2018

LTBI: persistent immune response to M. tb antigens stimulation without manifestations

Gold std for LTBI: -

Made: need of comprehensive management of LTBI

The cascade

1. Identify people at risk

2. Ruling out the active tb
3. Testing ltbi
4. Provide treatment
5. Monitoring adverse effect
6. Adherence and completion
7. Monitoring and evaluation

Detail:

1. Prevalence of LTBI
2. Risk progression to active TB
3. Incidence of active TB compared to general population

THE STEPS

A. Identify people at risk, for LTBI testing and treatment

1. PLWHIV
a. PLWHIV with (+) or unknown TST + unlikely to have TB => should receive preventive
treatment of TB (existing), regardless of immune status or status on ARV
S: TB is most frequent (1/3) cause of death in HIV despite increase in ART, and PLWHIV
21 timesmore develop active TB than non HIV
R: clear benefit of systematic testing and treatment of LTBI for PLWHIV, given additional
protection with ART
IPT is recommended also for people who were previously treated for TB but no evidence
was found, for preventive treatment of people who had successfully completed MDR TB
Rifamp and INH are safe for pregnant woman
In high TB settings, IPT 36 months or longeris recommended
b. Infant < 12 mo living with HIV with TB contact + no TB => should 6 mo of IPT (updated)
c. Infant => 12 mo living with HIV with no TB contact + unlikely TB => offered IPT 6 mo (in
high TB setting) (existing)
d. Children with HIV completed TB treatment => may receive 6 mo IPT (existing)
Protection against TB and reduce mortality in HIV-infected children

2. HIV negatives household contact with TB pulmo

 a. HIV (-) < 5 yo + bact confirm pulmo TB household contact => test and tx of LTBI
(updated)
b. All people with bact confirm pulmo TB household contact (in low TB country)=> test and
tx of LTBI (existing)
c. => 5 yo and older with household bact confirm pulmo TB contact (in high TB country)=>
may receive PTI (NEW)
The prevalence of LTBI is higher among children and adolescents aged > 15 years and
adults than in children < 5 years, who were at greatest risk for progression to active TB
disease.
All household contacts, regardless of their age or LTBI status, were nevertheless at
substantially higher risk for progression to active TB than the general population.
The GDG: significantly higher risk < 5 years for developing active TB, and the disease can
develop rapidly in young children, and they are at greatest risk for severe and
disseminated disease, associated with high morbidity and mortality -> strongly
recommended preventive treatment for child household contacts aged < 5 years
3. Other HIV negatives but Other Risks
a. people with anti-TNF treatment, dialysis, organ/hematological transplant, silicosis =>
tested and tx for LTBI (updated)
b. In low TB incidence countries, test and tx for LTBI are also for prisoner, HCW,
immigrants from high TB countries. Also for homeless and illegal drugs users (existing)
c. Not to diabetic patients, tobacco smokers, alcoholic and the underweight unless with
the conditions above (existing)
Remarks: test and test for LTBI should adhere human right like it shouldn’t affect
immigration status
All the populations in (a) and (b) are at increased risk for progression to active TB
disease and get the benefits of treatment outweigh the potential harm.
B. Rule out TB disease
1. Adults with HIV should be screened (clinical algorithm) for TB -> negative symptoms ->
offered IPT (updated)
2. PLWHIV => Offered Chest X ray => normal => offered IPT (new)
3. Adults with HIV should be screened for TB -> positive symptoms-> evaluated what is the
cause of the symptoms (TB or other) (updated)
 Contraindications include: active hepatitis (acute or chronic), regular and heavy alcohol
consumption and symptoms of peripheral neuropathy.
Xpert MTB/RIF should be used as the initial diagnostic test for TB.
4. Children with symptoms of TB or TB contact but no TB => offered IPT (updated)
Signs: poor weight gain, fever, current cough and a history of contact with a TB case
 All infants < 1 year of age should be given preventive treatment if they have a history of
household contact with a TB case.
5. Rule out in TB (-) age >5 and other risk: no symptoms and no radiological abnormalities
(new)

C. Testing for LTBI

1. TST or IGRA can be used to test for LTBI (new)
No for diagnosing active TB, and could be chosen based on the availability
No gold standard, need competent immune -> should not be a requirement for initiating TB
preventive treatment for people living with HIV and child household contacts aged < 5 years,
particularly in countries with a high TB incidence, given that clear benefits outweigh the
risks
The estimate for IGRA was slightly higher than that for TST, but TST fewer resources and
more familiar to the practitioners
The GDG strongly recommended the two tests as equivalent options, with relatively similar
advantages and disadvantages
BCG vaccination should not be a determining factor in selecting a test-> it doesn’t affect the
specificity of IGRA
2. PLWHIV with LTBI test (+) benefits more the IPT than the LTBI (-) (existing)
3. PLWHIV or with household contact age< 5; TST and IGRA are not really a requirement
(updated)
D. Treatment Options for LTBI
1. INH 6 months monotx for tx of LTBI (existing)
 Daily
6 mo tx is not different to 12 months of therapy
2. In high TB incident, alternatives are: Rifam + INH 3 months for < 15 yo (new)
Efficacy = 6 months of isoniazid
3. In high TB incident, alternatives are: Rifapentine + INH 3 months for adults (> 15 yo) (new)
Efficacy =
4. In low TB countries, alternatives are: weekly rifapentine + INH 3 month, 3-4 month of Rifam
+ INH, or 3-4 month of Rifam monotx (existing)
R: rifam 3 mo is equal in efficacy, even less hepatotoxicity
R: rifam and rifapentine- cont regimen should be prescribed with cautionsto PLWHIV on ART
because drug-drug interactions
5. In high TB countries, PLWHIV adults and adolescence with unknown or (+) TST and TB (-) ->
36 months of IPT (existing)
36 mo is more beneficial than 6 months
This recommendation is conditional, as continuous IPT depends on the epidemiology and
transmission of TB, the health infrastructure and programme priorities.

E. Preventive Tx for Contacts of Patients with MDR TB

1. In household contact with MDR TB, preventive TB treatment is individualized (new)
Drugs used should be based on reliable information on the drug resistance profile of the
source case. Later-generation fluoroquinolones (e.g. levofloxacin and moxifloxacin) are
considered to be important components of a preventive treatment regimen unless the
strain of the source case is resistant to them -> fluoroquinolones: retardation of children
cartilage development was shown in animals
For 6, 9 and 12 months (limited evidence)
Additional

1. Drug resistance and surveillance

No association resistance to TB drugs caused by LTBI treatment, but still TB is needed to be ruled
out (and should be follow up, make sure during preventive treatment, not develop active TB)
2. Interactions with ARV
Rifam and rifapentine -> drug-drug interactions with ARV (Protease Inhibitor or nevirapine)
3. Adverse event monitoring monthly
Isoniazid (asymptomatic elevation of serum liver enzyme concentrations, peripheral neuropathy
and hepatotoxicity), rifampicin and rifapentine (cutaneous reactions, hypersensitivity reactions,
gastrointestinal intolerance and hepatotoxicity)
Individuals at risk for peripheral neuropathy, such as those with malnutrition, chronic alcohol
dependence, HIV infection, renal failure or diabetes, or who are pregnant or breastfeeding,
should receive vitamin B6 supplements when taking isoniazid-containing regimens.
4. Adherence and compliance
5. Programmatic management of LTBI to facilitate implementations of the recommendations of
the guideline

INTRODUCTION

1.1. Background
1. LTBI = persistent immune response to M. tb antigen, without TB manifestations
2. 1/3 world populationsare infected with TB with risk to develop active TB (5-10% will)
3. No gold standard for LTBI => unknown burden
4. LTBI treatment: WHO End TB strategy
5. Efficacy: 60 – 90%
6. Mass LTBI testing and treatment barriers: imperfect test, risks of serious effects, high
cost and unproven public health impact
7. For high risk people, it is clear: benefit more than harms
1.2. Rationale
1. Management of LTBI is recommended for
a. PLWHIV
b. < 5 yo contact TB in high (>= 100/100.000) or low TB incidence
1.3. Scope
1.4. Target
To be used in national TB and HIV control programmes
1.5. Development of the Guidelines
a. Guideline steering group; prepare the scope which identify questions in PICO and
systematic reviews
The following seven key questions were identified:
 1. PICO 1: Prevalence of LTBI, risk of progression to active TB and cumulative
prevalence of active TB among household contacts without HIV in different age groups
in high TB incidence countries?
2. PICO 2: What is the accuracy of WHO symptomatic screening to exclude active TB in
individuals with HIV on antiretroviral treatment (ART)?
3. PICO 3: What is the accuracy of symptomatic screening and/or chest x-ray to exclude
active TB in contacts of pulmonary TB cases without HIV in high TB incidence countries?
4. PICO 4:1 Could Interferon-gamma release assays be used as an alternative to
tuberculin skin tests to identify individuals most at risk of progression from LTBI to
active TB in high TB incidence settings?
5. PICO 5: Should 3-month daily rifampicin plus isoniazid be offered as a preventive
treatment option for children and adolescents less than 15 years of age as an
alternative to 6 or 9 months isoniazid monotherapy in high TB incidence countries?
6. PICO 6: Should 3-month weekly rifapentine and isoniazid be offered as an
alternative regimen to isoniazid monotherapy for treatment of LTBI in high TB incidence
countries?
7. PICO 7: Should preventive treatment be recommended for contacts of patients with
multidrug resistant /rifampicin resistant-TB?
b. The GDG
c. External review group

There are 10 existing, 7 updated and 7 new recommendations.

1.6. Quality of Evidence and Strength of Recommendations

Assess by GRADE method
The higher the QoE, the more likely making strong recommendations
SoR reflects the degree of confidence of GDG that the benefit outweigh risk
1.7. Publication, Implementation, Evaluation
Will be updated 5 years or earlier
1.8. Presentation of the guideline and recommendations

IDENTIFICATION OF POPULATIONS FOR TESTING AND TREATMENT OF LTBI

Implementation

1. Ethical consideration
2. Program management, monitoring and evaluation