RNTCP guidelines for tuberculosis management: Extended version

PRESENTED TO: DR. SASWATI SINHA
PRESENTED BY:
(DR.)VISHNU.R.NAIR,
PHARM.D INTERN(AMRI HOSPITAL ACADEMIC TRAINEE),
NATIONAL COLLEGE OF PHARMACY, KERALA.

 GENERAL INTRODUCTION
 EPIDEMIOLOGICAL STATISTICS
 CLASSIFICATION OF ATDs(RNTCP CONCEPT)
 CLASSIFICATION OF TB-CASES(RNTCP CONCEPT)
 MANAGEMENT OF DRUG-SENSITIVE TB
 MANAGEMENT OF MDR-TB(PRINCIPLES INVOLVED)
 MANAGEMENT OF RR-TB
 MANAGEMENT OF MONODRUG RESISTANT TB
 MANAGEMENT OF PDR-TB
 MANAGEMENT OF INH-RESISTANT TB
 MANAGEMENT OF XDR-TB
 TREATMENT OF PATIENTS WITH ADRs to ATDs
 DELAMANID: A NEW INTRODUCTION IN INDIA

Full form: “Revised National Tuberculosis Control Program”
State-run TB control initiative of the Indian Government
Main objective of RNTCP : “To implement WHO guidelines for TB &
DOTS therapy strategy in Indian scenario”
Revised National Tuberculosis Control Programme: NATIONAL STRATEGIC PLAN FOR TUBERCULOSIS ELIMINATION 2017–2025.Available from
https://tbcindia.gov.in/WriteReadData/NSP%20Draft%2020.02.2017%201.pdf [Last accessed on January 22, 2019].
Tripathi K. Essentials of medical pharmacology. 8th ed. New Delhi: Jaypee Brothers Medical Publishers; 2018.

According to World Health Organization (WHO) estimates(2015):
- 10.4 million individuals developed active disease
- More than 1.8 million deaths occurred
- TB  stands among top 10 causes of death worldwide.
According to the United States Centers for Disease Control and Prevention
(CDC) statistics:
- One-third of the world's population is infected with TB
- TB represents a leading killer of individuals infected with HIV.
WHO Global Tuberculosis Report 2018. Available at https://www.who.int/news-room/fact-sheets/detail/tuberculosis. Last accessed on January 23, 2019.

 Tuberculosis (TB) is one of the top 10 causes of death worldwide.
 In 2017, 10 million people fell ill with TB, and 1.6 million died from the disease (including
0.3 million among people with HIV).
 In 2017, an estimated 1 million children became ill with TB and 2,30,000 children died of TB
(including children with HIV associated TB).
 TB is a leading killer of HIV-positive people.
 Multidrug-resistant TB (MDR-TB) remains a public health crisis and a health security threat.
 WHO estimates that there were 5,58,000 new cases with resistance to rifampicin – the most
effective first-line drug, of which 82% had MDR-TB.
 Globally, TB incidence is falling at about 2% per year.
 An estimated 54 million lives were saved through TB diagnosis and treatment between 2000
and 2017.
 Ending the TB epidemic by 2030 is among the health targets of the Sustainable Development
Goals.
WHO Global Tuberculosis Report 2018. Available at https://www.who.int/news-room/fact-sheets/detail/tuberculosis. Last accessed on January 23, 2019.

 MDR-TB has a rapid course, with worse outcomes
 In India  MDR-TB constitutes:
a. 3% of all new TB-cases
b. 17% of retreatment cases
 According to WHO global report(2015)  India has the HIGHEST NUMBER of MDR-TB
cases!(Approx. 71,000 cases annually)
 In 2015,the World Health Organization (WHO) estimated 480,000 incident multidrug resistant
TB (MDR-TB; resistance of both isoniazid and rifampin) cases globally.
 With an estimated 79,000 MDR-TB cases  India along with the Russian Federation and
South Africa accounted for 45% of the total notified combined MDR-TB and rifampin-
resistant (RR-TB) cases in 2015
World Health Organization. The Global Tuberculosis Report: 2016. Geneva,Switzerland: WHO, 2016. Available at http://www.who.int/tb/publications/global_report/
en/. Last accessed 2019, January 23.

CLASSIFICATION OF ANTI-TB DRUGS(RNTCP
CONCEPT)

 According to RNTCP guidelines  ATDs(Anti-tubercular drugs) have been classified into 5
groups, to facilitate proper management of the disease
 Groups include:
A. GROUP I(1st line oral drugs):
- Most potent
- Best tolerated oral drugs
- Used routinely
- Drugs include isoniazid(H), rifampin(R), pyrazinamide(Z) & ethambutol (E)
- Use code “RIPE” to remember drug names in this category!

B. GROUP II(Injectable drugs):
- Potent
- Bactericidal
- Injectables in nature
- Chiefly include aminoglycosides like Streptomycin(S), Amikacin(Am), Kanamycin(Km) &
Capreomycin
- Use code “SACK” to remember names of drugs in this category!

C. GROUP III (FLUOROQUINOLONES):
- Well-tolerated
- Bactericidal
- Oral drugs
- According to RNTCP guidelines  all patients with drug-resistant TB 
SHOULD RECEIVE ONE FLUOROQUINOLONE!
- Drugs include Ofloxacin, Levofloxacin, Ciprofloxacin and Moxifloxacin
- Use code “CLOM” to remember names of drugs under this category!

D. GROUP IV(2nd line oral drugs):
- Less-effective
- Bacteriostatic
- More toxic than 1st line oral agents!
- Drugs include ethionamide, prothionamide, cycloserine, terizidone, PAS, rifabutin and
rifapentine.
- Use code “PP-RR-ECT” to remember name of drugs in this category!
E. GROUP V(Unclear efficacy drugs):
- Drugs with unclear efficacy(Use code “CCC-LIB” to remember name of drugs in this
category!)
- Not recommended for MDR-TB!
- May be used as RESERVE DRUGS (in XDR-TB)!
- Drugs include bedaquiline, clarithromycin, clofazimine, linezolid, co-amoxiclav and
imipenem-cilastatin.
Revised National Tuberculosis Control Programme: NATIONAL STRATEGIC PLAN FOR TUBERCULOSIS ELIMINATION 2017–2025.Available from https://tbcindia.gov.in/WriteReadData/NSP%20Draft%2020.02.2017%201.pdf [Last
accessed on January 22, 2019].

CLASSIFICATION OF TB CASES(RNTCP
CONCEPT)

 For selection of appropriate ATT(Anti-tubercular therapy)  RNTCP(2016) has classified TB
cases into:
A. DRUG-SENSITIVE TB:
- In this case  patient’s bacilli  susceptible to all 1st line drugs
- Such patients  may include:
i. Newly-diagnosed patients
ii. Patients, pre-treated with TB in past
B. MULTI-DRUG RESISTANT TB(MDR-TB):
- In this case  patient’s bacilli  resistant to BOTH RIFAMPIN & INH!
- May/may not be resistant to other 1st line ATDs

C. RIFAMPIN-RESISTANT TB(RR-TB):
- In this case  patient’s bacilli  resistant to ONLY RIFAMPIN & NOT INH!
- May/may not be resistant to other ATDs.
D. MONO-DRUG RESISTANT TB:
- In this case  patient’s bacilli  resistant to ANY ONE 1st line ATD(Except rifampin)
E. POLYDRUG-RESISTANT TB(PDR-TB):
- In this case  patient’s bacilli  resistant to MORE THAN ONE 1ST LINE ATD(except
rifampin & INH)
F. EXTENSIVE DRUG RESISTANT TB(XDR-TB):
- In this case  patient’s bacilli  resistant to a FQ & a 2nd line injectable ATD!

MANAGEMENT OF DRUG-SENSITIVE TB

Usually treated by 1st line ATDs
Drug-sensitive TB includes 2 types:
A. Newly-treated patients:
- Treatment involves:
2 months of HRZE(Intensive phase) + 4 months of HRE(Continuation phase)
- Total duration: 6 months
B. Previously-treated patients:
- Treatment involves:
[2 months of HRZES + 1 month of HRZE](Intensive phase) + 5 months of HRE(Continuation
phase)
- Total duration: 8 months.

TYPE OF PATIENT INTENSIVE PHASE CONTINUATION
PHASE
TOTAL DURATION
New 2 months of HRZE 4 months of HRE 6 months
Previously-treated
patients
2 months of HRZES +
1 month of HRZE
5 months of HRE 8 months

MANAGEMENT OF MDR-TB(PRINCIPLES
INVOLVED)

MDR-TB has a rapid course, with worse outcomes
Treatment involves complex multiple 2nd line drug regimens, which
confer the following demerits:
a. Longer treatment duration
b. Expensive
c. High risk of toxicity!!

General principles of MDR-TB management
a. Include 4 effective drugs in regimen(6 drugs can also be included, provided
efficacy regarding any of them is uncertain; back-up!)
b. Avoid usage of cross-resistance drugs, chiefly:
- 2 FQs
- Kanamycin with Amikacin
- Ethionamide with prothionamide
- Cycloserine with terizidone
- Ethionamide with INH(low-level resistance)
c. When selecting drugs for treatment  select in a hierarchical order, for
example:
2 Group I drugs( Z, E) + one injectable drug(Group II) + One FQ(Group III) + 2 Group IV
drugs.

d. Standard RNTCP regimen for MDR-TB consists of :
- 6 drugs in “intensive phase”(for 6-9 months)
- 4 drugs in “continuation phase”(for 18 months)
e. Minimal 6 month of intensive phase  can be extended by 1 month each
time(to a total maximum of 9 months)  provided, sputum culture at 4th , 5th &
6th months of intensive phase turns out to be positive
f. Pyridoxine (at dose of 100 mg/day)  should be given to all patients during
therapy to avoid precipitation of neurotoxicity(attributed to ATDs)!

INTENSIVE PHASE(6-9 MONTHS) CONTINUATION PHASE(18 MONTHS)
Kanamycin(Km) Levofloxacin (Lfx)
Levofloxacin (Lfx) Ethionamide(Eto)
Ethionamide(Eto) Cycloserine(Cs)
Cycloserine(Cs) Ethambutol(E)
Pyrazinamide(Z)
Ethambutol(E)
STANDARD RNTCP REGIMEN FOR MDR-TB
N.B: Pyridoxine (100 mg/day) should also be added to above regimen

MANAGEMENT OF RIFAMPIN-RESISTANT
TB(RR-TB)

 According to both WHO & RNTCP(2016)  RR-TB is treated as MDR-TB
 Since patients with RR-TB are sensitive to INH  INH is also added to “intensive phase”
 Thus, RNTCP management strategy for RR-TB includes:
INTENSIVE PHASE(6-9 MONTHS) CONTINUOUS PHASE(18 MONTHS)
Kanamycin(Km) Levofloxacin(Lfx)
Levofloxacin(Lfx) Ethionamide(Eto)
Ethionamide(Eto) Cycloserine(Cs)
Cycloserine(Cs) Ethambutol(E)
Pyrazinamide(Z) INH
Ethambutol(E)
INH
N.B: Add pyridoxine (100 mg/day) to the above regimen

MANAGEMENT OF MONODRUG RESISTANT
TB

MANAGEMENT STRATEGY
Rifampin + two of 1st line drugs(sensitive to bacilli)
+ one injectable 2nd line drug + 1 fluoroquinolone
Total of 5 drugs, to be given in intensive phase.
- Stop injectable drug
- Continue with remaining 4 drugs for 6 months.
N.B: Add pyridoxine (100 mg/day) to the above regimen.

MANAGEMENT OF POLYDRUG RESISTANT
TB(PDR-TB)

MANAGEMENT STRATEGY
Rifampin + one injectable 2nd line drug + one
fluoroquinolone + any 1st line drug (to which bacilli
is sensitive) + one of the oral 2nd line
drugs(Ethionamide/ Cycloserine/ PAS)
Total of 5 drugs to be used in continuation phase.
• Stop injectable drug
• Continue remaining 4 drugs.
N.B: Add Pyridoxine(100 mg/day) to the above treatment regimen.

MANAGEMENT OF INH-RESISTANT TB

 In order to strategize treatment for INH-resistant TB  firstly an insight into mechanisms of
INH-resistance is important
 INH resistance can occur in 2 ways:
A. LOW-LEVEL INH RESISTANCE:
- inhA gene  plays role in activity of NAD-dependent enoyl-acyl carrier protein reductase
- In low-level INH resistance  mutation occurs in the inhA gene
- In such situations:
i. Focus on using HIGH DOSE OF INH (900 mg/day, for average body weight of 46-70 kg)
ii. Add pyridoxine to treatment regimen
iii. Monitor for potential neurotoxicity
iv. Avoid concurrent usage of Ethionamide(since it won’t be effective in low-level INH resistance)!

B. HIGH-LEVEL INH RESISTANCE:
- KatG gene  encodes for enzyme catalase peroxidase  helps in conversion
of INH to its active metabolite  shows antitubercular activity
- In high-level INH resistance  mutation in KatG gene occurs  conversion
doesn’t occur  drug is rendered ineffective!
- In such situations:
i. Avoid usage of INH!
ii. Ethionamide may be used(Since Ethionamide is effective in patients with high-level
INH resistance)!

MANAGEMENT OF EXTENSIVE DRUG-
RESISTANT TB(XDR-TB)

Extremely difficult to treat, necessitating use of Group-V drugs!
To prevent further progression of resistance  stop standard MDR-regimen
immediately!
Since Group-V drugs are both costly & toxic  an expert clinical panel may
decide on appropriate drug selection!
According to RNTCP(2016) guidelines:
- 7 drugs should be used in intensive phase(6-12 months)
- 6 drugs should be used in continuous phase(18 months)

STANDARD RNTCP GUIDELINES FOR XDR-TB MANAGEMENT:
INTENSIVE PHASE(6-12 MONTHS) CONTINUOUS PHASE(18 MONTHS)
Capreomycin (1000 mg) Moxifloxacin (400 mg)
Moxifloxacin (400 mg) INH high dose (900 mg)
INH high dose (900 mg) PAS (12 g)
PAS (12 g) Clofazimine(200 mg)
Clofazimine(200 mg) Linezolid (600 mg)
Linezolid (600 mg) Amoxicillin/clavulanate (875+125 mg);
2 tablets in morning & 1 tablet in
evening.
Amoxicillin/clavulanate (875+125 mg);
2 tablets in morning & 1 tablet in
evening.
Revised National Tuberculosis Control Programme: NATIONAL STRATEGIC PLAN FOR TUBERCULOSIS ELIMINATION 2017–2025.Available from https://tbcindia.gov.in/WriteReadData/NSP%20Draft%2020.02.2017%201.pdf
[Last accessed on January 22, 2019].
N.B:
Add pyridoxine (100
mg/day) to the ATD
regimen mentioned in
left-hand side

BODY WEIGHT CATEGORY(in kg) INTENSIVE PHASE CONTINUATION PHASE
HRZE HRE
25-39 2 2
40-54 3 3
55-69 4 4
70 and above 5 5
• For intensive phase  each tablet contains INH(75 mg), Rifampin(150 mg),
Pyrazinamide(400 mg) & Ethambutol(275 mg)
• For continuation phase  each tablet contains INH(75 mg), Rifampin(150 mg)&
Ethambutol(275 mg)

DRUG DAILY DOSE(in mg/kg)
INH 5 (4-6)
RIFAMPIN 10 (8-12)
PYRAZINAMIDE 25 (20-30)
ETHAMBUTOL 15 (15-20)
STREPTOMYCIN 15 (12-18)
PLEASE NOTE: If patient’s age > 50 years  maximum dose of streptomycin will be 0.75
g/day!

TREATMENT OF PATIENTS WITH ADRs TO ATDs

Even though 1st line ATDs are well-tolerated  minor ADRs may occur
 resolved by symptomatic management, without necessitating drug
discontinuation
Examples:
1. In case of nausea, anorexia  drug can be administered with small meals
2. In case of drowsiness  ATD can be administered before bedtime
3. For Pyrazinamide-induced arthralgia  analgesic NSAIDs may be opted
4. For INH-induced peripheral neuritis  pyridoxine can be used

If severe reactions occur
Stop all drugs promptly
On resolution of reaction
Introduce drugs, one at a time(challenge with small doses & increasing dose every 3 days)
If offending drug is identified
Stop that drug
Reconstitute treatment regimen.

Never reintroduce Rifampicin in cases of:
a. Hemolysis
b. Thrombocytopenia
c. Renal failure.
Discontinue ethambutol at 1st sign of optic neuritis!
Most common problem with ATDs: “Hepatotoxicity”
• Although 1st line ATDs(except streptomycin, ethambutol) are implicated  hepatotoxicity
tends to aggravate, when 1st line ATDs are used as combination therapy
• If hepatitis develops stop all drugs  allow reaction to subside
• In case of severe-TB  focus on non-hepatotoxic drugs(Streptomycin + Ethambutol + one
FQ)
• Discontinued drugs  should be started one at a time.

In general situations
Rifampin is introduced 1st
After 7 days
Introduce INH
If hepatitis recurs
Stop INH , and reconstitute the regimen.
If Rifampin & INH are tolerated
Do not restart pyrazinamide
Prolong treatment with “R”,”H” & “E” for 9 months.

If Rifampin is implicated in hepatitis
Give INH+ Ethambutol + Streptomycin (for 2 months)
Follow it up with combination of INH + Ethambutol (for 10 months)
If INH is implicated in Hepatitis
Give combination of Rifampin+ Ethambutol+ Pyrazinamide for 9 months.

DELAMANID: A NEW INTRODUCTION IN INDIA

DRUG CLASS: “Nitroimidazole”
MECHANISM OF ACTION:
- Delamanid  shows bactericidal effects in 2 ways:
a. Drug  blocks mycolic acid synthesis  prevents bacteria from creating building
blocks important for cell-walls
b. Poisoning bacterial cells with NO(metabolite activity)
DRUG HALF-LIFE: 36 hours.
Revised National Tuberculosis Control Programme; GUIDELINES FOR USE OF DELAMANID IN THE TREATMENT OF DRUG RESISTANT TB IN INDIA 2018. Available from:
https://tbcindia.gov.in/showfile.php?lid=3343 [Accessed on January 22, 2019].

One of the 2 drugs(other one being Bedaquiline) developed for
treatment of MDR & XDR-TB
First approved by EMA in November 2014
Indicated to be used as part of an appropriate combination regimen
for Pulmonary MDR-TB, in adults & adolescents(6-17 years), in cases
of refractory or drug-intolerance TB cases

In conditions, where an effective MDR-TB regimen(containing 4 second line
drugs), in addition to pyrazinamide cannot be designed
Documented evidence of resistance to FQ/2nd line injectable (in addition to
MDR)
Conditions of poor clinical outcome, that include:
a. Drug intolerance
b. Contraindication
c. Extensive/advanced disease.

Children < 6 years
Pregnant & lactating women
Patients with repeated demonstrations of QT interval > 450-500 ms
History of TdP, or any other cardiac function abnormalities, etc.
Drug hypersensitivity or to its excipients

 Treatment with delamanid should not be initiated in the following patients, unless “benefits
outweigh potential risks”:
a. Congenital prolongation of QTc interval
b. History of symptomatic arrhythmias
c. Pre-disposing cardiac conditions for arrhythmias(Severe HTN, LVH,etc.)
 Monitor ECG before initiation , at day 15 of treatment & then monthly during full course of
treatment (In normal ECG baseline)
 Frequent ECG monitoring  warranted for QTc (450-500 ms)
 Correct electrolyte imbalances(hypokalemia, hypocalcemia, hypomagnesemia) before
initiating therapy!!
 Stop all QTc prolonging drugs, if QTc > 500 ms is observed!!

Delamanid  prolongs QTc interval severely, if co-administered with:
a. Macrolides
b. FQs
c. TCAs
d. Triazole antifungals
e. Non-sedating antihistamines(astemizole, terfenadine)
f. Neuroleptics
g. Saquinavir, etc.

Use delamanid, only with appropriate combination regimen for
MDR-TB
Never add delamanid to a failing regimen!

As long as benefits outweigh risks  delamanid may be used!
No studies available on efficacy of delamanid in CNS-TB!

For children  delamanid may be used as 50 mg BD(6-11 years) and 100 mg
BD(12-17 years), for a duration of 24 weeks(6 months)
WEEK 0-24:
- Delamanid 100 mg (2 tabs of 50 mg); P/O; BD + Optimized background regimen
WEEK 25(From 7th month, till end of treatment):
- Continue with another 2nd line ATD(according to RNTCP guidelines)
- Delamanid can be taken with food to increase bioavailability!

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