REVISED NATIONAL TUBERCULOSIS CONTROL PROGRAME DAILY REGIMEN

REVISED NATIONAL TUBERCULOSIS CONTROL PROGRAME DAILY REGIMEN

1. RNTCP Daily Regimen
Dr. Satyadeo Choubey, M.D
Assistant Professor
Respiratory Medicine
MGM Medical College, Indore

2. Goal of TB Treatment

•Decrease case fatality & morbidity by ensuring
relapse free cure
•Minimize & prevent development of drug
resistance
•Render patient non-infectious, break the chain
of transmission and decrease pool of infection

3. Contribution of India to annual
notification among High Burden
Countries
New Smear positives Relapse
30%
70%
India
Other HBCs
50%
50%
Very high relapse notification in India

Continued transmission

4. Summary of evidences
•Relapse rates
–Relapse rates are high – more than many high burden
countries, over a period time, in all states
–Relapse rates high with treatment interruption but not
significantly different in patients without treatment
interruption
–Relapse rates are high among NSP TB patients in area with
no private sector presence
–Relapse rates are higher with intermittent regimen
•INH resistance
–Pre-treatment INH resistance is high (>10%)
–pre-treatment INH resistance lead to amplification of
resistance (acquired rifampicin resistance), leading to MDR

5. RNTCP regimen & body weight of Indian patients
•Current RNTCP regimens for adults
< 30 kg
30-60 kg
> 60 kg
•Dose of INH is inappropriately high for those in
the band of 30-40 kg. ( ~ 45% in our cohort)
•Drug toxicity related to INH in underweight
patients is possibly one of the reasons for adverse
effects and default.

6. Presumptive TB cases
Old guideline
•An individual having cough
for 2 weeks or more
•Contacts of smear-positive
TB patients having cough for
any duration
•Suspected/confirmed extra-
pulmonary TB having cough
for any duration
•HIV-positive patient having
cough for any duration.

New Guideline
•Cough >2 weeks,
•Fever >2 weeks,
•Significant weight loss,
•Haemoptysis,
•Any abnormalities in chest
radiography.

7. Presumptive DRTB cases
•TB patients who have failed treatment with first-
line anti-tubercular drugs (ATD)
•Paediatric TB non-responder
•TB patients who are contacts of DRTB
•TB patients who are found positive on any follow-
up sputum smear examination during treatment
with first-line ATD
•Previously treated TB cases
•TB patients with HIV co-infection.

10. Case definition: There are significant changes in the definition of cases
as per New Guidelines:
• Microbiologically confirmed TB case refers to a presumptive TB
patient with biological specimen positive for acid-fast bacilli, or
positive for mycobacterium TB on culture, or positive for TB
through Quality Assured Rapid Diagnostic molecular test.
•Clinically diagnosed TB case refers to a presumptive TB patient who
is not microbiologically confirmed, but has been diagnosed with
active TB by a clinician on the basis of X-ray abnormalities,
histopathology or clinical signs with a decision to treat the patient
with a full course of anti-TB treatment.


Microbiologically confirmed or clinically diagnosed cases of TB are
classified according to

Anatomical site of disease
•History of previous TB
•Drug resistance.

11. Classification on the basis of history of the previous
treatment
New case – A TB patient who has never had treatment for TB or has taken ATT for <1
month. (No change in new guidelines.)
•Previously treated patients have received one month or more ATD in the past. This may
be:
–Recurrent TB case – A TB patient previously declared as successfully treated (cured/treatment
completed) and who is subsequently found to be microbiologically confirmed TB case is a
recurrent TB case. (Previously called relapse.)
–Treatment after failure – Patients are those who have previously been treated for TB and
whose treatment failed at the end of their most recent course of treatment.
•Previously, it was called failure where a TB patient is sputum-positive at 5 months or
more after initiation of treatment.
Treatment after loss to follow-up – A TB patient previously treated for TB for one month
or more and who was declared lost to follow-up in their most recent course of
treatment and subsequently found microbiologically confirmed TB cases.
Previously called treatment after default – a patient who has received treatment for TB for
a month or more from any source and return for treatment after having defaulted, that
is, not taking ATD consecutively for 2 months or more and found to have smear-positive.

12. Classification done on the basis of drug resistance
•Mono resistance (MR) – A TB patient whose biological specimen is
resistant to one first-line anti-TB drug only.
•Poly resistance (PDR) – A TB patient whose biological specimen is
resistant to more than one first-line anti-TB drug, other than both INH
and Rifampicin.
•Multi-drug resistance (MDR) – A TB patient whose biological specimen is
resistant to both INH and Rifampicin with or without resistance other
first-line ATD, based on results from a Quality Assured Laboratory. (No
changes.)
•Rifampicin resistance (RR) – Resistance to Rifampicin detected by
phenotypic or genotypic methods with or without resistant to other ATD
excluding INH. Patient with RR should be managed as if they are in MDR
TB case.
•Extensive drug resistance (XDR) – MDR TB case whose biological
specimen was resistant to a Fluroquinolone (FQ) and a second-line
injectable ATD from a Quality Assured Laboratory. (No changes.)

13. •Drug regimen in the new guidelines:
Principle of treatment of TB has been shifted towards daily regimen
with administration of daily fixed dose combination of first-line ATT as
per appropriate weight bands.
For new TB cases
Treatment in IP will consist of 8 weeks HRZE in daily dosages as per
four weight bands categories
•There will be no need for extension of IP
•Only Z will be stopped in CP while the other three drugs will be
continued for another 16 weeks as daily dosages.
For previously treated cases:
IP will be of 12 weeks, where injection Streptomycin will be stopped
after 8 weeks and the remaining four drugs in daily dosages as per
weight band for another 4 weeks
•No need of extension of IP
•At the start of CP, Pyrazinamide will be stopped while rest of the drugs
will be continued for another 20 weeks as daily dosages.
•

16. •Management of extra-pulmonary TB (new guidelines) –
There is only one change as follows:

The CP in both new and previously treated cases may
be extended 3–6 months in certain TB such as CNS,
skeletal, disseminated TB, and so on based on clinical
decision of the treating physicians
•Extension beyond 3 months will only be on
recommendation of experts of concerned field.(In the
previous guidelines, extension of ATD in case of CNS
and skeletal TB was maximum 3 months).

17. In patients above 50 years of age, maximum dose of Streptomycin should be 0.75 g.

19. Follow up
•Follow-up of treatment: There are some changes in the new guidelines:

Clinical follow-up – (new addition)
Should be at least monthly – the patient may visit the clinical facility, or the medical officer may
conduct the review when she/he visits the house of the patient to observe improvement of chest
symptoms, weight gain, control the co-morbid conditions such as HIV and diabetes and to monitor
any adverse reaction to ATD.

Follow-up laboratory investigation
For PTB cases – sputum smear examination at the end of IP and at the end of treatment. (In the
previous guidelines, follow-up sputum smear to be done at 2, 4 and 6 months for new cases and 3,
5 and 8 months in previously treated cases.)

In case of clinical deterioration, the Medical Office may consider repeat sputum smear even during
CP. (New addition.)
•At the completion of treatment, sputum smear and culture should be done for every patient
•CXR – to be offered whenever required and available.
•
Long-term follow-up

After completion of treatment, the patient should be followed up at the end of 6, 12, 18 and 24
months. Any clinical symptoms and/or cough, sputum microscopy and/or culture should be
considered. (New addition) However, there was no provision of long-term follow-up in the previous
guidelines.

21. Treatment outcomes
Cured
A microbiologically confirmed TB at the beginning of the treatment who was
smear- or culture-negative at the end of complete treatment. (Changed).
Treatment success
TB patients either cured or treatment completed are accounted in the treatment
success. (New addition).
Failure
A TB patient whose biological specimen is positive by smear or culture at the end
of the treatment. (Changed).
Failure to respond
For paediatric TB patients. (New addition).
Lost to follow-up
A TB patient whose treatment was interrupted for one consecutive month or
more. (New addition).
Not evaluated
A TB patient for whom no treatment outcome is assigned. (Former transfer out).
Treatment regimen changed

Previously, it was called as switched over to MDR treatment.

23. Isoniazid Preventive Therapy (IPT) for PLHIVs

•Adult and adolescents living with HIV should be screened for TB and those
who are unlikely to have active TB should be offered IPT
•Children with HIV who have no TB symptoms and who are unlikely to have
active TB on symptom-based screening should be offered IPT regardless of
their age
•All children with HIV who have successfully completed treatment for TB
disease should receive IPT.


Dosage of INH preventive therapy:

Adult and adolescent: INH 300 mg + Pyridoxine 50 mg per day for 6
months.

Children above 12 months: INH 10 mg/kg + Pyridoxine 25 mg per day for 6
months.

24. DRTB
•MDR/RR TB cases (without additional resistance)

Treatment regimen for MDR TB contains 6–9 months of
IP with Kanamycin, Levofoxacin, Ethambutol,
Pyrazinamide, Ethionamide and Cycloserine and 18
months of CP with Levofoxacin, Ethambutol,
Ethionamide and Cycloserine (no change).

But if INH resistance is not known or DST result shows
sensitivity to INH, then addition of INH in the above-
mentioned regimen of ATD is to be done. (New
addition)

25. •All MDR TB cases would be subjected to LC and DST at baseline for
Kanamycin and Levofloxacin.
•Appropriate modification of the treatment regimen can be done in
case of additional resistance.

If isoniazid resistance is found, the use of isoniazid depends on:

If high-level resistance detected by liquid culture – omit INH.
•If low-level resistance detected by LC – add high dose INH.
•If LPA reports INH resistance by Kat G mutation – omit INH.
•If LPA reports INH resistance by INH A mutation – add high dose
INH.

26. •There are some new additions

If RR by CBNAAT, then add INH in the standard dose till result of LPA or LC
and DST.
•For new patients diagnosed as TB and RR by CBNAAT – repeat CBNAAT and
send the sample for liquid culture
–If second CBNAAT shows RR then start standard MDR till result for culture DST
available. Perform DST to INH and SLDST on liquid culture.
–If second CBNAAT shows R sensitiveness, continue regimen for new TB cases
and wait for LC and DST. As soon as LC result is available, modify the regimen
as follows:
•If LC shows R sensitiveness – continue regimen for new TB cases
•If LC shows R resistance – refer the patients to DRTB centre for decision regarding
starting MDR or continuing regimen for new TB cases depending on the response to
treatment given so far.
•For mixed resistance pattern, consider oral drug in the sequence of
preference – Pyrazanamide, Ethambutol, Ethionamide, Cycloserine, PAS,
Clofazimine, Linezolide, Coamoxyclave, high dose INH, Clarythromycin
•Regimen designing or modification will be prerogative of the DRTB centre
committee only.

28. Follow up MDR/RR
Schedule for sputum culture examination for MDR TB (no change):

29. • For mono DR and poly DRTB patients –

Schedule for sputum culture examination:

Microbiological: Sputum smear and culture at second and third months and then culture
examination at three monthly interval till completion of the treatment.

For mono/poly DRTB patients –
–IP should given for at least 3 months
–After this, the patient will be reviewed
–If after the 3 months the smear result remains positive, the sputum sample is sent for genotypic DST
to Rifampicin for CBNAAT or LPA and liquid/solid culture and DST to see for resistance amplification
–Shifting from IP to CP will be based on the result of culture
–The IP can be extended maximum 3 months
–Duration of CP is 6 months
•

MDR TB patients with additional drugs resistance including XDR TB patients

Change from IP to CP will be done after achievement of culture conversion, that is, two
consecutive negative cultures taken at least one month apart
•In case of delay in culture conversion, IP can be extended from 6 months to maximum 12
months.
•

30. Outcome for RR/MDR and/or XDR TB patients (new guidelines)

Cure – Treatment completed as recommended by the National Policy without evidence of failure and three or
more consecutive cultures taken at least 30 days apart are negative after IP
Treatment completed – Treatment completed as recommended by the National Policy without evidence of failure but
no record that three or more consecutive cultures taken at least 30 days apart are negative after IP
Treatment success – The sum of cured and treatment completed
Treatment failed – Treatment terminated or need for permanent regimen change of at least two or more ATD in CP
because of lack of microbiological conversion by the end of IP or microbiological reversion in the CP after
conversion to negative or evidence of additional acquired resistance FQ or second-line injectable drugs, or
adverse drug reaction.


Outcomes for mono/poly drug-resistant TB patient
Cure – A microbiologically confirmed TB at the beginning of treatment who was culture-negative in the last month of
treatment and on at least one previous occasion
Treatment completed – A patient who has completed treatment according to the guidelines but does not meet the
definition for cure or treatment failure due to lack of microbiological results
Failure – Treatment terminated or need for permanent regimen change of at least two or more anti-TB drugs in CP
because of:
Evidence of additional acquired resistance to Rifampicin, Rluroquinolone or second-line injectable during treatment
Severe ADR
Culture-positive during CP or at end of treatment
Died – A patient who dies for any reason during the course of M/X DRTB treatment
Loss to follow-up – A patient whose treatment was interrupted for one month or more for any reasons
Not evaluated – A DRTB patient for whom no treatment outcome is assigned, and this included former ‘transfer out’.
•

31. Side effects of first line drugs
Drug Main effects Rare effects
Isoniazid Peripheral neuropathy
Skin rash
Hepatitis
Sleepiness and lethargy
Convulsions
Psychosis
Arthralgia
Anaemia
Rifampicin Gastrointestinal: abdominal
pain, nausea, vomiting
Hepatitis
Generalised cutaneous
reactions
Thrombocytopenic purpura
Osteomalacia
Pseudomemberanous colitis
Pseudoadrenal crisis
Acute renal failure
Haemolytic anaemia
Pyrazinamide Arthralgia
Hepatitis
Gastrointestinal
Cutaneous reactions
Sideroblastic anaemia
Ethambutol Retrobulbar neuritis Generalised cutaneous
reactions
Arthralgia
Peripheral neuropathy
Hepatitis (very rare)

32. Side effects of second line drugs
Drugs Side effects
Injectables – Kanamycin /
Capreomycin
Ototoxicity (6,7)
Nephrotoxicity
Vertigo
Electrolyte imbalance
Quinolones – Ofloxacin,
Levofloxicin, Moxifloxacin
Gastro Intestinal symptoms: diarrhoea, vomiting, and abdominal pain
Central nervous system (CNS): dizziness and convulsions
Phototoxicity and photosensitivity
Tendinopathy and tendinitis
Skin rash
Cardiotoxicity – QT prolongation
Arthralgia
Ethionamide Gastro-intestinal: epigastric discomfort, anorexia, nausea, metallic taste,
vomiting,
excessive salivation, and sulfurous belching
Psychiatric: hallucination and depression
Hepatitis
Hypothyroidism and goitre with prolonged administration
Gynaecomastia, menstrual disturbances, impotence, acne, headache, and
peripheral
neuropathy
Cycloserine CNS: dizziness, slurred speech, convulsions, headache, tremor, and
insomnia
Psychiatric: confusion, depression, altered behaviour, and suicidal tendency
Hypersensitivity reaction
PAS Gastro-intestinal: anorexia, nausea, vomiting, and abdominal discomfort
Skin rash
Hepatic dysfunction
Hypokalemia
Hypothyroidism and goitre with prolonged administration

33. Warning symptoms for some serious
adverse reactions
Warning Symptoms For Medical officer / General practitioner (GP):
When to refer the patient
Rash
Skin lesions on oral cavity, nose
If mucous membranes are involved OR rash is more than 1/10
th

of body surface area without mucous membrane involvement
OR associated with fever and generalized swelling (edema); refer
to specialist / tertiary care center immediately.
Pain in eye/s, Blurring of vision and
Disturbance in color vision
Indicates Eye toxicity.
Refer the patient to specialist for evaluation.
Loss of hearing / Diminished hearing,
Ringing in the ears, Dizziness and Loss of
balance
Indicates Ear toxicity.
Refer the patient to specialist for evaluation.
Puffiness of face, Swelling over feet and
Oliguria, Anuria
Indicates Kidney toxicity.
Treat the symptoms and refer the patient to specialist for
evaluation.
Hallucinations, Seeing abnormal things and
Suicidal or abnormal thoughts or actions
Indicates Psychiatric disturbances.
Refer the patient to specialist for evaluation.

34. Absolute contraindications of anti-TB drugs:( Benefit – Risk)
Drug Absolute contraindications Reason
Rifampicin With Saquinavir and Ritonavir

Potential for hepatotoxicity is increased. Rifampicin
is CYP3A4 inducer and can decrease Saquinavir
level and effect
Ethambutol Optic neuritis Ethambutol can cause optic neuritis
Pyrazinamide Acute porphyria
Gouty arthritis
Hepatic diseases
Pyrazinamide can precipitate acute porphyria
Can inhibit excretion of urates
Can cause drug induced hepatitis
Neomycin Kanamycin,
Tobramycin, Amikacin,
Capreomycin,
Streptomycin
Concurrent use of two aminoglycosides
With potent diuretics e.g. Furosemide
Soon after use of anesthetics and muscle relaxants
Can potentiate nephrotoxicity
Can potentiate ototoxicity
Can result in respiratory paralysis
Levofloxacin, Ofloxacin,
Moxifloxacin
History of tendon disorders Associated with risk of tendinitis and tendon
rupture

Ethionamide Severe hepatic impairment Risk of worsening
Cycloserine

Epilepsy,
Psychiatric illness - Depression, Severe anxiety,
Psychosis
Severe renal insufficiency
Can precipitate seizures
Can lead to severe psychosis and depression
Can lead to Cycloserine toxicity
Clarithromycin

With Pimozide, Astemizole
With Lovastatin or Simvastatin
Hypokalemia and in patients with prolonged QT
interval
Risk of QT prolongation
Can cause rhabdomyolysis
Risk of further QT prolongation
Imipenem With Valproic acid and Probenecid Decrease in valproic acid concentration and
Increase in plasma levels of imipenem
Linezolid

With Monoamine oxidases A or B inhibitors (e.g.
phenelzine, isocarboxazid, selegiline, moclobemide)
within two weeks
Risk of MAO inhibition leading to serotonin
syndrome

35. Algorithm for reintroduction of anti-TB drugs
Adverse drug reaction Advice on reintroduction
Hepatotoxicity  Reintroduction after liver enzyme returns to ≤ 2 X ULN
Ocular toxicity  Main suspect drug is EMB
 Reintroduction of Ethambutol is not recommended
Immune mediated Nephritis  Main suspect drug is RIF
 Reintroduction with RIF is not recommended
Non serious cutaneous ADRs - no mucous
membrane involvement or less than 10 % of
BSA.
 After withholding all drugs reintroduce one drug at a time
Serious Cutaneous adverse drug reactions -
mucous membrane involvement or more than
10 % of BSA.
 Reintroduction is not recommended (applies for all anti-TB
drugs).
Immune thrombocytopenia  Main suspect drug is RIF
 Reintroduction with RIF is not recommended
Gynecomastia  Symptoms takes long time to resolve (4-12 month) hence usually
reintroduction is not required.
Aplastic Anemia  Main suspect drug is INH
 Reintroduction with INH is not recommended
Nephrotoxicity  Main suspect drugs are AGs.
 AGs can be reintroduced at low doses after the renal function
returns to normal.
Ototoxicity  Main suspect drugs are AGs.
 Reintroduction of AGs is not recommended.
Cardiac arrhythmias including Torse de
pointes (TdP)
 Main suspect drugs are FQs.
 Reintroduction with FQs is not recommended.
Diarrhea  Reintroduction is recommended with one drug at a time every
fourth day, once diarrhea is resolved
Seizures  Main suspect drugs are FQs.
 Reintroduction with FQs is not recommended.
Psychosis  Main suspect drugs is cycloserine.
 Reintroduction with cycloserine can be done at low dose but if
symptoms recur than completely discontinue the drug.

36. Stepwise increase in the dosage for Reintroduction
Drug Day 1 Day 2 Day 3
Isoniazid 50 mg Full dose Full dose
Rifampicin 75 mg 300 mg Full dose
Pyrazinamide 250 mg 1000 mg Full dose
Ethionamide /
Prothionamide
125 mg 250 mg Full dose
Fluoroquinolones 50 mg 200 – 250 mg Full dose
Cyclosporine 125 mg 250 mg Full dose
Ethambutol 100 mg 500 mg Full dose
PAS 1 g 4 g Full dose
Capreomycin 125 mg 500 mg Full dose
Kanamycin 125 mg 500 mg Full dose
Amikacin 125 mg 500 mg Full dose

37. Commonly used ancillary medicines
Indication Drugs
Nausea, vomiting, Stomach upset Domeperidone, metoclopramide, prochlorperazine, promethazine, ondansetron
Heartburn, indigestion and acidity H2-blockers (ranitidine etc.), proton pump inhibitors (omeprazole, pantoprazole etc)
Antacid syrups and the antacids if prescribed should be taken at least 2 hours apart from anti-TB
drugs
Oral candidiasis Fluconazole, clotrimazole lozenges, nystatin suspension
Diarrhoea ORS sachets
Prophylaxis of neurological complications of
cycloserine and isoniazid
Pyridoxine (vitamin B6)
Musculoskeletal pain,
Arthralgia, headaches
Give paracetamol / ibuprofen / aspirin / diclofenac.
If caused by fluoroquinolones, refer to specialist immediately. Tendonitis can progress to tendon
rupture.
Cutaneous reactions, itching Hydrocortisone cream, calamine lotion
Systemic hypersensitivity
Reactions
Antihistamines (diphenhydramine, chlorpheniramine, dimenhydrinate)
Systemic corticosteroids (prednisone, prednisolone, Dexamethasone) are reserved only for very
severe reactions
Bronchospasm Inhaled beta-agonists (salbutamol, albuterol, etc.), inhaled corticosteroids (beclomethasone, etc.)
Hypothyroidism Levothyroxine
Electrolyte wasting Potassium and magnesium replacement therapy (oral formulations)
Depression Selective serotonin reuptake inhibitors (fluoxetine, sertraline), tricyclic antidepressants
(amitriptyline)
Severe anxiety Lorazepam, diazepam, clonazepam
Insomnia Any hypnotic
Psychosis Haloperidol, thorazine, risperidone (consider benzotropine or biperiden to prevent
extrapyramidal Effects), Buromazine, thioridazine
Seizures Phenytoin, carbamazepine, valproic acid, phenobarbital
Peripheral neuropathy Amitriptyline, gabapentin

38. Introduction of new ATD under RNTCP
Bedaquiline (BDQ):
–New class of drug, diarylquinoline that targets mycobacterial ATP
synthase, and enzyme essential for supply of energy to mycobacterium
TB
–Strong bactericidal and sterilizing activities against MTB
•It has no cross-resistance with first- and second-line ATD
•Significant benefit in improving the time to culture conversion
in MDR TB patients
•RNTCP introducing BDQ at six sites in the country initially
•Basic criterion – Adult aged ≥18 years having pulmonary MDR
TB
•Female should not be pregnant.

48. Thank You