Diagnosis & Management of Latent TB...
Transcript of Diagnosis & Management of Latent TB...
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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Diagnosis of LTBI in high prevalence countries
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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
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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
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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
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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
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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
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2. Most appropriate algorithm to identify persons to be treated for LTBI
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Public Health impact of LTBI screening & Treatment has been very low in all studies
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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
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3. Best Treatment options
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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Potency of anti-TB drugs against M. tuberculosis
Gatifloxacin
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