all lead to four fold increase in risk of TB disease

• Chronic renal failure & hemodialysis: 10 to 20 fold increase in TB risk

1. Identification of at risk populations for LTBI diagnosis by Targeted TST

• For resource limited countries• People living with HIV

• Children below 5 yrs of age who are household contacts of people with TB & who after appropriate clinical evaluation, are found not to have active TB but have LTBI

• In high income & upper middle income countries [TB incidence < 100 per 100,000 population]

• People living with HIV

• Adult & child contacts of pulmonary TB

• Pt. initiating anti TNF treatment

2. Most appropriate algorithm to identify persons to be treated for LTBI

Public Health impact of LTBI screening & Treatment has been very low in all studies

Active TB must be ruled out before staring treatment for LTBI

• Individuals must be asked about symptoms of TB before being tested for LTBI

• Chest X Ray can be performed to rule out abnormalities

• Individuals with TB symptoms of X Ray abnormalities must be investigated further to rule out active TB by ZN staining, Culture & Gene Expert

• IGRA shouldnot replace TST in low & middle income countries

• HIV testing should be incorporated into medical evaluation of LTBI

• 8 head to head studies: Risk ratio TST 2.58; IGRA 4.94

3. Best Treatment options

Summary of evidence

• Shorter duration regimens preferred

• 3 M rifapentine + INH should be given under direct observation

• Caution in persons on ARV treatment because of drug druginteraction

4. Best way to monitor & manage hepatic toxicity• Mandatory to minimize risks during treatment

• INH: • asymptomatic elevation of liver enzymes,• Peripheral neuropathy• Hepatotoxicity

• Rifampicin & Rifapentine• Cutaneous reactions• Hypersensitive reactions• Gastro-intestinal intolerance• Hepatotoxicity

• Routine regular clinical monitoring every month

• Baseline laboratory testing: serum aspartate and alanine aminotransferase and bilirubin

• Development of anorexia, N & V, Abdominal discomfort, persistent fatigue, dark coloured urine, pale coloured stool, jaundice

5. Interventions to improve initiation, adherence & completion of LTBI treatment

• 25 articles reported on LTBI treatment

• 35 % treatment completion in 8 different population groups

• Varied from 22% in prisoners to 82% in people living with HIV

• Inversely proportional to the duration of treatment chosen

• Factors detrimental to treatment completion• Adverse drug reactions• Longer duration• Distance from health facility• Absence of perception of risk• Presence of stigma• Time lag between diagnosis & initiation of treatment

Effective physician interventions to increase LTBI treatment completion rate

• Client education

• Patient reminder system

• Ongoing education of providers

• Patient involvement in treatment decision making

• Directly observed therapy

6. Preventive therapy for contacts of MDR TB

• For contacts of MDR TB better to be guided by comprehensive individual risk assessment• Strict clinical observation

• Close monitoring for 2 years

7. Is treatment for LTBI cost effective

• Cost of testing for detecting LTBI • Using TST : US$ 10 to 31

• Using IGRA: US$ 22 to 97

• Side effect monitoring• US$ 8 to 687

• Average cost US$ 381 to 1130

• Drug cost is only 10% of total cost. Will require additional resources for close follow up & monitoring to detect serious adverse events & compliance.

8. Should treatment for LTBI be offered in India: Pros & cons

• LTBI are non infectious

• Life time risk of developing active TB is 5 to 10%

• Greatest risk of progression in the first two years

• Risk increases in immunocompromised patients• HIV pts with LTBI have 10% risk per year

• Program focus is on detecting & treating active cases of TB

• Diagnosis & treatment of LTBI will increase financial burden

• One time treatment will not ensure complete eradication of infection & future treatment may be required

• Persons having irreversible risk factors may require lifelong therapy

Protection of INH against development of active TB in HIV infected individuals in low income countries

Study Year Country Risk reduction compared to placeboTST +ve TST -ve

Pape et al 1993 Haiti 76 30

Whalen et al 1997 Uganda 70 26

Hawken et al 1997 Kenya 40 0

Mwinga et al 1998 Zambia 72 18

Samandari et al 2009 Botswana 90 14

Pooled 2010 All 60 16

In high burden, low income countriesWho would benefit from Treatment ?

• Children < 5 years

• Close household contacts of sputum positive pulmonary TB

• Immunosuppressed individuals

• Recent tuberculosis converter are good candidates for treatment

• Targeted Testing by TST & Treatment

Potency of anti-TB drugs against M. tuberculosis

Gatifloxacin