Clinical guidance · NTEP
TB Preventive Treatment
Find TB infection early and treat it before it becomes disease. Who is eligible, how to test, which regimen to use, and how to follow up, as per the National TB Elimination Programme and Kerala State policy.
90%
LOWER RISK OF TB DISEASE
11.1% → 1.2%
35–40 crIndians estimated to have TB infection, the highest burden globally
26 lakhestimated to develop TB disease every year (18–36 lakh)
5–10%of those infected develop TB disease in their lifetime
12%annual decline in TB incidence from effective TPT alone
01 · TB infection
Why we need to treat TB infection
“From the pool of infected but asymptomatic persons, most cases of tuberculosis will arise.”
11.1%develop TB disease without TBI treatment
1.2%develop TB disease after TB preventive therapy
- Tuberculosis infection (TBI) is a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens, with no evidence of clinically manifest active TB.
- Most cases of TB disease arise from the pool of infected but asymptomatic people. On average, 5–10% of those infected will develop active TB disease over the course of their lives, usually within the first 5 years after initial infection.
- The risk of active TB disease after infection depends on several factors, the most important being immunological status.
- TB preventive therapy lowers the risk of developing TB disease by 90%: from 11.1% in those not taking TBI treatment to 1.2% in those who take it.
- Effective implementation of TB preventive therapy alone would bring about a 12% decline in annual TB incidence, independent of other background interventions.
Burden of TB in India
India has the highest estimated burden of TB infection globally
- Nearly 35–40 crore Indians have TB infection, of whom 26 lakh (18–36 lakh) are estimated to develop TB disease every year.
- 5–10% of those infected will develop TB disease over the course of their lives, usually within the first 2 years after initial infection.
- The risk of TB disease after infection depends on several factors, the most important being immunological status.
How much higher is the risk?
>25×
Contacts of bacteriologically confirmed TB patients, compared with the general population
16–21×
People with HIV co-infection
3–4×
Other immunocompromised states, such as diabetes
02 · The TB spectrum
From exposure to disease
People around an untreated pulmonary TB patient may remain healthy, become infected, or progress to subclinical or active TB.
Untreated pulmonary TB patient
The index patient whose contacts are at risk
The index patient whose contacts are at risk
Healthy contacts
- Not infected
TPT target
TB infected individuals
- No symptoms
- X-ray normal
- CyTB / IGRA positive
Subclinical TB
- No symptoms
- X-ray abnormal
- NAAT positive
Active TB
- Symptoms present
- TB diagnostic test results positive
TB diagnosis & treatmentSubclinical and active TB, once diagnosed and treated, return to health.
Left untreatedActive TB spreads to others in the household and community, and can be fatal.
Adapted from a World Health Organization illustration.
03 · Eligibility
Who is eligible for TPT?
Eligible groups
- All household contacts of pulmonary TB (PTB)
- All PLHIV and CLHIV above 1 year
- CLHIV below 1 year in contact with active TB
- Other risk groups
- Immunosuppressive therapy
- Silicosis
- Anti-TNF treatment
- Dialysis
- Organ transplantation
- Health care workers
Definition
Household / close contact
A person who shared the same enclosed living space as the index patient for one or more nights or for frequent or extended daytime periods during the three months before the start of current treatment.
04 · Safety
Contraindications and drug resistance
Contraindications for TPT
- Active TB disease Absolute
- Acute or chronic hepatitis
- On hepatotoxic drugs
- Regular or heavy alcohol consumption
- Peripheral neuropathy
- Allergy to any drug in the regimen
Not a contraindication for TPT: pregnancy, past history of TB, or renal disease.
Does TPT lead to drug resistance?
- There is no evidence of a significant association between the development of resistance to H or R and the use of these drugs for TPT.
- TB disease must be ruled out before TPT is initiated.
- Regular follow-up to rule out development of active TB disease.
- Rapid molecular DST must be offered to all patients if TB disease is detected before, during or any time after TPT.
05 · Step by step
The cascade of TPT
Every person offered TPT moves through the same seven steps.
- Contact tracing
- Screening & ruling out active TB
- Counselling for TPT
- Testing for IGRA / CyTBIGRA ≥5 yrs · CyTB ≥18 yrs
- Initiate TPT
- Follow up
- Documentation
06 · Before starting
Rule out active TB
Active TB must be ruled out in every person before initiating TBI treatment.
History & clinical examination
The starting point for every person being considered for TPT.
Chest X-ray
A chest X-ray shall be taken to rule out active TB. If the CXR shows any abnormality, the child shall be further evaluated for TB according to the national guideline.
Lymph nodes & EP TB
Clinical examination for lymph nodes, and a thorough history for signs and symptoms of extrapulmonary TB.
District clinical committee
A clinical committee is constituted at district level to take decisions on doubtful cases.
07 · Counselling
Initial counselling
Before starting TPT, the person and family should understand:
- The rationale for TBI management and its benefits to the individual, the household and the community
- That TBI management is available free of charge through national programmes
- The TBI management regimen prescribed, including duration, directions for taking the medicines and the follow-up schedule
- Potential side effects and adverse events, and what to do if they occur
- The importance of completing the full course of TBI management
- The reasons for, and schedule of, regular clinical and laboratory follow-up for treatment monitoring
- The signs and symptoms of TB, and what to do if symptoms of TB develop
An informed choice
People should not feel forced to take treatment.
They have the right to make an informed decision not to take treatment, or to stop it.
But our success is when they decide to take the drugs, complete the course and undergo regular follow-up.
08 · Testing
Tests for TB infection
Two tests are currently recommended and available for TBI. Both measure immune sensitisation (type IV, delayed-type hypersensitivity) to mycobacterial protein antigens that occurs following infection by M. tuberculosis.
Cy-TB skin test
18 years and olderAn intradermal skin test that is read as induration at the injection site. Details below.
Interferon-Gamma Release Assay (IGRA): blood test
5 years and olderIGRAs measure the amount of interferon-gamma released in vitro by white blood cells when mixed with M. tuberculosis antigens, or the number of T-lymphocytes producing interferon-gamma.
Testing is not required before TPT for household contacts aged below 5 years, or for people living with HIV.
09 · Cy-TB
Cy-TB: the next-generation skin test
Cy-TB is the next-generation skin test for detection of tuberculosis infection.
Background
- First manufactured at Statens Serum Institute, Denmark.
- Composed of recombinant versions of two M. tuberculosis-derived antigens, ESAT-6 and CFP-10, cloned and expressed in Lactococcus lactis.
- Currently approved in India for 18 years and older.
Why Cy-TB?
- Easy to use (simple)
- Point-of-care (in the field)
- Specific (based on the ESAT-6 and CFP-10 antigens of M. tb)
Product details
Composition
- rdESAT-6 and rCFP-10 (Cy-Tb) injection
- 1 vial = 10 doses
- One test dose (0.1 mL) contains rdESAT-6 0.05 µg and rCFP-10 0.05 µg
Pharmaceutical form
- Solution for injection
- Clear, colourless to yellow solution
Shelf life
- Unopened vial: 18 months
- After first opening, the vial can be used for up to 28 days, provided it is stored at 2°C – 8°C
Storage
- Store in a refrigerator (+2°C to +8°C)
- Do not freeze
- Store in the original package to protect from light
Method of administration
- PrepareDraw 0.1 mL of Cy-Tb into a 1 mL syringe with a short-bevel 26-gauge needle.
- SiteInject in the middle third of the forearm.
- TechniqueGive as an intradermal injection using the Mantoux technique.
- InsertStretch the skin slightly and hold the needle almost parallel to the skin surface with the bevel upwards. Insert the tip into the superficial layer of the dermis; the needle should be visible through the epidermis.
- Inject slowlyInject the 0.1 mL slowly. A small blanched papule of 8–10 mm diameter will appear, and should disappear after about 10 minutes.
- No papule?Repeat the injection on the other arm, or on the same arm at least 4 cm away from the first injection site.
Evaluating the reaction
≥5 mmPositive
- Intradermal Cy-Tb may induce an induration at the injection site: a raised area with a clearly defined margin at and around the site. Erythema may accompany it, but only the induration should be measured.
- Measure the induration 48–72 hours after the injection. Measure its largest diameter with a ruler; a flexible (easily bendable) ruler makes this easier.
- Interpretation: an induration of ≥5 mm is a positive result, indicating infection with Mycobacterium tuberculosis.
- Normally, the induration and erythema decrease after 4 days and disappear within 28 days of the injection.
10 · Regimens
TPT regimens: State policy
| Category | Regimen | IGRA / Cy-TB |
|---|---|---|
| PLHIV <13 years | 6H (daily) | Not required |
| PLHIV >13 years | 1HP (daily) | Not required |
| Household contacts <5 years | 3HR (daily) | Not required |
| Household contacts 5–15 years | 3HR (daily) | Required |
| Household contacts >15 years | 3HP (weekly) | Required |
| Other risk groups | 3HP / 6H | Required |
Revised guidance on TPT for people living with HIV
| # | PLHIV category | Preferred TPT regimen | Remarks |
|---|---|---|---|
| 1 | PLHIV 13 years of age and older | INH & rifapentine daily for 28 days (1HP) | Dose modification of dolutegravir is not required with 1HP |
| 2 | PLHIV less than 13 years of age | INH daily for six months (6H) | — |
| 3 | Pregnant & breastfeeding women living with HIV | INH daily for six months (6H) | — |
| 4 | PLHIV on protease inhibitor (PI) based ARV regimens | INH daily for six months (6H) | The “-navir”, “-previr” and “-trelvir” group of drugs |
11 · Dosage
Regimen dosages by age and weight
3HR: three months of daily rifampicin and isoniazid
Isoniazid (H)
- Age 10 years & older: 5 mg/kg/dayd
- Age below 10 years: 10 mg/kg/day (range 7–15 mg/kg)
Rifampicin (R)
- Age 10 years & older: 10 mg/kg/day
- Age below 10 years: 15 mg/kg/day (range 10–20 mg/kg)
| Weight band | 4–7 kg | 8–11 kg | 12–15 kg | 16–24 kg | ≥25 kg |
|---|---|---|---|---|---|
| RH 75/50 mg (FDC) | 1 | 2 | 3 | 4 | Use adult formulation |
- d Maximum dose of H, if given daily, would be 300 mg/day.
6H: six months of daily isoniazid monotherapy
- Age 10 years & older: 5 mg/kg/dayd
- Age below 10 years: 10 mg/kg/day (range 7–15 mg/kg)
3HP: three months of weekly rifapentine plus isoniazid (12 doses)
| Age 2–14 yearsc | |||||
|---|---|---|---|---|---|
| Medicine, formulation | 10–15 kg | 16–23 kg | 24–30 kg | 31–34 kg | >34 kg |
| Isoniazid, 100 mga | 3 | 5 | 6 | 7 | 7 |
| Rifapentine, 150 mg | 2 | 3 | 4 | 5 | 5 |
| Isoniazid + rifapentine FDC (150 mg/150 mg)b | 2 | 3 | 4 | 5 | 5 |
| Age >14 yearsc | |||||
| Medicine, formulation | 30–35 kg | 36–45 kg | 46–55 kg | 56–70 kg | >70 kg |
| Isoniazid, 300 mg | 3 | 3 | 3 | 3 | 3 |
| Rifapentine, 150 mg | 6 | 6 | 6 | 6 | 6 |
| Isoniazid + rifapentine FDC (300 mg/300 mg)b | 3 | 3 | 3 | 3 | 3 |
- a The 300 mg formulation can be used to reduce the pill burden.
- b Expected to become available in the near future.
- c Dosage may differ among adults and children in overlapping weight bands.
- d Maximum dose of H, if given daily, would be 300 mg/day.
Source: TPT regimen options and recommended dosages of medicines (Table 5.1, national TPT guidelines).
12 · Supportive care
Role of pyridoxine and its availability
Peripheral neuropathy
- Secondary to deficiency of vitamin B6 (pyridoxine).
- Common during TB treatment; infrequent with standard doses of H for TPT.
- Recognised as symmetrical numbness and tingling of the extremities.
- Usually easily reversible on withdrawing H and giving high-dose pyridoxine at a therapeutic dose of 100–200 mg/day.
Prophylactic dose of pyridoxine
10 mg/day
Children
25 mg/day
Adults
50 mg/day
Adult PLHIV
Recommended groups for pyridoxine prophylaxis on an isoniazid-based regimen
- Malnutrition
- Chronic alcohol dependence
- HIV infection
- Renal failure
- Diabetes
- Pregnant or breastfeeding
TPT should not be withheld if pyridoxine is not available. Multivitamin / B-complex formulations with the required prophylactic dose of pyridoxine, available in the general health system, may be considered instead.
If pyridoxine, multivitamins or B-complex are in short supply, restrict them to those at highest risk, such as the severely malnourished and people with problem alcohol use. Close monitoring for peripheral neuropathy during treatment is important so that treatment can be started early.
13 · During treatment
Monthly clinical follow-up
Everyone on TBI treatment should be seen by a Medical Officer at least once a month, looking for:
Signs & symptoms of TB disease
Adverse reactions
Especially symptoms and signs of hepatitis.
Adherence to the regimen
Find out the reasons for any missed dose and extend the support needed for future adherence.
Management of missed doses: 3HP
| Duration of interruption | Management steps |
|---|---|
| Up to 3 weekly doses missed |
|
| More than 3 weekly doses missed |
|
Management of missed doses: 6H, 6Lfx or 4R
| Duration of interruption | Management steps |
|---|---|
| Less than 2 weeks |
|
| More than 2 weeks |
|
14 · Outcomes
Treatment outcomes
A number of endpoints are proposed that could be used to trigger a review of persons on TPT and, in some instances, changes to treatment.
| Regimen | Total duration (months) | Expected number of doses | 80% of recommended doses (days) | Extended time for completion (days) treatment duration + 33% |
|---|---|---|---|---|
| 6H (daily) | 6 | 180 | 144 | 239 |
| 3HP (weekly) | 3 | 12 | 11* | 120 |
| 6Lfx (daily) | 6 | 180 | 144 | 239 |
| 4R (daily) | 4 | 120 | 96 | 160 |
| 1HP (daily) | 1 | 28 | 23 | 40 |
- * 90% of the recommended number of doses.
Outcome definitions
Treatment completed
A person initiated on TPT who consumed at least:
- 3HP: 90% of recommended doses (11/12) within 133% of the planned duration (120 days)
- 1HP: 80% of recommended doses (23/28) within 133% of the planned duration (40 days)
- 3RH: 80% of recommended doses (68/84) within 120% of the planned duration (100 days)
Treatment failed
A person initiated on TPT who developed active TB disease at any time while on the TPT course.
Died
A person initiated on TPT who died for any reason while on the TPT course.
Lost to follow-up
TPT interrupted by the person for:
- 4 consecutive weeks (1 month) or more for 3HP or 4R
- 10 consecutive days for 1HP
- 8 consecutive weeks (2 months) or more for 6H or 6Lfx
TPT discontinued due to toxicity
A person whose TPT is permanently discontinued by the doctor due to adverse events or drug–drug interactions.
Not evaluated
For example, records lost, or transfer to another health facility without a record of TPT completion.
15 · After treatment
Long-term follow-up
Follow-up continues at 6, 12, 18 and 24 months.
6m6 months
12m12 months
18m18 months
24m24 months
- All household contacts of pulmonary TB shall be followed up by the primary health care team, looking for development of active symptoms of TB.
- The same vigil shall continue for everyone diagnosed with TBI, even after they complete treatment.
- If anyone initiated on TPT later develops TB, tests for resistance to INH and rifampicin shall be offered at baseline if a biological specimen is available.
16 · Drug-resistant TB
TPT for contacts of DR-TB patients
6Lfx
Six months of daily levofloxacin
For contacts of rifampicin-resistant, fluoroquinolone-sensitive patients.#
- Age >14 years, by body weight: <45 kg, 750 mg/day; ≥45 kg, 1 g/day
- Age <15 years (approx. 15–20 mg/kg/day), by body weight:
- 5–9 kg: 150 mg/day
- 10–15 kg: 200–300 mg/day
- 16–23 kg: 300–400 mg/day
- 24–34 kg: 500–750 mg/day
4R
Four months of daily rifampicin
For contacts of isoniazid-resistant, rifampicin-sensitive patients.*
- Age 10 years & older: 10 mg/kg/day@
- Age below 10 years: 15 mg/kg/day (range 10–20 mg/kg)
- # Levofloxacin 100 mg dispersible tablets are available for children. Children receiving 6Lfx should be watched for joint abnormalities.
- * In children aged 0–14 years, 4R should only be used after ruling out active TB, in limited geographies/populations, for evidence generation to guide future country-wide scale-up.
- @ Maximum dose of R would be 600 mg/day.
Note: 6H can be considered as the TPT option for contacts of index patients with RR-TB that is FQ- and H-sensitive, after ruling out active TB in them.
Criteria for completion of TPT among DR-TB contacts
- The efficacy of TPT is greatest if at least 80% of doses are taken within the duration of the regimen.
- The total number of doses taken is also a key determinant of the extent of TB prevention.
| Regimen | Duration (months) | Expected doses | 80% of doses (days) | Extended time (days) duration + 33% |
|---|---|---|---|---|
| 6Lfx (daily) | 6 | 180 | 144 | 239 |
| 4R (daily) | 4 | 120 | 96 | 160 |
Abbreviations used on this page
- TPT
- TB preventive treatment
- TBI
- TB infection
- PTB
- Pulmonary TB
- EP TB
- Extrapulmonary TB
- HHC
- Household contacts
- PLHIV
- People living with HIV
- CLHIV
- Children living with HIV
- IGRA
- Interferon-gamma release assay
- NAAT
- Nucleic acid amplification test
- DST
- Drug susceptibility testing
- FDC
- Fixed-dose combination
- DR / RR-TB
- Drug-resistant / rifampicin-resistant TB
- H · INH
- Isoniazid
- R
- Rifampicin
- P
- Rifapentine
- Lfx · FQ
- Levofloxacin · fluoroquinolone
Prevention is elimination
Every contact protected is a case prevented.
TB preventive treatment is available free of charge through the National TB Elimination Programme. Explore our guidelines or reach out to the Coalition.
Content adapted from National TB Elimination Programme (NTEP) training material on TB Preventive Treatment and Kerala State policy. Intended for healthcare professionals; always refer to the latest national guidelines.