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LTBI

THE TICKING CLOCK:

PPP MOHD AHNAF AKRAM BIN ASAHARI UKKP HRPZII

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LEARNING OBJECTIVES

To learn about the definition & diagnosis of LTBI

To learn about the investigations & algorithms of LTBI

To learn about the treatment target groups & treatment regimens of LTBI

KURSUS PENGURUSAN KLINIKAL DAN SURVELAN TB & KUSTA BERIMPAK TINGGI PERINGKAT JKWPKL&P| 25 SEPTEMBER 2025

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References

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Abbreviations

LTBI – Latent Tuberculosis Infection

TST – Tuberculin Skin Test (Mantoux Test)

IGRA- Interferon-Gamma Release Assays

TPT – Tuberculosis Preventive Treatment (formerly known as IPT – Isoniazid Preventive Treatment)

PLHIV, PLWH– People Living With HIV

CLHIV – Children Living with HIV

PLWoH – People without HIV

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Epidemiology

25% of world population is infected (1.7 billion )

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Definition :

A state of persistent immune response to stimulation by M. tuberculosis antigens with no clinical evidence of TB.

Infected people have no signs or symptoms of TB but are at risk for TB disease.

5 – 10%

When a person is infected with M tuberculosis, the infection can take 1 of a variety of paths, but many of those infected will develop adequate immunity to keep the infection at bay.

Some will acquire the infection. Those infected but remain asymptomatic are said to have Latent TB Infection (LTBI).

Because immunocompetent hosts will control the mycobacterial growth at distant foci before becoming immunosuppressed and develop active disease.

Those with compromised immune systems, such as people living with HIV, malnutrition or diabetes, or people who use tobacco, have a higher risk of reactivation of TB.

Therefore, Identification and treatment of LTBI, the reservoir for M. tuberculosis, should be an effective strategy to prevent and reduce further transmission,

morbidity and mortality of TB disease.

[CLICK] Sometimes, our clients prefer more objective evidence (%) in understanding why LTBI should be treated.

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Household or Close Contacts

Individuals who live in the same house
Share the same air space with index case
In close proximity for prolonged periods
Risk of infection :

Large bacillary load in sputum
Exposure to high aerosol from index case

Reasonable duration of time ?
Reasonable proximity ?

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People Living With HIV (PLHIV)

18 times more likely to develop TB
Leading cause of death
Annual risk of reactivation in untreated HIV : 3 – 16% per year
TPT increases survival of PLHIV who are on anti retroviral treatment

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Latent TB Infection in Children

Children less than 5 years– highest risk to progression:

Disseminated TB
CNS TB

46 studies (34 countries, 130,000 children):

19% develop active TB due to untreated LTBI.

Early investigation must be initiated for TPT

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Diagnosing LTBI

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DIAGNOSTIC CRITERIA

No symptoms to suggest active disease
Normal CXR (usually)
Negative sputum smear for AFB (if collected)
Positive TST (Mantoux Test)/IGRA

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Tests for LTBI

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Tests to confirm LTBI

There is NO gold standard test for direct identification of M. tuberculosis
All available tests are indirect

Detect immune response to mycobacterial protein antigens
May be false negative

Recommended Tests :

Tuberculin Skin Test (TST) (Mantoux Test)
Interferon-Gamma Release Assays (IGRA)

Not necessary before TPT :

PLHIV , CLHIV
Child contacts < 5 years

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TST

Mantoux test
A delayed hypersensitive reaction
Method :

Intradermal injection of 0.1ml of 5 tuberculin units of purified protein derivative solution
Reading by healthcare worker – 72 hours later

Window period – 8 to 10 weeks
False Positive :

Previous BCG Vaccination
Non-TB mycobacteria infection

False Negative:

Immunodeficient
Infants younger than 3 months

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TST Cut Off Values for Positive Reactions

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IGRA

Measures T cell release of gamma interferon following stimulation by protein antigens
Selective to M. tuberculosis
Not affected by previous BCG vaccination
2 to 3 specific antigens are utilized in IGRA, expressed in M. tuberculosis complex, but absent from all strains of BCG & majority of NTM
Because ESAT-6 & CFP-10 is not shared by BCG & most NTM, T-cells of individuals with BCG vaccination or NTM infection alone, will not be stimulated to produce interferon-γ

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IGRA

Needs accurate handling to prevent indeterminate reading
Performs better at predicting progression of LTBI to active TB.
Preferred in children :

Children > 2 years
Children < 2 years & CLHIV – controversial
Positive IGRA – LTBI
Negative IGRA – cannot exclude LTBI
Indeterminate IGRA – do not use for clinical decision

Children – IGRA specificity 95%, and NPV 99% , TST specificity 73%, NPV 99.9%

Out of the 533 children with TST-positive and IGRA-negative results but not treated for LTBI, which included 54 children <2 years old, none developed disease.

The use of IGRAs in children aged <2 years has been controversial and WHO cautions on their use in children <2 years old and children living with HIV because of concerns about the reduced sensitivity of the test. WHO, 2020b However, a study in an US-based health system including 116 children <2 years (7 to 23 months) tested with QFT-GIT, none of the children who were TST positive but IGRA negative and went untreated developed TB disease

The American Academy of Paediatrics supports the use of IGRAs in children < 2 years as it is used by some experts even the practice is not yet widespread. AAP, 2018

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Children at High Risk

Household contacts of smear positive TB

Evaluation for active TB – History, Examination, CXR, TST / IGRA.
If TST is negative – repeat after window period

Children less than 5 years

Window Prophylaxis if active TB has been ruled out
Repeat TST after 8 to 12 weeks
If repeat TST is negative – consider stopping TPT
If TST is not available – Initiate TPT

Children 5 or more years

Immunocompetent – Start TPT if LTBI confirmed
If test is negative – may wait for repeat test after window period from last contact with index case

CLHIV

Annual screening for TB
More than 12 months – TPT regardless of CD4 count
Less than 12 months - TPT ONLY if there is a close contact to a positive case

Treatment for LTBI should be initiated if there is no evidence for active TB, even in the absence

of positive TST or IGRA results. This approach is known as "window prophylaxis". ATS, 2000, level

III It is warranted because the child's cellular immune response to TB may not have fully

developed by the time of testing

All HIV-infected children should undergo annual screening for TB beginning at 3 through to 12 months of age (for perinatal infected infant) or at the time HIV infection is diagnosed (in older children and adolescents)

WHO strongly recommends LTBI treatment for children aged ≥12 months living with HIV after excluding active TB despite the inconsistent/low quality evidence in the relevant studies. This is because of the clear benefits seen in adults with HIV and the high-risk of active TB among all PLHIV including children.WHO, 2020b

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TB Preventive Treatment (TPT)�Algorithm

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PWoHIV

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PLWH

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CHILDREN

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TB Preventive Treatment (TPT)

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Why do we need to treat an asymptomatic person ?

Prevent progression to clinically active TB infection
TPT can prevent 60-90% cases from progression
Effective, Safe and Short regimes
BENEFIT must outweigh the HARM

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Treatment Regimes

Effective Regimes (local review):

Isoniazid 6 months
Isoniazid 12 – 72 months
Rifampicin / Isoniazid 3-4 months
Rifampicin / Isoniazid /Pyrazinamide
Rifampicin / Pyrazinamide

PLHIV / CLHIV on:

Protease Inhibitors
Nevirapine
Intergrase Inhibitors

Abbreviation :

H – ISONIAZID

R – RIFAMPICIN

P - RIFAPENTINE

A local technology review showed the following LTBI treatment regimens were effective compared with placebo in preventing active TB:Romli EZ et al., 2019, level I

Rifampicin has an excellent safety profile compared to isoniazid and the cost is lower than rifapentine.

One of the main challenges with 4R however may be to deal with the perception that rifampicin needs to be protected for use as a first-line TB medicine and concerns that its use in TPT may increase levels of rifampicin resistance in the community or promote misuse of the agent as monotherapy for TB disease. There is however no evidence till date demonstrating the significant increase in rifampicin resistance levels due to scale-up of TPT services.

WHO currently recommends the use of 1HP among people aged 13 years and above (this was the age limit used for the study population in the single RCT of the regimen whose results have been published to date (54)

The use of 3HR/3HP/4R [CLICK]

o is contraindicated in patients receiving protease inhibitor-based antiretroviral therapy

o requires dose adjustment of dolutegravir

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Isoniazid 100 mg

Rifampicin 300mg

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Treatment Regimes

Traditionally – Isoniazid for 6 month
Long duration, side effects

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Monitoring Clients on TPT

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Adherence to TPT – ADULTS

Adherence is required for effectiveness
Medication Adherence Counselling :

Reason for TPT
Side Effects
Red Flags
Link to care when needed.

Regular follow up

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Medication Adherence

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Adherence to TPT – CHILDREN

Breakthrough TB infection is possible in children
Frequent dose adjustment may be needed

Infants – 2 to 4 weekly
Older children – 4 to 6 weekly

Plot and monitor serial weight.

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Adherence to TPT – CHILDREN

Good quality counselling to parents to ensure completion of treatment
Parents may default appointments:

Appearance of side effects
Children refusing to take medication

Alert parents regarding red flag symptoms
If the child is exposed to a new active TB case:

Reinvestigate – Assess , TST if needed , CXR

There is NO ROLE to repeat IGRA to assess effectiveness of TPT
Baseline LFT is not required for healthy children.
Watch out for hepatitis during TPT:

Early signs : Anorexia, Nausea, Vomiting , Abdominal discomfort
Late Signs – Pale stools, dark urine, persistent fatigue, jaundice, drowsiness

Children with malnutrition, obesity, HIV, liver disease, on hepatotoxic drugs – refer to specialist for assessment and TPT.

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Adverse Drug Reactions

Most common :

Lethargy: Reassurance.

Discolouration of body secretions (urine, tears, semen and sweat) red or orange: reassurance

Rifampicin

Gastrointestinal symptoms, such as nausea, anorexia and abdominal pain, are rarely severe enough to discontinue treatment.

Hepatotoxicity, evidenced by transient asymptomatic hyperbilirubinemia, may occur in 0.6% of persons taking rifampicin. Hepatitis is more likely when rifampicin is combined with isoniazid.

Cutaneous reactions, such as pruritis (with or without a rash), may occur in about 6% of persons taking rifampicin. These are generally self-limiting and may not be true hypersensitivity. Continued treatment may be possible.

Rifamycin hypersensitivity syndrome has been reported in the past with use of rifampicin characterized by flu-like symptoms. The syndrome, when it occurs, typically develops after a few weeks from start and in most instances, TB treatment can be tolerated subsequently (96,97). Rarely, rifamycins can be associated with hypersensitivity reactions, including hypotension, nephritis or thrombocytopenia manifested by symptoms such as fever, headache, dizziness/light-headedness, musculoskeletal pain, petechiae and pruritis.

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Managing Adverse Events

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Managing Adverse Events

Drug Induced Hepatitis

Transient asymptomatic increase - 20%
Red flags : Vomiting, Mental changes, Bleeding
Withhold if :

More than 3 x ULN with symptoms
More than 5 x ULN without symptoms

Jaundice

Stop all treatment
Investigate cause
Once resolved - decision regarding rechallenging

Asymptomatic elevation of serum liver enzyme concentrations occurs in 10–20% of people taking isoniazid which usually return to normal even if treatment is continued. However, it is generally recommended that isoniazid be withheld if transaminase levels exceed three times the upper limit of normal and symptoms develop, or five times the upper limit of normal even in the absence of symptoms.

Drug-induced hepatitis

– Features that indicate the need to stop medication: Transient, asymptomatic increases in serum

liver transaminases occur during the early weeks of treatment. There is no need to interrupt or change treatment unless there is anorexia, malaise, vomiting or clinically evident jaundice. Clinical features of concern include protracted vomiting, mental changes, and signs of bleeding – all of which suggest impending acute liver failure and require immediate discontinuation of medication.

– Management of jaundice and other severe features: If jaundice or any of the clinical features suggestive of acute liver failure develop, all drugs must be stopped until jaundice or hepatic symptoms have resolved, and liver enzymes have returned to baseline levels. If liver enzymes cannot be measured, it is advisable to wait two weeks after the jaundice has disappeared before starting TPT. Other causes of hepatitis must be explored.

– Reintroduction: Once hepatitis has resolved, the same drug regimen can be reintroduced, either gradually or all at once (“rechallenge”). However, if hepatitis has been life-threatening and was unlikely to have been caused by something else (such as alcohol, viral infection), it is probably safer to switch to an alternative regimen.

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Managing Adverse Events

Skin Rash

Mild / Itching without rash : Reassurance and symptomatic treatment
Moderate or severe rash – mucosal involvement, hypotension, fever :

Withhold TPT
T. Prednisolone 40-60mg daily until resolution
Discuss for alternative regimen

Peripheral Neuropathy

Paresthesia, Numbness, Limb pain – 0.2%
Prevention : Co administer T. Pyridoxine 30 mg daily
Appearance of established peripheral neuropathy : T. Pyridoxine 100 – 200 mg daily

GI symptoms

Mild - Reassurance
Persistent – Withhold until resolution of symptoms , take medication with food

Peripheral neuropathy (paraesthesia, numbness and limb pain) occurs in less than 0.2% of people taking isoniazid at normal doses. It is more likely in the presence of other conditions associated with neuropathy, such as diabetes, malnutrition, HIV, renal failure and alcoholism. Routine pyridoxine (vitamin B6) supplementation is recommended only in such conditions or when there is other risk of isoniazid toxicity.

Gastrointestinal reactions with rifampicin (abdominal pain, nausea, vomiting): If symptoms

are mild, the episode is usually self-limiting, and reassurance may suffice. If gastrointestinal intolerance is severe enough to risk interruption of treatment, suspend rifampicin for three or four doses, use medications that provide symptomatic relief (such as metoclopramide to counteract vomiting), or as a last resort give rifampicin with small amounts of food to allow continued use of the medicine. Although concomitant ingestion of food reduces the absorption of rifampicin slightly, this is preferable to complete discontinuation of rifampicin.

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THANK YOU