Treatment Guidelines of Childhood Tuberculosis and

RNTCP

Presenter: Dr. Chinmoy Lath

1st June’12

Aims of Therapy in Tuberculosis

The main objectives of anti-TB treatment are to:• Cure the patient of TB (by rapidly eliminating most of the

bacilli).• Prevent death from active TB or its late effects.• Prevent relapse of TB (by eliminating the dormant bacilli).• Prevent the development of drug resistance (by using

combination of drugs).• Decrease TB transmission to others.

Evolution in Treatment of TBClassical (long course) chemotherapy regimen :

• 18 months duration daily regimens• Used INH with one or two bacteriostatic drugs• High failure and relapse rate• Poor compliance

Short course chemotherapy regimen

• Combination of 3-4 drugs used in intensive phase (2 mths)• Drugs give either daily / intermittently• Minimum duration of treatment – 6 months• Drugs – preferably given together and as single dose

Advantages• Faster, powerful bactericidal and sterilizing action• Patient exposed to toxic drugs for shorter duration• Less expensive• Reduction in emergence of drug resistant bacilli• Good tolerance and adherence

Results of six month treatment regimen for TB

Author, country & year

Diagnostic Criteria

No. of children

Regimen Results

Al Dossary et al, USA, 2002

Clinical and radiological

175 2 weeks daily HRZ f/b 6 wks HRZ2 / 4RH2

81% t/t completion 1 relapse

Te Water Naude et al, S. Africa, 2000

Clinical & radiological

89117

2 RHZ2/4RH26RHZ

t/t outcome & adherence equivalent 1 relapse

Varudkar, India, 1985

Clinical & radiological

1004045

2 HRE/4HE2 HZE/4HE6 HRE3

0 failures,0 relapses

Kumar et al, India, 1990

Clinical & bacteriological

3739

2 HRZ / 4HR29 HR

2 deaths not related to TB 0 relapse

Ramachandran et al, India, 1998

Clinical & bacteriological

6869

2 HRZ3 / 4RH23 (2%) died, 0 failures, 3 relapses

TRC studies on extrapulmonary TBStudies Rx regimen Duration

(mon)No. of pts

Follow-up period (months)

Overall favourable response

%

TB spine 6 HR7 + modified HongKong Surgery

6 78 120 90

6HR76 78 120 94

TBM 2 HRS7/ 4HE7S2 / 6HE7

12 69 24 33

2R2 HZS7/ 10HE7 12 70 24 36

Pott’s paraplegia

2SHER7 / 7HR2 9 11 60 73

Abd TB 2HRZ7/4HR76 85 60 94

Brain tubeculoma

3HRZ7 / 6HR2 9 47 24 89

• Tuberculosis Research Centre (TRC) studies have clearly established efficacy of short course treatment.

• Intermittent regimens proven as effective as daily regimen

• Overall favourable response varied from 87-99% except in TBM (33%) and Pott’s spine (73%)

• In TBM, outcome is related to stage of disease at the start of treatment and duration of symptoms prior to admission

• Similarly in Pott’s spine recovery influenced by factors like initially motor power, presence or absence of bed sores and duration of kyphosis

• Therefore early diagnosis and treatment is recommended for these two conditions

Management of pediatric TB under RNTCP –

Diagnosis

Suspected cases of pulmonary TB include• Fever and/or cough > 2 wks• Weight loss or failure to thrive• H/o contact with suspected / diagnosed case of active TB in

last 2 yrs• Suspect TBM in child with neurological symptoms,

irritability, refusal to feed, headache, vomiting, altered sensorium

Bacteriological testing• Sputum examination whenever possible• Gastric lavage if sputum not available (yield is 20%)• Multiple samples to be takenTuberculin Test• Mantoux test using 1 TU PPD RT 23 Tween 80• +ve test >10 mm induration at 48-72 hrsRadiology• CXR – suggestive findings mediastinal / hilar lymphadenitis

with / without parenchymal lesions, pleural effusion, miliary and fibro-caseous pictures

• Persistent pneumonia >4 wks inspite of antibiotic therapy

PCR• Low sensitivity for gastric aspirates• Routine use not recommended• May be useful in neuro TB• Sensitivity ranges from 4-80% & specificity 80-100%Serology• Low sensitivity, specificity and positive predictive value

RNTCP diagnostic algorithm for pediatric pulmonary TB

Standard Case Definitions

New case• Pt. who never had treatment for TB / or taken ATT <4 wksRelapse• Pt. declared cured of TB in past after one full course of

ATT, and has become sputum smear +veTreatment failure• A pt. who while on treatment remained or become again

smear positive 5 months or more after starting therapy• A pt. initially smear negative become sputum +ve after 2nd

month of therapy

Treatment after interruption

• Patient who interrupts t/t for 2 months or more, and return with smear +ve

Chronic case

• Patient who remained or become smear +ve after completing fully supervised re-treatment regimen

Smear positive pulmonary TB

• One or more initial sputum smear +ve for AFB

Smear negative pulmonary TB

• At least 2 sputum specimen –ve for AFB• Radiological abnormality consistent with active pulm TB• No response to a coarse of broad spectrum antibiotics• Decision by clinician to treat with full course of ATT

Treatment OutcomesCure• Initially sputum smear-positive patient who

• has completed treatment and• had negative sputum smears on two occasions, one of

which was at the end of the treatment.Treatment completed• Pt. who has completed t/t without proof of cure.Treatment failure• Pt. who remaining or becomes again smear +ve at 5

month / later during t/tTransfer out• Pt. transferred to other reporting unit

Treatment RegimenTreatment category

Type of patients TB treatment regimens

Intensive phase

Continuation phase

Category I New sputum smear-positive PTB Seriously ill sputum smear-negative PTB Seriously ill extrapulmonary tuberculosis

(EPTB)

2H3R3Z3E3 4H3R3

Category II Sputum smear-positive relapse, Sputum smear-positive treatment failure, Sputum smear-positive treatment after

default

2S3H3R3Z3E3/ 1H3R3Z3E3

5H3R3E3

Category III Sputum smear-negative and EPTB not serious ill

2H3R3Z3 4H3R3

New RNTCP Classification

Category I &

III

Category II

• Seriously ill sputum smear negative pulm. TB: all forms of PTB other than primary complex

• Seriously ill EPTB: TBM, disseminated miliary TB, TB pericarditis, TB peritonitis and intestinal TB, B/L or extensive pleurisy, spinal TB with or without neurological complications, genitourinary tract TB, bone & joint TB

• Not seriously ill EPTB: lymph node TB and U/L pleural effusion

• In pts with TBM on category I treatment, 4 drug use during intensive phase should be HRZS instead of HRZE. Continuation phase to be given for 7 months. Total duration of treatment 9 months

• Steroids to be used initially in hospitalized cases of TBM and TB pericarditis for 6-8 weeks.

Suggested pediatric dosages for intermittent therapy

Drug Dosage (mg/kg)

Weight range in kg

6-10 11-17 18-25 26-30

Isoniazid 10 75 150 225 300

Rifampicin 10 75 150 225 300

Pyrazinamide 30-35 250 500 750 1250

Ethambutol 30 200 400 600 1000

Streptomycin 15

• During intensive phase, patient swallows drug under supervision of Health worker 3 times a week

• In continuation phase, pt is issued medicine for 1 wk in multiblister combipack of which 1st dose swallowed in presence of health worker

Chemoprophylaxis• Asymptomatic children <6 yrs exposed to infectious TB

should be given 6 month of INH (5 mg/kg daily)Monitoring & evaluation• Sputum examined after 2 month of intensive phase in

Category I, after 3 months in Category II, if +ve IP given for 1 more month.

Lacunae in RNTCP

• Children can’t appreciate symptoms / bring out sputums difficulty in diagnosis

• CXR – intra and interreader variations, not available at primary health centres

• Tubeculin test, gastric lavage and FNAC – limited to hospitals, not available in primary health centres

• Problem in direct observation of t/t – non-availability of child due to clash with school timing, non-availability of parents due to work

• Social stigma, especially for female pts

Consensus Statement

Recommendations of IAP, 2010

Diagnostic algorithm for tubercular lymphadenitis

Recommended doses of antitubercular drugs

• All drugs to be given empty stomach single dose• Vit B6 – not needed in children taking INH• Daily treatment regimen is advised• Fixed dose combination of INH and rifampicin acceptable• Use pyrazinamide separately

Prednisolone

Indications• Tubercular meningitis.• Tubercular pericarditis.• Mediastinal compression syndrome due to Tuberculosis.• Endobronchial tuberculosis.• Pleurisy with severe dystress.• Milliary disease with alveolocapillary block.• Dose:2-4 mg/kg/day for 2-4 wks then tapper over 2 weeks.

Microbiological Basis of TreatmentTypes of bacterial population• Group I – metabolically active continuously growing bacilli

in neutral pH present extracellularly, killed by INH f/b rifampicin and streptomycin

• Group II – intermittent multiplying organisms (semidormant) in hypoxic environment of cacious material killed by rifampicin

• Group III – intracellular bacilli in acidic pH killed by pyrazinamide

• Group IV – drug resistant mutants, acted upon by rifampicin and INH

Pharmacological principles• Drugs are divided in three categories

1. Early bactericidal activity – ability to kill bacilli in first few days of t/t, max. in INH f/b Etham. and Rifampicin2. Sterilizing activity – ability to eradicate persisters - intracellular bacilli, seen with Rifampicin & Pyz3. Prevention of drug resistance to companion drug, seen

in INH and Rifampicin

CLASSIFICATION OF

ANTITUBERCULAR DRUGS

Tuberculocidal Tuberculostatic

Isoniazid, Rifampicin Streptomycin, AmikacinPyrazinamideCapreomycin, Quinolones, Rifamycin

Ethambutol (except in inflamed meninges)Thiacetazone, EthionamidePara-aminosalicyclic acidCycloserine

TRADITIONAL CLASSIFICATIONFIRST LINE DRUGS:

INH (H)

RIFAMPICIN (R) PYRAZINAMIDE (Z)ETHAMBUTOL (E)STREPTOMYCIN (S)

SECOND LINE DRUGS:

AMIKACIN, KANAMYCIN

FLUOROQUINOLONESPAS, CYCLOSERINE

RECENT WHO CLASSIFICATION

GROUP 1 (FIRST LINE ORAL AGENTS)– INH

GROUP 2 (INJECTABLE AGENTS)– KANAMYCIN

GROUP 3 (FLUOROQUINOLONES)– LEVOFLOXACIN

GROUP 4 (ORAL BACTERIOSTATIC AGENTS)– ETHIONAMIDE

GROUP 5 (AGENTS WITH UNCLEAR EFFICACY)– LINAZOLID, AMX-CLV

ANTI-TB DRUGS USED IN RNTCP

FIRST LINE DRUGS:INH (H)RIFAMPICIN (R) PYRAZINAMIDE (Z)ETHAMBUTOL (E)STREPTOMYCIN (S)

SECOND LINE DRUGS: AMIKACIN, KANAMYCIN,FLUOROQUINOLONES,CAPREOMYCIN, ETHIONAMIDEPAS, CYCLOSERINE, etc…

Adverse effects of ATT drugs

Drug Adverse effects

Isoniazid Hepatotoxicity, peripheral neuritis, hypersensitive reactions may precipitate epilepsy, drug induced lupus, psychotic changes

Rifampicin Hepatotoxicity, gastrointestinal, autoimmune reactions (more with intermittent administration), which include flu syndrome, thrombocytopenias, purpura, respiratory shock syndrome, acute hemolytic anemia, ARF)

Pyrazinamide Hepatotoxicity, arthralgia, hyperuricemia, gastrointestinal, allergic reactions

Ethambutol Optic neuritis, colour blindness, gastrointestinal, allergic reactions, hyperuricemia

Streptomycin Vestibular dysfunction, deafness, nephrotoxicity, neuromuscular blockade, peripheral neuritis

Adverse effects of ATT drugs (contd…)

Drug Adverse effects

Thioacetazone Exfoliative dermatitis, Steven Johnson syndromeQuinolones GI symptoms, CNS, phototoxicity, tendinopathy &

tendinitis, nephrotoxicity, skin rashEthionamide GI symptoms, psychiatric (hallucination & depression),

hepatitis, hypothyroidism, GynaecomastiaCycloserine CNS (convulsions), psychiatric (depression, suicidal

tendency)PAS GI symptoms, hepatic dysfunction, hypokalemia,

hypothyroidism

Second-line anti-TB drugs for t/t of MDR-TB in children

Drug Mode of action Recommended daily doseRange (mg/kg bw) Max

(mg)Ethionamide or prothionamide

Bacteriostatic 15-20 1000

Fluoroquinolones

Ofloxacin Bactericidal 15-20 800 Levofloxacin Bactericidal 7.5-10 - Moxifloxacin Bactericidal 7.5-10 - Gatifloxacin Bactericidal 7.5-10 - Ciprofloxacin Bactericidal 20-30 1500Aminoglycosides

Kanamycin Bactericidal 15-30 1000 Amikacin Bactericidal 15-22.5 1000 Capreomycin Bactericidal 15-30 1000Cycloserine terizidone Bacteriostatic 10-20 1000

Contraindications for anti TB drugs

Isoniazid

• Known hypersensitivity to isoniazid• Active hepatic disease

Rifampicin

• Hypersensitivity to rifampicin• Hepatic dysfunction

Pyrazinamide

• Known hypersensitivity to pyrazinamide

• Severe hepatic impairment• Gout

Streptomycin

• Hypersensitivity• Auditory nerve impairment• Myasthenia gravis• Pregnancy

Ethambutol

• Hypersensitivity• Preexisting optic neuritis• Pts with creatinine clearance

of <50 ml/min

Important side effects with clinical implications

Hepatotoxicity

• Hepatotoxicity drugs include INH, rifampicin, PYZ

• Chances if higher doses / combination are used

• Children with severe disease like TBM, miliary TB are at greater risk

• Children with preexisting liver dysfunction and malnutrition more predisposed

• Routine lab monitoring needed in high risk cases

Hepatotoxicity (clinically evident jaundice / ALT >5 times normal)

Stop IHN, Rifamp & Pyz, start Etham & Strepto

Repeat AST, ALT If they stay as normal / or show a declining trend

Rifamp 10. mg/kg/day + add INH 2.5 mg/kg/d (repeat LFT)

PZA (30 mg/kg/d)+ INH (5 mg/kg/d)

(7 days)

Ocular toxicity• Seen in 5%, if doses of Ethambutol b/w 25-50 mg/kg/d.• Rare in dose of 15 mg/kg/day.• Result in reversible optic neuritis, blurred vision, scotoma,

colour blindness.• Literature review suggests it is safe in children at a dose of

15-25 mg/kg/day.Peripheral neuritis• Clinically manifest peripheral neuritis is rare in children.• Manifest and pins and needle sensation in hands and feet.• More common in malnourished children, HIV +ve,

breastfeeding infants.• Supplemental pyridoxine 5-10 mg/kg/day is recommended

in the predisposed population.

Role of Surgery in TBPulmonary TB

Indications

• Major airway obstruction due to– Extraluminal LN compression – nodal curettage– Intraluminal granulation tissue - bronchoscopy

• Post-TB pulmonary destruction – lung resection• Late pleural fibrosis – decortication• Release of post-tubercular constrictive pericarditis• Drainage of active TB lung abscess

Neuro TB

Indications• Failure of medical management• TB with hydrocephalus and uncontrolled raised ICT• Cerebral abscess• Tuberculoma – for diagnosis of difficulty cases / features of

SOL• Tubercular spinal arachnoiditis compressing cord

Early VP shunts for mild to mod. Hydrocephalus, morbidity & mortality, no effect on stage III pts prognosis

Abdominal TB

Indications• Diagnostic in case of peritoneal abd. TB• Exploratory laparotomy in acute abdomen• Management of complications like stricture, adhesion,

fistula, bleedingPeritoneal

Wet / Ascitic Dry / Sclerosing

Laparoscopy and biopsy Open biopsy

Intestinal

Ulcers MassStricture Perforation

Local resection

Local resection (ileoceocotomy)

Minimal narrowing

Local resection /

enterostomy (rarely)

Significant narrowing

Multiple or very long stricture

ATT Stricturoplasty Local resection

Genitourinary TB

For complications like• Ureteral stricture, abscesses and non-functioning kidneysRadical procedures• Nephrectomy• Partial nephrectomy• EpididymectomyReconstructive procedures• Strictures

– For PUJ obstruction: Pyeloplasy, percutaneous nephrostomy– Ureteric strictures: Double J stenting, resection anastomosis– Vesicoureteric junction obstruction: ureteric reimplantation

Potts spine

Indications for surgery• Paraplegia despite conservative treatment• Sudden acute paraplegia• Paraplegia accompanied by uncontrolled spasticity• Paraplegia in flexion• Flaccid paraplegia• Surgical procedure – anterolateral decompression

MDR-TB

An MDR TB SUSPECT Whose SPUTUM Is CULTURE POSITIVE for M.Tb that are invitro resistant to Isoniazide AND rifampicin with or without resistant to other drugs from an RNTCP accredited laboratory.

Treatment of Multi-Drug Resistant TB• Prevalence of primary MDR in India – <3%

• Prevalence of MDR TB among treated cases – 12-17%(Paramsivan et al, IJMR 2004; 277-86)

Initial drug resistance

• INH – 20-30%, Streptomycin <10%, Rifampicin – 2-3%

Acquired drug resistance

• INH – 50-60%, Rifampicin – 20-30%, Streptomycin – 15-30%(Amdekar YK. Indian Pediatr 1998; 35: 715-18)

Drug-resistant TB should be suspected if any of the features are present

• Features in the source case suggestive of drug-restating TB– Contact with a known case of drug-resistant TB– Remains sputum smear-negative after 3 months of t/t– H/o previously treated TB– H/o treatment interruption

• Features of child suspected of having drug-resistant TB– Contact with a known case of drug-resistant TB– Not responding to the anti-TB treatment regimen– Recurrence of TB after adherence to treatment

Types of resistance

Natural resistance

• Species specific resistance to drug without strain being ever exposed to it

Primary resistance

• Pt infected with drug-resistant population without having received prior treatment

Secondary (acquired) drug resistance

• Pt harbous organisms which were previously drug susceptible but resistance developed during course of t/t

Alternative method of grouping ATT drugsGrouping Drugs (abbreviation)

Group 1: First line oral Anti TB agents

Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z)

Group 2: Injectable Anti TB agents

Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vi)

Group 3: Fluoroquinolones Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lfx); Moxifloxacin (Mfx); Gatifloxacin (Gfx)

Group 4: Oral bacteriostatic second-line anti TB agents

Ethionamide (Eto); Protionamide (Pto); Cycloserine (Cs); Terizidone (Trd); p-aminosalicylic acid (PAS); Thioacetazone (Th)

Group 5 – Anti TB agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB pts)

Clofazimine (Cfz); Amoxicillin / Clavulanate (Amx / Clv); Clarithromycin (Clr); Linezolid (Lzd)

Principles of Treatment• Never add one drug to a failing regimen.• Treat child according to the drug susceptibility pattern and

using t/t history of source case strain if isolate from child is not available

• Use at least 4 drugs with certain effectivity• Use daily treatment, directly observed• Use bactericidal drugs as far as possible• Use all oral 1st line drug to which isolate is sensitive• An injectable agent is used for minimum of 6 months after

culture conversion

Principles of Treatment contd..

• Oral quinolone used for entire duration of therapy • t/t to be given for at least 18 months after cultures are –ve• Drug dosing to be determined by body weight• Counsel caregiver regarding adverse events & compliance• Follow-up is essential – clinical, radiological and

bacteriological• Monitor LFT, KFT, hearing periodically

Concept of DOTS plusIndividualized treatment regimen • Regimen designed as per resistance pattern of strain

infecting pt.• Heavily dependent on drug sensitivity testing• Unlikely to fail• Less applicable in resource poor countriesStandardized regimen• Based on common resistance pattern identified in a given

population• Low cost, simpler implementation, less dependent on

laboratories

Management of MDR TB under RNTCP• RNTCP will be using a Standardized Treatment regimen

RNTCP CATEGORY IV REGIMEN: 6 (9) Km Lvx Eto Cs Z E / 18 Lvx Eto Cs E

• Minimum recommendation is that intensive phase to be given for 6 months

• After 6 months – continuation phase started if 4th month culture are negative

• If 4th month culture is still awaited after 6 months of t/t, IP is extended

• After maximum of 9 months CP started for 18 months

MDR patient referred to state level DOTS plus site with DTS result

DOTS plus site decides on whom to start Rx

Pt admitted at DOTS plus site for 1 monthDischarged with 1 wk drug supply

Given treatment at a facility near to home

Indications for Surgery in MDR-TB• As adjuvant may improve results of chemotherapy in

selected cases• Ideally operate early in therapy, b/w 6-9 month• After surgery continue therapy for 18 months• If disease is resectable, surgery considered in following

– Absence of response despite 6-9 mon of t/t– High risk of failure or relapse due to high degree of resistance– Morbid complications e.g. haemoptysis, bronchiectasis,

bronchopleural fistula– Recurrence of positive smear or culture during t/t– Relapse after completion of anti-TB treatment

MDR TB in special situations

MDR-TB in pts with renal failure

• Drugs requiring dose or interval adjustment in renal failure are – ethambutol, quinolones, aminoglycosides, cycloserine, PAS, ethionamide

• Monitor blood urea, nitrogen and creatinine frequently

• In mild renal failure – dose of aminoglycoside reduced

• In severe renal failure – aminoglycosides are discontinued

Drug Method of modi-

fication

GFR (ml/min)

>50 10-50 <10

Kanamycin D, I 7.5-15 mg/kg/24 hr 4-7.5 mg/kg/24 hr 3 mg/kg/48 hr

Ethambutol I 20 mg/kg/24 hr 20 mg/kg/24-36 hr 20 mg/kg/48 hr

Pyrazinamide D 30 mg/kg/24 hr 30 mg/kg/24 hr 15-30 mg/kg/24 hr

Ofloxacin D 100% 50-75% 50%

Ethionamide D 100% 100% 50%

Cycloserine D 100% 50-100% 50%

PAS D 100% 50-75% 50D = dose adjustment; I = interval adjustment; *%age of recommended dose to be given

MDR-TB in pts with pre-existing liver disease• In category IV regimen, PYZ, PAS and ethionamide are

hepatotoxic• Most of the 2nd line drugs can be safely used in mild

impairment as they are less hepatotoxic than 1st line drugs• PYZ should be avoided in such patientsMDR-TB in pts with seizure disorders• If seizures are not under control, initiation of anti-seizure

drugs will be needed prior to start of MDR-TB therapy• Cycloserine, ethionamide, quinolone have been associated

with seizures, use carefully• Pyridoxine should be given with cycloserine to prevent

seizures

• Avoid cycloserine in pts with uncontrolled seizures• Anti-epileptic drugs may have interaction with cycloserine

and quinolones, monitoring of serum levels may be needed

MDR-TB in pts with psychosis

• High baseline incidence of depression and anxiety in pts with MDR-TB due to chronicity and socioeconomic factors

• Quinolones, ethionamide – associated with psychosis• Pyridoxine prophylaxis recommended• Cycloserine causes severe psychosis but not abs. C/I• If pt. on cycloserine develop psychosis, stop cycloserine

and start anti-psychotics• Resume cycloserine once pt is stabilized

XDR TB(extensively drug resistance TB)

• XDR TB is resistance to at least INH and rifampicin (i.e. MDR TB) + resistance to any fluoroquinolones and any one of the second line anti-TB injectable drugs (Am, Cm, Km)

• Worldwide noted in 41 countries till date• Isolated reports indicate existence of XDR TB in India, but it

is not possible to estimate its magnitude from present data• Effective treatment of MDR pts through DOTS plus can

prevent XDR TB generation• Extremely difficult to treat with poor outcomes

SUMMARY(RNTCP)

DIAGNOSIS OF PTB

• DURATION OF COUGH

3 WEEKS 2 WEEKS

–NUMBER OF SPUTUM SMEARS TO BE COLLECTED

3 SMEARS 2 SMEARS

–NUMBER OF + SMEARS REQUIRED FOR DX OF PTB+

2 SMEARS 1 SMEAR

• CATEGORY III HAS BEEN PHASED OUT

• NEW (DOTS)

• PREVIOUSLY TREATED (DOTS)

• CATEGORY IV FOR MDRTB

• CATEGORY V FOR XDRTB

SUMMARY(RNTCP)

TREATMENT OF PTB

Treatment of Congenital TBAs per IAP

• Continue breastfeeding

• BCG given at birth

• If CXR normal – 6 HR

• If CXR abnormal – 2 HRZ/7HR

• Congenital TB – 2 HRZ/7 HR

As per WHO – active pulm TB diagnosed after delivery

<2 months after >2 months afterTreat mother, breastfeed, INH x 6 m (5 mg/kg/d), BCG after stopping INH

Treat mother, breastfeed, INH x 6 m (5 mg/kg/d), if BCG not given at birth give after stopping INH

>2 month <2 month beforeSmear-ve just before delivery Smear +ve just before

deliveryTreat mother, breastfeed, INH x 6 m (5 mg/kg/d), BCG after stopping INH

Treat mother, breastfeed, no preventive CT, BCG at birth

Treat mother, breastfeed, INH x 6 m (5 mg/kg/d), BCG after stopping INH

As per WHO – active pulm TB diagnosed before delivery

As per RNTCPTreat mother

Continue breast feeding

Mother

Sputum +ve Sputum -ve

Chemotherapy to infant x 3 months

BCG given

No chemotherapyMTx at 3 months

+ve -ve

BCG givenBCG not given continue CT x 6 mths

As per National Neonatology Forum (NNF)If child has clinical features of perinatal TBStart ATT• 2 HRZ + 7 HR• May add streptomycin for first 2 months• HIV co-infection – 2 HRZS + 7 to 10 HR• Extra pulmonary TB – 2 HRZS + 7 to 10 HR• MDR TB – 12 to 18 HRZS or RHZEAdd steroids (prednisolone 1-2 mg/kg/d for 4-8 wks) if• Meningitis, neuro TB, miliary TB, TB involving serous

layers, endobronchial / segmental lesions, genitourinary TB, sinus formation

Breastfed infants / neonates on INH must be supplemented with B6

If the child is clinically normal but mother high riskMother Mx negative (induration <10 mm)

Symptomatic Asymptomatic

CXR abnormal CXR normal Presumed uninfected

Investigate & treat mother

No investigationsNo t/t

Investigate & treat mother, no t/t of baby

Screen baby

Normal

Abnormal

Chemoprophylaxis (6 HR)

T/t as perinatal TB

If the child is clinically normal but mother high riskMother Mx Positive (induration >10 mm)

Abnormal Normal

CXR

No active TB Active TB

Screen mother

Continue breastfeedFollow-up

T/t mother

Screen baby

Normal

Abnormal

Chemoprophylaxis (6 HR)

T/t as perinatal TB

Symptomatic Asymptomatic

Screen mother Breastfeed, no t/t

High risk mothers

• Old case of TB and on irregular t/t• Sputum +ve• Having signs and symptoms• Miliary TB or CXR• TBM

General instructions

• Continue breastfeeding• Give BCG at birth• Separation not needed• Follow-up both mother and child

Discontinue breastfeeding + separation

• Mother so sick to need admission• MDR TB suspected• Proven default• Sputum +ve mother not put on ATT

TB and HIV• 60% of PLHA develop TB• 16-18% of children with TB have HIV• Active TB is commonest OI among HIV infected individualsDiagnosis of TB in HIV infected children

3 or more of following• Chronic symptoms s/o TB• Physical signs s/o TB• CXR s/o TB• Positive Mx >5 mm induration

Problems in treatment• Potential for drug interactions, esp. b/w rifampicin and anti-

retroviral agents• Problems of drug toxicity and adverse effects• IRIS• Pill burden, adherenceKey therapeutic principles• Treatment of TB takes precedence over t/t of HIV infection• In pts already on HAART, continue same with modification

in both HAART and ATT• If pt. not receiving HAART, timing of initiation of ART

decided on basis of immune suppression and CD4 counts and type of TB

WHO recommends ART be given to• All pts with extrapulmonary TB (stage 4)• All those with pulm TB unless CD4 count >350 cells/mm3

• ART recurrence and fatality rates in TBClassification of HIV-associated immunodeficiency in

children

Classification of HIV-associated

immunodeficiency

Age-related CD4 values

11 months (%)

12-35 months (%)

35-59 months (%)

5 years (cells/mm3)

Not significant >35 >30 >25 >500

Mild 30-35 25-30 20-25 350-499

Advanced 25-30 20-25 15-20 200-349

Severe <25 <20 <15 <200

Initiation of first-line ART in relation to anti-TB therapy

WHO pediatric clinical stage

Timing of ART following start of anti-TB t/t

Recommended ART regimen

4 (extrapulm TB other than LN TB)

Start ART soon after anti-TB t/t (b/w 2 & 8 wks following start of anti-TB t/t)

In children aged <3 yrs • preferred: triple NRTI first line

regimen – d4T or AZT + 3 TC + ABC

• Alternative: standard first-line regimen – two NRTIs + NVP

In children aged 3 yrs • Preferred: triple NRTI first-line

regimen – two d4T or AZT + 3TC + ABC

• Alternative: standard firstline-line regimen – two NRTIs + EFV

3 (pulm TB and LN TB)

With clinical management alone•Start ART soon after start of anti-TB t/t (b/w 2-8 wks following start of ATT)•Consider delaying start of ART until anti-TB t/t is completed – if excellent clinical response to ATT in first 2-8 wks and child is stable

WHO pediatric clinical stage

Timing of ART following start of anti-TB t/t

Recommended ART regimen

3 (pulm TB and LN TB)

When CD4 values are available

• Severe immunodeficiency CD4 <200 – start ART b/w 2-8 wks as soon as ATT tolerated

• Advanced immunodeficiency (CD4 200-350) – start ART 8 wks after starting ATT

• Mild or no immunodeficiency (CD4 >350) – consider delaying start of ART until ATT completed

Regimens as recommended above

• EF V is not currently recommended for <3 yrs / <10 kg and not given to postpubertal adolescent girls who are sexually active and not using contraception

ART recommendations for pts who develop TB within 6 months of starting a first-line ART regimen

1st line or 2nd line ART regimen

ART regimen at the time of TB occurs

Management options

1st line ART (AZT or D4T) + 3TC + EFV Continue with two NRTIs + EFV(AZT or D4T) + 3TC + NVP Substitute NVP with EFV, or

Substitute with triple NRTI regimen

AZT + 3TC + TDF Continue with triple NRTI regimen

2nd line ART Two NRTIs + PI Substitute or continue with LPV/r – containing regimen and adjust the dose of RTV

Immune reconstitution inflammatory syndrome• Characterised by clinical deterioration after initial

improvement• Occurs in 1/3rd of pts on ATT who have started ART• Presents within 3 months of ART initiation• Fever, worsening of pre-existing LAP + resp disease• Most cases resolve without intervention• Serious reactions may require use of steroidsART failure• If TB occurs within 6 months of initiation of ART, it should

not be considered as failure of t/t• If episode occurs after 6 months of ART, with no other

clinical / immunological evidence of disease progression, it should not be considered ART failure

• Extrapulm TB should be considered ART failure

Drug interactions and toxicity

• Thiacetazone is contraindicated in HIV pts

• HIV pts more prone to develop INH induced peripheral neuritis therefore given pyridoxine supplementation

• Both ATT and NVP – cause hepatotoxicity close monitoring needed

• Rifampicin induces cyt p450 enzymes and reduces conc of PI by 80%, NVP level by 20-58%, EFV level by 25%

• PI resistant mutants of HIV may emerge if unboosted PIs are used with rifampicin

Chemoprophylaxis (6HR)

• All HIV pts with MTx >5 mm given prophylaxis

• Also in anergic pts exposed to active TB

BCG vaccination

• WHO recommends all asymptomatic HIV infected children should receive BCG except those with symptoms of AIDS related complex / AIDS. This is especially true for high TB prevalent countries like India

• BCG should not be given to HIV-infected children in low TB prevalence countries