Epidemiology of tb with recent advances acknowledged by who

Epidemiology and Recent Advances in Tuberculosis with

Update in the Programme

Name of the PresenterDr.Rama Shankar

PG resident

Name of the ModeratorDr.J.V.Singh

Professor and Head

Department of Community MedicineMuzaffarnagar Medical College

7/09/15

Outline of the Presentation• Introduction

• Approaches to the Epidemiology of Tuberculosis

• Global Burden of Tuberculosis

• TB Burden in India

• National Tuberculosis Control Program and its evolution in India

• MDR and XDR-TB

• TB and HIV

• TB and Pregnancy

• Recent advances in the field of diagnosis/Treatment/Vaccine acknowledged by WHO

• Post 2015 TB Strategy in the backdrop of SDG

• Summary

• References

Introduction• Tuberculosis is an infectious disease caused by Mycobacterium

tuberculosis.

• PTB is the most common form of TB (>85% of all cases ), while EPTB can affect almost all organ of the body.

• Transmission occur by airborne spread of infectious droplets and droplet nuclei containing the tubercle bacilli.

• Period of infectivity remains as long as Sputum positive TB are not treated.

• Reservoir of Infection: Persons suffering from TB disease whose sputum is positive for tubercle bacilli are reservoir of infection

Mycobacteria• Mycobacteria are obligate aerobes,facultative intracellular parasite ( ingested

by phagocytes and is resistant to intracellular killing). Discovered by Robert Koch on 24th March 1882.

• M. tuberculosis has an unusual, waxy coating on its cell surface (primarily due to the presence of mycolic acid), which makes the cells impervious to Gram staining. The Ziehl-Neelsen stain, or acid-fast stain is used instead of it.

• Importance to man are the human and bovine strains

• Atypical Mycobacteria: Four groups ( RUNYON Classification)

• Runyon 1:Photochromogens ( M Kansasii)

• Runyon 2:Scotochromogens ( M.Scrofulaceum)

• Runyon 3:Non-photochromogens (M intercellulare) ( Battery Bacillus)

• Runyon 4:Rapid growers (M. Fortuitum)

https://en.wikipedia.org/wiki/Gram_stain

Infection to Tubercle Bacilli• Infectious agent must remain suspended in the air to be

transmissible.

• Size of the droplet nuclei must be large enough to remain buoyant in air without evaporating and small enough to reach the alveoli in the periphery of the lungs.

• 5000 bacilli/mL in the sputum gives chance for sputum smear examination to be positive. 10,000/mL, there is 95% probability of correct identification of positive result.

• Hence this forms the mainstay diagnostic tool in tuberculosis in India.

• Exposure to Tubercle Bacilli depends on:

• Number of incident infectious cases in community and its duration

• Number and nature of interactions between case and contact per unit time of infectiousness.

Host factors• Age/Sex Incidence: 3 peak of Incidence in less developed countries ( one in early childhood, one in adolescent

age and one in old age).More among men than women but death reported more in women. More than 80% of TB cases fall in age group of 15-54 yrs.

• Nutrition: Malnutrition in children especially is a risk factors

• Socio environmental factors ( Social Disease): prevalence of social factors like

• poverty,illiteracy,ignorance,poor standard of living, overcrowding etc.

• Immunity: No inherited immunity but acquired by infection,or by immunization..

• Incubation Period: Time from receipt of infection to the development of a positive tuberculin test ranges from 3 to 6 weeks and thereafter development of disease depends upon

• closeness of contact,

• extent of disease

• dose of infection

• host parasite relationship.

• Thus the incubation period may be weeks, months or years.

Approaches to Epidemiology of Tuberculosis

• Three approaches to Epidemiology of TB

• The Etiologic Approach ( Analytical Epidemiology): Dealing with risk factors associated with the agent- M Tuberculosis

• The Descriptive Approach: Dealing with traditional incidence and prevalence of tubercular infection

• The Predictive Approach:Dealing with what happens next- forecasting the tubercular infectionHence understanding the risk factors for a given community provide an insight to develop effective tools for cure.

Epidemiological Indices• Incidence: New cases+ recurrent (relapse) episodes of TB

in a given year.

• Prevalence: Number of TB cases at a given point or period of time.

• Mortality:Number of death caused by TB in HIV-negative people

• CFR: Risk of death due to TB among people with active TB disease.

• Case notification rate:Number of new and recurrent cases of TB notified in a given year expressed per 100,000. Important in estimation of incidence of TB

• Case detection rate:Number of notification of new and recurrent cases divided by estimated incidence of such cases in the same year

• Prevalence of infection:%age of individuals who show positive reaction to the standard tuberculin test.

• Incidence of infection ( AIR/TCI): % of population under study who will be newly affected by MTB among the non-infected of the preceding survey during the course of one year. It expresses the attacking force of TB in a community.

• 1% of AIR in developing countries correspond to 50 new cases of smear-positive PTB per 100,000 population. Best indicator for evaluating TB problem and its trend.

Epidemiological Indices

Tuberculin Test• 1st discovered by Von Pirquet. It is the only means of estimating prevalence of infection in a population. In India

PPD-RT 23 with Tween 80( a detergent added to tuberculin to prevent their absorption) is used.

• Mantoux test: Inject 01 TU of PPD in 0.1 ml intradermally on the flexor surface of left forearm.

• The result is read after 48-96 hrs but 72 hours is the ideal.

• Induration > 10 mm considered +ve/6-9 mm- doubtful/<6 - negative.

• Two step Testing ( TST)

• If the first test is +ve, patient is infected.

• If the first test is -ve, give a second test one to 3 weeks after the first one

• If the 2nd test is positive, consider the person previously infected.

• If the 2nd test is negative, the person is uninfected.

In countries with high BCG coverage which also produces tuberculin hypersensitivity, tuberculin test has lost its sensitivity

as an indicator of the true prevalence of infection. It is aptly said that tuberculin test " must be approached with

respect, administered with care, read with deliberation and interpreted with sentiment discrimination".

Pathogenesis

Clinical Features• Persistent cough with sputum

which can be mucoid, purulent or blood stained.

• Loss of weight

• Fever especially evening rise of temperature.

• Pain in the chest resulting from pleurisy, myalgia

• Breathlessness

• Fine crepitations in upper part of of one or both lungs. These heard particularly on taking deep breath after coughing ( PTC)

Complications

• Haemoptysis

• Pneumothorax

• Secondary infection of cavity

• Pleural effusion

• Empyema

• Fibrosis

• Bronchiectasis

WHO Global TB Report 2014• 9 million people fell with TB in 2013 ( 126 cases /100000 population),

including 1.1 million cases among PLHIV

• 1.5 million people died from TB, including 360,000 among people who were HIV positive.

• 510,000 women died from TB in 2013, including 180,000 among women who were HIV-positive.

• Of the overall TB deaths among HIV-positive,50% were among women.TB is one of the top killer of women of reproductive age.

• An estimated 550,000 children became ill with TB and 80,000 children who were HIV- negative died of TB in 2013.

• In 2013, 5.7 million new diagnosed cases were notified to National TB programme. Therefore 3 million people with TB were "missed"

The TB mortality rate has decreased 45% since 1990

MDR-TB Burden Globally• In 2013, an estimated 480,000 people developed MDR-TB and there

were an estimated 210,000 deaths from MDR-TB

• People diagnosed with MDR-TB reached to 136,000 worldwide.

• 97,000 patients were started on MDR-TB treatment in 2013, leaving 39,000 on waiting list.

• 48% of MDR-TB patients globally had a successful treatment outcome.

• XDR-TB reported by 100 countries in 2013. An estimated 9% of people with MDR-TB have XDR-TB

Multidrug-resistant tuberculosis: is a form of TB caused by bacteria that do not respond to at least isoniazid and rifampicin, the two most powerful 1st line anti-TB drug.Extensively drug-resistant TB (XDR-TB): is a form of MDR-TB that responds to even fewer available medicines including the most effective 2nd-line anti-TB drugs.

Estimation of TB burden 2013 Number ( thousands) Rate( per 100000 population)

Mortality ( excludes HIV+TB) 240 (150-350) 19 (12-28)

Mortality ( HIV+ TB Only) 38( 31-44) 3( 2.5-3.5)Prevalence ( includes HIV+TB ) 2600 ( 1800-3700) 211 (143-294)Incidence ( includes HIV + TB) 2100 (2000-2300) 171 (162-184)

Incidence ( HIV + TB only) 120 (100-140) 9.7 (8.3-11)Estimation of MDR-TB Burden 2013 New Previously

% of TB cases with MDR-TB 2.2(1.9-2.6) 15 (11-19)

MDR-TB cases among notified 20,000 (17,000-24,000) 41000 (30,000-52,000)

TB notification in 2013 NumberTotal new and relapse 1243905 5% of the total case is among

age >15 yrs ( 64726)Previously treated excluding relapse 171712Total case notified 1415617

Case tested for RR/MDR-TB 182145Laboratory confirmed RR/MDR-TB 23162 13%

Patient started on MDR-TB treatment 21093 91%TB/HIV 2013 Number %

TB patient with known HIV 887903 63%HIV positive TB patients 44027 5%

HIV positive patient with CPT therapy 41827 95%

HIV positive patient on ART 38754 88%

Treatment Success (%)

New and relapse case registered in 2012 88%

Previously treated cases excluding relapse registered in 2012 74%

HIV-positive TB cases, all types, registered in 2012 77%

RR/MDR-TB cases started on SLD in 2011 50%

WHO India TB Report 2014

National Tuberculosis Control Programme:The Beginning

• Before RNTCP came into force the existing TB programme had the following objectives:

★ To identify and treat as large a number of TB patients as possible so that infectious case are rendered non-infectious.

★ To reduce the magnitude of TB problem in the country to a level where it ceases to be public health problem.

Organisation, Administration and Programme implementation ( Prior to

RNTCP)• Central Level:(CTD) Central Tuberculosis division in the Directorate

General Health services, NTI Bangalore and TB Research centre at Chennai.

• District Level: Functional unit of the NTCP and called as District TB Control Programme

• Peripheral Level: PHCs/CHCs.

• Programme activities were

• Case detection

• Case treatment

• Health education

• BCG vaccination

Evolution of TB Control In India

• 1950s-60s Important TB research at TRC and NTI• 1962 National TB Programme (NTP)• 1992 Programme Review (GOI, WHO and SIDA)

» only 30% of patients diagnosed; » of these, only 30% treated successfully

• 1993 RNTCP pilot began• 1998 RNTCP scale-up ( 2% of the total population coverage by

RNTCP)• 2001 450 million population covered• 2004 >80% of country covered

• 2006 Entire country covered by RNTCP

RNTCP• Launched in 1997 based on WHO DOTS Strategy.

Entire country mapped by Mar 2006 through rapid expansion of DOTS

• Implemented as 100% centrally sponsored Programme

• Objectives

• To achieve and maintain a cure rate of at least 85% among newly detected infectious cases

• To achieve and maintain detection of at least 70% of such cases in the population

Strategy• Augmentation of organizational support at central and

state level for meaningful coordination

• Increase in Budgetary outlay

• Sputum microscopy as primary method of diagnosis

• STR with uninterrupted supply of drugs at the most peripheral level

• Augmentation of peripheral level supervision through creation of subdistrict supervisory unit.

• Emphasis on training, IEC, research and involvement of NGOs

Core Element of Phase 1• To ensure high quality DOTS expansion in

the country with 5 primary DOTS

strategy

• Political and administrative

commitment

• Good quality Diagnosis through

sputum microscopy

• DOT

• Systematic monitoring

• Accountability

RNTCP Phase II

• Consolidate the achievement of phase 1

• Maintain its progress trend and effect further improvement in functioning

• Achieve TB related MDG goals while retaining DOTS as its core strategy.

Structure of RNTCP

Difference in NTP and RNTCP

NTP RNTP

Case detection and treatment 70% case detection and 85% cure rate

Case finding was active by the health worker

Case finding is passive by quality microscopy

Only one sputum smear examination used to be done

2 sputum examination ( spot, morning)

Patients not categorised for treatment

Patient categorised into two types for treatment purpose

Chemotherapy was not supervised Chemotherapy is supervised by DOTs-agent

Case detection rate and success rate less than 50%

Case detection rate is more than 85% and success rate is more than

85%

Diagnosis of Tuberculosis

• Laboratory Network

• RNTCP endorsed TB diagnostics

• Diagnostic Algorithm for Pulmonary TB

• Diagnostic Algorithm for Paediatric Pulmonary TB

• Newer Rapid Diagnostic tools

Laboratory Network• 13,309 DMC established and supervised by IRL at state level and

NRL and CTD at the National Level.

• 3 Microbiologist and 4 Laboratory technicians have been provided by the RNTCP on contractual basis to each NRL.

• They visit each assigned state at least once a year for 2 to 3 days as a part of OSE.

• 6 NRL are as mentioned below1) NIRT Chennai2) NTI Bangalore3) Lala Ram swarup Institute of TB and respiratory diseases (LRS) Delhi4) JALMA Institute Agra5) Regional Medical Research centre, Bhubaneswar6) Bhopal Memorial Hospital and Research Centre, Bhopal

• One IRL designated at State Tuberculosis Training and Demonstrations centres (STDC)/Public health laboratory/Medical college of the respective state.

Laboratory Network Contd.

• Culture and DST Laboratories

• 51 RNTCP certified C & DST laboratories in the country which includes laboratories from public sector ( IRL and Medical Colleges,) (Private sector and operated by NGOs).

• Solid culture certification: 37 Lab. for C & DST certified. This include 4 NRLS, 18 IRLS, 6 medical colleges, 3 NGOs, 4 ICMR institutes and 2 private laboratories

• Liquid culture certification: 12 Lab. for liquid culture, which include 4 NRLs, 4 IRLs, one NGO lab. and 2 private Lab.

• LPA:Molecular test which can provide the DST results within one day. 41 Lab. certified by RNTCP. This include 4 NRLs, 24 IRLs, 8 medical colleges, 4 NGOs and one private medical colleges.

• Second Line DST (SLD): 5 Lab (3 NRL, 01 IRL and one NGO Lab) are performing SLD in solid and liquid culture.

• New Initiatives:Completed the feasibility study of introducing Genexpert in RNTCP in 18 tuberculosis units in 12 states. RNTCP is using CB NAAT for the diagnosis of TB and MDT-TB in high risk population like HIV positive and Paediatric groups.

Quality Assurance• QA is a total system consisting of

internal quality control (IQC), assessment of performance using external quality assessment ( EQA) methods and continuous quality improvement (QI) of laboratory services

• 3 components of EQA are:

• Onsite Evaluation (OSE)

• Random Blinding Re-checking (RBRC)

• Panel Testing

Monthly EQA-OSERBRC

Quarterly

Quarterly & yearly report

OSE- yearly

OSE- yearly

Monthly & quarterly report

Quarterly & yearly report

RNTCP endorsed diagnostics• Smear Microscopy for AFB

• Sputum smear stained with Z N staining

• Fluorescence stains and examined under direct or indirect microscopy with or without LED

• Culture

• Solid ( LJ) media

• Liquid Media ( Middle Brook) using semi-automatic or automatic machines,e.g., Bactec, MGIT etc

• Rapid Diagnostic molecular test.

• Conventional PCR based LPA for MTB complex

• Real time PCR based NAA test for MTB complex,e.g GeneXpert

Sputum Microscopy• ZN staining technique is used in RNTCP. Sputum

microscopy has the following advantages

• Simple, inexpensive, requires minimum training

• High specificity and reliability

• can be used for diagnosis, monitoring and defining cure.

• Results available quickly and feasible at peripheral health institution.

Therefore this is the Key diagnostic tool used for case detection in RNTCP

Zeihl Neelsen Staining• Make a smear from the yellow muck-purulent portion of the sputum ( 2cm x 2 cm, neither two

thick nor two thin.

• Dry in air for 15-20 minutes. Fix it over a flame 3 to 5 times for 3 to 4 seconds each time.

• Pour 1% filtered carbol fuchsin to cover the slide. Heat gently till vapour rise. leave it for 5 mins.

• Rinse the slide with tape water until CF stain is washed away. Pour 25% sulphuric acid and leave for 2 to 4 mins.Rinse it with tap water

• Pour 0.1% methylene blue onto the slide and leave it for 30 seconds. Rinse again with tap water and allowed to dry.

• Examine the slide under the microscope using the x40 lens to select a area and then examine this under x100 lens using a drop of immersion oil.

If the slide has No. of fields to be examined

Grading Results

No AFB in 100 oil immersion fields 100 0 Neg1-9 AFB per 100oil immersion fields 100 Scanty Pos

10-99 AFB per 100 oil immersion fields 100 1+ Pos

1-10 per oil immersion fields 50 2+ PosMore than 10 AFB per oil immersion

fields 20 3+ Pos

Diagnosis of Drug Resistant-TB• Culture of M Tuberculosis is a very sensitive and specific

tool.

• It is used for the diagnosis of drug resistant TB but is expensive and time consuming.

• Laboratory based diagnosis either phenotypically ( growing the bacteria and demonstrates the ability of bacteria to grow in the presence of anti-TB drugs ( DST) or genotypical by demonstrating the presence of resistance genes using molecular methods.

• The conventional and newer rapid tools used are

• Solid cultural medium- Egg based Lowenstein Jensen or Agar-based &H11/10 medium.

• Liquid culture medium- Commercial automated MGIT 960

Newer Rapid Diagnostic tools

• Non-commercial solid culture methods: Nitrate Reductase Assay using the property of M.tb to reduce nitrate to nitrite as means of detection of drug resistance.

• Non- commercial liquid culture methods: MODS using 7H9( medium in micro titre wells and observing growth using inverted microscope for both culture and DST.

• Liquid culture system: MGIT available in automated MGIT-960 and MGIT manual system. Detect growth of bacteria as early as 4 days from inoculation and DST will be available in 21-28 days.

• Molecular Assays: PCR based technologies used to detect putative resistance genes ( rpo8 for rifampicin, KatG and inna for INH etc). commonly used are LPA/NAAT

• Newer tools include, Cepheid GeneXpert

X- RAY• It is more sensitive but less specific.

• It is useful for diagnosis of extra PTB like pleural and pericardial effusion, Mediastinal adenopathy and miliary TB.

• Limitations as diagnostic tool are:

• High inter and intra reader variation

• No shadow is characteristic of TB

• 10-15% culture positives cases remain undiagnosed

• 40% patients diagnosed as having TB by X-ray alone may not have active TB disease.

Diagnostic Algorithm for PTB

Pulmonary TB suspects• Fever and/or cough ( 2 weeks)/loss of weight/No weight gain• History of contact with suspected or diagnosed case of

active TB

Sputum examination

Sputum smear negative/Sputum not

availableSputum smear

positive

Child has1) Already received a complete

course of antibiotics2) Sick look or

3) Severe respiratory distress4) Any other reason for XRC

No

Yes

7 day course of Antibiotic e.g Amoxicillin

No response

XRC & Tuberculin test (TST)

XRC suggestive of TB &TST Positive

Diagnostic Algorithm for

Paediatric PTB

Smear Positive PTBTreat accordingly

GL/IS/BAL

Smear negative

Smear-negative PTB ( initiate T/T)

Either or both negative

Flow Chart in next slide.

Smear positive

Further investigations in paediatric PTB suspect who has persistent symptoms and dose not have highly suggestive chest skiagram

XRC non-specific shadowsTST positive/negative

XRC normalTST positive

XRC normalTST negative

Review for alternate diagnosis Repeat XRC after course

of antibiotic (if not already received)

XRC-persistent non specific shadows.TST positive/negative

GL/IS/BALsmear positive smear negative

Smear positive PTBTreat according to guidelines

Look alternative diagnosisIf no alternative-treat as smear negative PTB

Review for alternate diagnosis

Yes, give specific diagnosis NO

Look for extra-pulmonary site TBIf no then:Seek expert helpCT chest & otherinvestigation may be needed.

Administering Treatment

• Domiciliary treatment

• Short course chemotherapy

• Intermittent regimen

• Direct observation of treatment

Domiciliary Treatment• As effective as sanatoria treatment

• Studies in India have shown that smear-positive TB

patients treated on a domiciliary basis have

achieved higher cure rates and as good as when

treated at Sanatorium

• Social benefits for sure is an added advantage

Short- Course Chemotherapy• SCC used to treat & cure TB patients in as short a period as 6 to 8

months.

• Reduction possible due to introduction of Rifampicin and Pyrazinamide.

• Role of IP:use of multi drug in IP leads to rapid killing of actively multiplying bacillary population. this will eliminate naturally occurring drug resistant mutant.

• Role of CP: CP with fewer drugs for longer time ensure elimination of persisters which are responsible for relapses.

Drugs Early Bactericidal Sterilising activity

Prevention of emergence of drug resistance

Isoniazid (H) ++++ ++ ++++

Rifampicin (R) +++ ++++ +++

Streptomycin (S) +++ - ++Pyrazinamide (Z) ++ +++ +Ethambutol (E) + - ++

• Based on the existence of "Lag period".

• "In vitro, culture of M.tuberculosis when exposed to certain drugs for some time, it take several days before new growth occur".

• Hence there is no need to maintain blood level of drugs for 24 hours in the treatment of TB.

• The ability of the drugs to continue to exert its antimicrobial activity even after their withdrawal is called as lag period.

• Hence this renders intermittent regimen possible with below mentioned advantages

• As effective as daily treatment

• Facilitates DOT

• Reduction in total quantity of drugs consumed

• Fewer adverse reactions

Intermittent Treatment

• Studies reveals that 1/3rd of patients do not consume medicine regularly.

• DOT is a supportive mechanism that ensures the best possible results in treatment of TB.

• Many patients leave drug once they feel better which is neither predictable nor preventable.

• Studies have shown poor treatment outcome and high death rate in the absence of DOT.

Directly Observed Treatment

Hence by providing DOT RNTCP ensures that patient receive "the right drugs, in the right doses, at the right intervals and for right duration".

(DOT-PLUS)• Five components of DOTS-PLUS

• Sustained political and administrative commitment

• Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing

• Treatment strategies that utilises 2nd line drug

• Uninterrupted supply of 2nd line drugs

• Recording and reporting system designed for DOTS-Plus programme.

Definitions: Revised definitions as per WHO

• Presumptive case: Patient who present with symptoms or signs suggestive of TB ( earlier known as TB suspect)

• Case Definitions

• A bacteriologically confirmed TB case (BCTB): Biological specimen positive by microscopy, culture or Xpert MTB/RIF.

• A clinically diagnosed TB case (CDTB): Clinically diagnosed by the practitioner but not bacteriologically confirmed.

• Both the above case can be classified according to

• Anatomical site of disease

• History of Previous treatment

• Drug resistance

• HIV resistance

• PTB:Any BCTB or CDTB case involving the lung parenchyma or tracheobronchial tree. A person with both PTB and EPTB should be classified as PTB

• EPTB:Any BCTB or CDTB involving organs other than lungs.

Classification based on anatomical site of disease

Classification based on history of previous TB treatment. ( Patient registration group)

• New patients:Never been treated or taken ATT for less than one month.

• Previously treated patients: Patients who received 01 month or more of ATT in the past;

• Relapse

• Treatment after failure

• Treatment after loss to follow up

• Other previously treated patients

• Patients with unknown previous TB treatment history

Previously treated patients

Declared cured or treatment completed

diagnosed with recurrent episodes of TB

treatment failed at the end of treatment

earlier called as Treatment after default

declared lost to follow up at the end of treatment

outcome not known or undocumented

Previously treated patients but does not fit in any above category

Relapse




Treatment after Failure

Treatment after loss to follow up

Other previously treated patients

Patients with unknown previous TB treatment history

Classification based on Drug Resistanceresistance to one 1st line Anti-TB drug only

Monoresistanceresistance to more than one 1st line Anti-TB drug

only

Polydrug resistance

resistance to at least both H and R

Multi drug resistance

resistance to any fluoroquinolone and at least 3 second line injectables ( Capreomycin, Kanamycin and amikacin) in addition to MDR

Extensively drug resistanceresistance to Rifampicin with or without resistance to other

drugs

RR-TB

Classification based on HIV status

BCTB or CDTB

HIV positive result

HIV - Positive TB patients

HIV negative result

HIV - Negative TB patients

No result of HIV testing

HIV - status unknown TB patients

Treatment outcome definition

Treatment outcome definition

Treatment RegimensTreatment groups Type of Patient IP CP

Pre-treatment

sputum

Test at

month

If result is Then

New (Cat I)

Sputum smear-positivesputum smear-negativeExtra-pulmonary

Others

2H3R3Z3E3 4H3R3

+ 2

- Start continuation phase, test sputum again at 4 & 6 months

+Continue intensive phase for one more month, test sputum again at

3,5 and 7 months

-

2

- Start continuation phase, test sputum again at 6 month


3,5 and 7 months

Previously Treated ( Cat II)

Smear positive relapseSmear-positive failureSmear- positive treatment after default

Others

2H3R3Z3E3 S3

1H3R3Z3E3

5H3R3E3 + 3

- Start Continuation phase, test sputum at 5 and 8 months


4,6 and 9 monthsRegimen for IP CP

Blisters

Doses

Extended IP blister and doses

Blisters

Doses

Cat-1 24 24 12 18 54

Cat-2 36 36 12 22 66

Drugs Dose ( thrice a week)

Number of tablets in blister pack

Isoniazid (H) 600 mg (10-15 mg/kg) 2X300 mg

Rifampicin (R) 450 mg (10mg/kg) 1X 450 mg

Pyrazinamide (Z) 1500 mg (35 mg/kg) 2X 750 mg

Ethambutol (E) 1200 mg (30 mg/kg) 2X600 mg

Streptomycin (S) 0.75 gm (15 mg/kg)One blister in IP contain one day dose

One blister in CP contain one week dosePt weighing more than 60 kg should be given 150 mg additional dose of Rifampicin

Pt with age more than 50 yrs should receive streptomycin 500 mg.

Management of patients who were smear-negative at diagnosis and who interrupt treatment

T/T received before

interruptionLength of interruption Do a sputum

examination

Results of sputum smear

examinationOutcome Re-

registration Treatment

<1 month

< 2month No - - - Resume treatment and complete doses

2 month or more YesNegative - - Resume treatment

Positive Default New Begin CATI Fresh

>1month< 2 month No Negative - - Resume treatment and complete

all doses

> 2 month Yes Positive Default Treatment after Default Begin CAT II treatment afresh

Management of new smear-positive cases who interrupt treatment ( Category 1)

T/T received before

interruption

Length of interruptio

n

Do a sputum

examination


examinationOutcom

e Re-registration Treatment

<1 month

< 2 weeks No - - - Continue CAT I

2-7 weeks No - - - Start again on CAT I

8 weeks or more Yes

Positive Default New Start again on CAT I

Negative - - Continue CAT I

1-2 months


2-7 weeks YesPositive - - 1 extra month of IP of CAT

I


8 weeks or more Yes

Positive Default Treatment after default Start on CAT II


> 2 months


2-7 weeks YesPositive Default Other Start on CAT II


8 weeks or more Yes

Positive Default Treatment after default Start on CAT II


Management of retreatment of smear-positive cases who interrupt treatment ( Category II)

T/T received before

interruptionLength of

interruptionDo a sputum examination


examination

Outcome

Re-registratio

nTreatment

<1 month

< 2 weeks No - - - Continue CAT II

2-7 weeks No - - - Start again on CAT II

8 weeks or more YesPositive Default

Treatment after

DefaultStart again on CAT II

Negative - - Continue CAT II

1-2 months


2-7 weeks YesPositive - - 1 extra month of IP of CAT II



Treatment after

defaultStart again on CAT II


> 2 months


2-7 weeks YesPositive Default Other Start again on CAT II



Treatment after

defaultStart again on CAT II


Drugs Product code (PC)-13 Product code (PC)-14 PC-15 PC-16

IP 24 blisters CP 18 blisters IP 24 blisters

CP 18 blisters 12 blisters 12 blisters

H 75 mg 75 mg 150 mg 150 mgProlongation of IP for PC

13Prolongation of IP for PC

14R 75 mg 75 mg 150 mg 150 mgZ 250 mg 500 mgE 200 mg 400 mgWeight band For New cases Prolongation of IP

IP CP6-10 Kg PC 13 PC 15

11-17 Kg PC 14 PC 16

18-25 Kg PC 13+PC 14 PC 15+PC1626-30 Kg PC 14+PC 14 PC 16+ PC 16

Weight band For Previously treated cases Prolongation of IPIP CP

6-10 Kg (PC 13+PC 15)+ 24 vials Inj SM (PC 13+54 Tab E 200mg )+(PC 15 without Z) PC 15

11-17 Kg (PC 14+PC 16)+ 24 vials Inj SM (PC 14+54 Tab E 400mg )+(PC 16 without Z) PC 16

18-25 Kg (PC 13+PC 14+PC 15+PC 16)+ 24 vials Inj SM

(PC 13+ PC 14+54 Tab E 600 mg)+(PC 15+PC 16 without Z) PC 15+PC16

26-30 Kg (PC 14X 2)+(PC 16X2)+ 24 vials Inj SM

(PC 14X2+54 Tab E 800 mg)+(2XPC 16 without Z) PC 16X2

Paediatric Treatment in RNTCP

Non -DOTS Treatment Regimen under RNTCP

• Needed for • Those with ADR to Rifampicin and Pyrazinamide• 'New' patients who refuse DOTS despite all effort

• Non DOTS regime 1( smear positive PTB, EPTB)• Treatment regimen of 12 month duration, comprising 2 months

of SHE and 10 months of HE ( 2 SHE/10 HE)• Dose administered /day in the regimen are:• Isoniazid- 300 mg• Ethambutol- 800 mg• Streptomycin- 750 mg ( 500 mg for those> 50 yrs of age).

• Non DOTS regime 2 (ND2): For smear -ve pulmonary not seriously ill patients and extra pulmonary non seriously ill patients- 12 HE

Management of MDR-TB• Diagnosis of MDR TB is at IRL accredited to perform C & DST. After Diagnosis, t/t

initiated at DOTS-Plus site which are established at tertiary centres.

• Pretreatment evaluation: Detailed history, height CBC, Blood sugar, LFT, blood urea and serum creatinine, XRC pregnancy test for women in child bearing age.

• DTO verify the address and meet the family members. DOT provider and centre is established.

Best way to Prevent MDR/XDR TB is cure TB patientswith DOTS

Famous saying is "FIRST HIT IS BEST HIT"

Drugs 16-25 Kg 26-45 Kg > 45 Kg

Kanamycin (km) 500 mg (15-20 mg/kg) 500mg 750 mgLevofloxacin (LVX) 200 mg 7.5-10 mg/kg 500 mg 750 mg

Ethambutol (E) 400 mg (25 mg/kg) 800 mg 1000 mgEthionamide (Eto) 375 mg (15-20 mg/kg) 500 mg 750 mgPyrazinamide (Z) 500 mg (30-40 mg/kg) 1250 mg 1500 mgCycloserine (Cs) 250 mg (15-20 mg/kg) 500 mg 750 mg

PAS 5 g (150 mg/kg) 10 g 12 gPyridoxine 50 mg 100 mg 100 mg

RNTCP MDR-TB Treatment Regimen• Standardised treatment regimen• 6 drugs (Km,Lvx,Eto,Z,E,Cs) during 6-9 months of an IP. 4

drugs (Lvx,Eto,E and Cs) during 18 months for CP. • Patient to receive drugs under direct observation on 6 days

of the week. On 7th day (Sunday), the oral drug will be administered unsupervised.

• Intolerance to E and Cs should be treated by replacing it with PAS and we need to split the dose into two ( morning and evening).

• 100 mg of Pyridoxine given to all MDR-TB.• Follow up schedule during Dr-TB treatmentIP monthly follow up

Extension of IP (1-3 months

CP Quarterly follow up examination in months

1st FU 2nd FU 3rd FU 4th FU 1st qtr II qtr III qtr IV qtr V qtr VI qtr

NO IP Extension 3 4 5 6 - - - 7 9 12 15 18 21 24

IP extension 1 month 3 4 5 6 7 8 10 13 16 19 22 25

IP extension 2 month 3 4 5 6 7 8 9 11 14 17 20 23 26

IP extension 3 month 3 4 5 6 7 8 9 10 12 15 18 21 24 27

• MDR-TB patient diagnosed as XDR-TB would need "• Switched to regimen for XDR-TB"• IP (6-12 months) 7 drugs ( capreomycin , PAS,

Moxifloxacin, High dose INH, Clofazimine, Linezolid and Amoxyclav.

• CP (18 months) 6 drugs ( PAS, Mfx, High dose INH, Clofazmine, Linezolid and Amoxyclav.

RNTCP XDR-TB Treatment Regimen

Drugs Less than equal to 45 Kg > 45 kgInj. Capreomycin 750 mg 1000 mg

PAS 10 gm 12 gmMfx 400 mg 400 mg

High dose INH 600 mg 900 mgCfz 200 mg 200 mgLzd 600 mg 600 mg

Amoxyclav 875/125 mg BD 875/125 mg BDPyridoxine 100 mg 100 mg

Reserve drugsClarithromycin 500 mg 500 mgThiacetazone 150 mg 150 mg

Algorithm for management of M/XDR who default and return for treatment within 6 months of discontinue regimen ofr M/XDR-TB

Algorithm for management of M/XDR who default and return for treatment after 6 months

Treatment During Pregnancy ( in relation to MDR-TB)

• In general, H,R and E for 2 months followed by H, & R for additional 7 months

• Streptomycin is contraindicated in pregnancy because it cause congenital deafness.

• Epi-info based EPI- CENTRE software was used for electronic data transfer from district level onwards.

• Central TB Division (CTD) along with NIC developed Case based Web Online application called Nikshay. Launched in May 2012.

• The software has following components• Master management/user details/registration and details of diagnosis,

DOT provider, contact tracing, follow up, outcomes etc.• Details of solid and liquid culture and DST, LPA, CBNAAT etc.• Referral and transfer of patients. Private health facility registration and

TB notification. Mobile application for TB patients• SMS alert to patients on registration/to programme officers• Automated periodic reporting• Case finding/Sputum conversion/Treatment outcome.

TB surveillance in India with NIKSHAY

State ( 2nd Quarter RNTCP 2015 report) Uttar Pradesh India

1 Population (in lakh) covered by RNTCP1 2151 953

2 No. of suspects examined 365857 2270323

3 Suspects examined per lakh population/Qtr 170 2381

4 No of Smear positive patients diagnosed2 47603 252917

5 Suspects examined per smear positive case diagnosed 8 9

6 Total patients registered for treatment3 72491 392242

7No (%) of pediatric cases out of all New cases

3445 20260

8 6% 6%

9 3 month conversion rate of new smear positive patients 89% 89%

10 3 month conversion rate of retreatment patients 72% 72%

11 No (%) of all Smear Positive cases started RNTCP DOTS within 7 days of diagnosis

36673 192872

12 89% 89%

13 No (%) of all Smear Positive cases registered within one month of starting RNTCP DOTS treatment

40866 210629

14 99% 97%

15 No (%) of all cured Smear Positive cases having end of treatment follow- up sputum done within 7 days of last dose

29663 147797

16 87% 85%

17 No (%) of cases (all forms of TB) registered receiving DOT through a community volunteer

52438 21642818 75% 58%

19 Proportion of all registered TB cases with known HIV status 63% 78%

20 Proportion of TB patients known to be HIV infected among tested 1% 3%

21 Proportion of TB patients known to be HIV infected among registered 0% 3%

22 Proportion of HIV infected TB patients put on CPT( RT report) 56% 95%

23 Proportion of HIV infected TB patients put on ART( RT report) 84% 93%

States Uttar Pradesh India

New Smear Positive1

Regist-ered 35030 172602

Cure 82.56% 83.22%Comp-leted 5.60% 3.88%

Died 3.29% 4.13%

Failure 1.02% 1.56%

Defaulted 6.58% 5.59%

Trans out 0.65% 1.05%

Switched to Cat IV 0.29% 0.59%

New Smear Negative2


Comp-leted 89.60% 88.64%

Died 2.22% 3.85%

Failure 0.24% 0.30%


Trans out 0.77% 1.33%


New Extra Pulmonary2


Comp-leted 95.64% 93.93%

Died 0.70% 2.22%

Failure 0.06% 0.08%


Trans out 0.47% 0.89%


Treatment outcome of all HIV infected New TB cases - 2nd quarter 2014

State Total New Cases Treatment Success Died Failure Default Transfer Out Switch to CAT 4

Uttar Pradesh 136 73% 10% 2% 10% 4% 1%

Treatment outcome of all HIV infected Re-treatment TB cases - 2nd quarter 2014

States Total Retreatment Cases Treatment Success Died Failure Default Transfer Out Switch to CAT 4

Uttar Pradesh 86 68.60% 15.12% 1.16% 6.98% 5.81% 2.33%

TB and HIV• TB is the most important opportunistic

infection among PLHIV.• TB infection: 10% life time risk of getting TB

disease• HIV infection: 30% life time risk of getting TB

disease• Dual infection of TB and HIV:50% life time of

getting TB disease.Features of PTB Stage of HIV infection

Early Late

Clinical Picture Often resembles post-primary TB Often resembles primary TB

Sputum Smear result Often positive Often negativeChest X-Ray Appearance Often cavities Often infiltrates with no

cavities

Treatment of TB disease in HIV infected patients

• Patients treated with RNTCP "New" or previously treated" regimen

according to history.

• HIV- infected TB patients should be referred to ICTC. The visit should

be at least 2 weeks after initiation of TB treatment to ensure

reduction in TB transmission from these patients to large HIV-

infected persons.

• NACO and WHO recommendation on ART is as mentioned belowCD4 cell count ART recommendation Timing of ART in relation to treatment of MDR-TB

<=350 cells/mm3 Recommend ART After 2 week, as soon as the treatment for MDR-TB is tolerated

> 350 cells/mm3 Defer ARTRe-evaluate patient monthly for consideration of ART.

CD4 is recommended every 3 month during t/t for MDR-TB.

Not Available Recommend ART After 2 week, as soon as the treatment for MDR-TB is tolerated

Cotrimoxazole Preventive therapy (CPT)

• CPT shown to reduce mortality among HIV-infected TB patients and recommended by NACP.

Treatment of TB in HIV positive patients on 2nd line ART/alternate First Line with Protease inhibitors ( PI) based regimen

• PI should not be used with rifampicin-containing regimens due to hepatic enzyme inducing capacity of rifampicin which reduces PI level sub-therapeutic.

• Rifabutin a less potent inducer of liver enzyme can be used along with PI.

• In patients taking lopinavir/ritonavir (LPV/r) based ART regimens, NACP and RNTCP have recommended the substitution of Rifabutin for rifampicin for duration of TB treatment. Dosage of Rifabutin is 150 mg dosed thrice-weekly for all patients >30 kg weight.

The STOP TB STRATEGY• Vision: A TB Free world• Goal:To reduce the global burden of TB by 2015 in line with MDG goals.• Objectives: • Achieve universal access to high quality care for all people with TB.• Reduce human suffering and socioeconomic burden. Protect vulnerable population from TB,

TB/HIV and MDR-TB• Support development of new tools• Protect and promote human rights in TB prevention,care and control.

• Targets: • By 2015:

• Prevalence and death rate will be reduced by 50% related to 1990 levels.• Reducing prevalence level to 150/100,000 per year or lower and deaths to

15/100000/year by 2015• Number of people dying to be less than 1 million by 2015.

• By 2050• Incidence less than or equal to 01 case per million population/year

• The 6 Components• Pursue high quality DOTS expansion and enhancement• Address HIV-TB , MDR-TB and the need of poor and vulnerable populations• Contribute to health system strengthening based on PHC• Engage all care providers• Empower people with TB and communities through partnership.• Enable and promote research

Xpert MTB/RIF Test

• Fully automated diagnostic molecular test.

• It detect simultaneously TB and rifampicin drug resistance.

• Provide accurate result in less than 2 hours, hence patient can be offered proper treatment on the same day.

• Diagnostic test in adults and children presumed to have MDR-TB and HIV-associated TB.Also used in testing CSF from patients presumed to have TB meningitis

WHO recommend use of Bedaquiline with dose of 400 mg daily

for 2 weeks first, then thrice weekly (200mg)for 22 weeks ( total of 6 month)

To be used with caution in HIV patient and other cor-morbidities.

POST 2015 Strategy to end TB

• Vision: A world free of TB ( Zero death, disease and suffering due to tuberculosis)

• Goal: End the global tuberculosis epidemicIndicator Milestones Target

2020 2025 SDG 2030 End TB 2035

Reduction in number of TB deaths compared to 2015(%) 35% 75% 90% 95%

Reduction in TB incidence rate compared with 2015 (%)

20%<85/100,000

50%<55/10000

0

80%<20/1000

0090%<10/100000

TB affected families facing catastrophic costs due to TB (%) Zero Zero Zero Zero

Tuberculosis Vaccine Development

• BCG vaccine developed in 1921 remains the only available vaccine against TB.

• It is partially effective: some protection against severe form of paediatric TB but not completely. It is unreliable against adult pulmonary TB.

• Multiple vaccine development strategies are;• Prevention of infection: ( prior to mtb exposure)• Prevention of disease:(after exposure to mtb, to people at

risk of developing disease.• Prevention of recurrence:( after infection, and treatment of

mtb, disease to prevent reactivation and subsequent transmission

• 16 different vaccine candidates are in trial ( 5 based on whole cell mycobacteria and remainders are recombinant proteins.)

Summary of the Seminar• Tuberculosis remains a major health problem

• SEA Region account for 39% of global burden of TB in terms of incidence and India alone account for 24% of the world's TB case ( Highest TB Burden country in the world)

• DOTs and DOTS-Plus remains central to the public health approach to TB control well incorporated by RNTCP

• In 2006 STOP TB Strategy announced by WHO and well adopted by RNTCP.

• RNTCP outlines a clear cut treatment regimen for MDR/XDR with all possibilities

• SDG for TB well defined based on accomplishment of MDG. The bottom line is "FIRST HIT IS BEST HIT" .Strict adherence to the policy of DOT is theKey to success. Find treat and Cure TB

References1. RNTCP Training Module for Medical Practitioners prepared by central TB

division, IMA and WHO-India2. http://www.who.int/tb/new drugs3. http://www.who.int/laboratory/mtbrifrollout4. http:www.who.int/tb/challenges/mdr5. TB India 2014 RNTCP Annual status report by central TB division MOHFW (

www.tbcindia.nic.in)6. http://www.who.int/tb/theendtb strategy7. WHO Global TB Report 20148. WHO India TB Report 20149. RNTCP DOTS plus guidelines by CTD MOHFW GOI Jan 2010.10.Park Textbook of PSM 23rd Edition (Epidemiology of communicable

disease/National Health programme.)11.Community Medicine with recent advances by Suryakantha 3rd edition

/Epidemiology of communicable disease.12.Textbook of Community Medicine by Sundarlal, Adarsh and Pankaj 4th

edition.13.Prep Manuals for Medicine 3rd edition by Mathew, Aggarwal.

http://www.who.int/tb/new

http://www.who.int/laboratory/mtbrifrollout

http://www.tbcindia.nic.in/

http://www.who.int/tb/the

Thank You and its open for discussion!!

Tuberculosis disease burden in India

TB Burden Number ( Millions) (95% CI)

Rate/100,000 persons (95% CI)

Incidence 2.2(2.0-2.4) 176 (159-193)

Prevalence 2.8 (1.9-3.9) 230 (155-319)

Mortality 0.27 (0.17-0.39) 22 (14-32)

TB Burden Number ( Millions) (95% CI)

Percent (95% CI)

HIV among estimated incident TB Patients 0.13 (0.12-0.14) 5.6% (5.4-6.2)

MDR-TB among notified pulmonary TB Patients

0.064 (0.049-0.079) 2.2% (1.9-2.6)

MDR-TB among notified Re-Treatment Pulmonary TB Patients 0.27 (0.17-0.39) 15% (11-19%)

• India is the second most populous country in the world. 1/4th of the global incident TB cases occur annually in India.

• 42% reduction in TB mortality rate by 2012 as compared to 1990. 51% reduction in TB prevalence rate by 2012 as compared to 1990 level.

• In 2012 out of global annual incidence of 8.6 million, 2.3 million cases occurred in India.

Data source: TB India 2014 RNTCP annual status report, Central TB Division DGHS, MOHFW Delhi

Extra slide

• Bactericidal action: ability of ATT to kill numbers of actively metabolising bacilli rapidly. H is the most potent Bactericidal action.

• Sterilising action: capacity of ATT to kill slow or intermittent metabolising semi-dormant bacilli the so called persisters. Refampicin and Pyrazinamide are main sterilising agent.

Fall and Rise phenomenon

• Fall: SSP at commencement of therapy. Therefore bacillary content declines and become negative on smear microscopy and positive on culture- The fall" ( fall of drug sensitive bacilli)

• Still later the sputum bacillary content increases and the sputum smear becomes positive again-the rise" ( rise of drug resistant mutants of the strain

Revised Definitions of tuberculosis cases and treatment

• Presumptive treatment also called TB suspect• Bacteriologically confirmed case• Clinically diagnosed• Classification as mentioned below:• anatomical site of lesion• History of previous treatment• Drug resistance• HIV status• Treatment outcome definition

• Normal TB• MDR/XDR TB patient.

Weight loss and evening rise of temperature

• Alveolar macrophages releases TNF alpha and IL1 which is responsible for granuloma formation and systemic effects like weight loss and low grade fever. Cortisol also releases which counter IL1 hence fever is low grade.

• Cortisol burst in human is in morning and hence this lead to evening rise of temperature and night sweating

Empyema

• Accumulation of pus in pleural cavity also called pleural empyema, pyothorax or purulent pleuritis

Programme Performance and Evolution of RNTCP

• Despite nationwide network of facilities, NTCP failed to yield results.

• The case finding efficiency was only 30 of the expected level.

• GOI launched the RNTCP in 1997 encouraged by the results of pilot studies tested in 1993-94.

• New: TB patients never had t/t for TB or has taken anti-TB drugs for less than one month

• Relapse: A TB patient who declared cured or treatment completed and who reports back to HF and found to be sputum SP.

• Transferred in: A TB patients who received for t/t in a TU, after starting t/t in another TB unit where s/he has been registered.

• Treatment after default:A patient who has received t/t for TB for a month or more and return to treatment after having defaulted i.e., not taken Anti-TB drugs consecutively for 2 months or more and found to be smear positive.

• Treatment failure: Any TB patient who is SP at 5 month or more after initiation of treatment.

• Chronic: A patient who remains smear positive after completing regimen for previously treated but not initiated MDR-TB treatment

• Others: A patient who does not fit in any of the above types. The reason need to be mentioned in the TB register

Type of Cases

Treatment Outcome• Cured: Initially Sputum SP patient who has completed treatment and had sputum SN

on two occasions, one of which was at the end of treatment.

• Treatment completed: Initially Sputum SP patient who has completed treatment with negative smear at the end of IP/two months in the CP, but none at the end of the treatment. Or sputum SN patient who has received full course of treatment and has not become SP at the end of treatment. Or EPTB who has received full course of treatment and has not become SP during or at the end of treatment.

• Died: Patient who died during the course of treatment regardless of cause.

• Failure: Any TB patient who is smear positive at 5 months or more after initiation of the treatment and not put on MDR-TB

• Defaulted: A patient after treatment initiation has interrupted treatment consecutively for > 2 months

• Transferred out: A patient who has been transferred to another TU and whose treatment outcome is still not available

• Switched over to MDR-TB treatment: A patient who has been diagnosed as having MDR-TB by an RNTCP accredited Laboratory prior to being declared as failure and is placed on RNTCP MDR-TB treatment regimen.

Management of MDR-TB

• Identification of MDR-TB: The criteria are

• A new SPP remaining SP at the end of 5th month

• A new SNP becoming SP at the end of 5th month

• A patient treated with Cat II remaining positive at 4th

month

• SP contacts of an established/confirmed MDR-B case.Best way to Prevent MDR/XDR TB is cure TB patientswith DOTS

Famous saying is "FIRST HIT IS BEST HIT"

Health & Medicine

Epidemiology of tb with recent advances acknowledged by who