COURSE FOR PHARMACISTS (PHI) ON NTEP

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Resources

• Global Tuberculosis Report, 2020; Geneva: World Health Organization, 2020
• Training Modules (1-4) for Programme Managers and Medical Officers India: Central TB Division, MoHFW, Government of India,July 2020

• Globally, an estimated 11 million people fell ill with TB (incidence) in 2021.
• Historically, it has been the top infectious disease killer. In 2021, there were an estimated 1.4 million TB deaths and an additional 187 000 deaths among HIV-positive people.
• Three countries accounted for 42% of global cases in 2021: India (26%), the Russian Federation (8.5%) and Pakistan (7.9%).

Image Figure: Estimated TB incidence in 2021, for countries with at least 100 000 incident cases; Source: Global TB Report, 2022.

Resources​

• Global tuberculosis report 2022.

TB is one of the top burdensome infectious diseases in India. It is estimated that, around 1/4th (26%) of the world's TB cases are in India, translating to about 30 Lakhs new TB cases emerging each year (TB incidence). Against this estimated incidence the National TB Elimination program reported around 19 lakh new and relapse cases in the year 2021.

An estimated 5 Lakhs deaths occur due to TB each year in the country, translating to about 1 case of TB death every one-two minutes. Compared to this, there are only about 60 thousand deaths due to HIV and about 77 deaths due to Malaria each year.

TB diagnosis and treatment services although provided free of cost in the public sector, the cost of accessing these services and related loss of wages drive the affected people with poverty (catastrophic costs). TB also has a huge impact on the world's and the country's economy because of loss of workdays (100 million workdays per year).

Assessment

Resources:

• ^*WHO Global TB Report 2021
• ^{^}Status of National AIDS Response
• ^$PIB MOHFW

TB is caused due to the infection by a bacterium called Mycobacterium tuberculosis.

It often affects the lungs, and in such cases it is called Pulmonary Tuberculosis. But, it can affect almost any part of the body (except the hair and the nails), in which it is known as Extra-Pulmonary Tuberculosis.

Resources:

• Technical and Operational Guidelines for TB Control in India 2016

Tuberculosis is transmitted mainly through the air via droplet nuclei generated when a TB patient coughs or sneezes. 

It is estimated that every sputum smear-positive patient spreads the infection to 10 – 15 persons annually, if untreated..

Figure: Transmission of TB bacteria through air via droplet

Resources:

• Technical and Operational Guidelines for TB Control in India 2016
• WHO - Fact sheet details on Tuberculosis

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Determinants are any characteristics that affect the health of a patient.

TB can affect anyone but it is more prevalent in some communities which are vulnerable to TB disease due to various factors which are mentioned below:

Increased exposure of TB due to where they live or work

• prisoners
• slum dwellers
• miners
• hospital visitors
• healthcare workers

Limited access to Quality TB services

• Migrant workers
• Women in settings with gender disparity,
• Children
• Physically challenged
• Transgender population
• Tribal and population living in hard to reach areas
• Refugees or internally displaced people
• Illegal miners and undocumented migrants

Increased risk because of biological or behavioural factors that compromise immune functions in people who:

• People who live with HIV
• have diabetes or silicosis
• undergo immunosuppressive therapy
• are undernourished
• use tobacco
• suffer from alcohol use disorders.
• inject drugs 

• TB Infection (or previously known as Latent TB infection) is a stage in between uninfected and having active TB. In this stage the person has no symptoms and can only be identified using laboratory tests.

• The vast majority of infected people may never develop TB disease. However, to achieve TB elimination, it is important to treat TB infection in people at risk of developing active TB disease.

• It is a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifested active TB.

• There is no single acceptable/reliable test for direct identification of Mycobacterium tuberculosis infection in humans. Tuberculin Skin Test (TST) and Interferon-gamma release assay (IGRA) are commonly used tests for identifying TB infection.

Resources:

• Latent Tuberculosis Infection Guideline

• Guideline for Programmatic Management of Tuberculosis Preventive Treatment in India

After exposure to infective droplets containing M.TB, only a small proportion gets infected and further progresses to active TB disease.

• Majority of those that get infected persist in a stage of clinical latency known as TB infection (previously known as Latent TB infection). They do not have TB disease and do not show any symptoms of TB and no evidence of any TB related changes on chest X-ray.
• A small proportion of those with prior infection may progress to active TB disease due to various environmental/ agent/ host factors.

Figure: Flow chart for TB disease progression

Resources:

• Understanding delayed T-Cell Priming, Lung Recruitment, and AirwayLuminal T-Cell Responses in Host defence against Pulmonary Tuberculosis

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Resources:

• Technical and Operational Guidelines for TB Control in India 2016

Chemotherapy for TB is the use of an anti-TB drugs to kill, or prevent the replication of, TB mycobacteria in the patient’s body. Effective anti-TB chemotherapy renders the patient non-contagious and cures the patient, thereby interrupting the chain of transmission. Mortality rates of TB range from 50-80% in untreated smear-positive individuals and drop to lower than 5% under chemotherapy.

Most of the bacteria are killed during the first 8 weeks of treatment; however, there are persistent organisms that require longer treatment. TB disease must be treated for at least 6 months and in some cases even longer. The use of multi-drug therapy reduces the incidence of drug-resistant cases and increases the overall effectiveness of treatment.

If treatment is interrupted, any surviving bacteria may cause the patient to later become ill and infectious again, potentially with drug-resistant disease.

How infectious are tuberculosis patients under chemotherapy?

Under effective chemotherapy, there is a substantial decline in infectiousness in two weeks time, and may not be a major source of risk to any contacts. This decline is indicated by the rapid fall in the number of viable organisms in the sputum, and reduced frequency of coughing.  

Types of Chemotherapy in TB

1. Preventive Chemotherapy: Regimen for healthy but TB infected persons with a high risk of developing TB, in order to prevent them from developing TB.
2. Standard Chemotherapy: Two-phased chemotherapy for an average of 6-8 months based on the combination of at least four major drugs (HRZE) given for 2 months during the initial intensive phase of treatment and followed by a combination of at least 2 drugs given for at least 4 months during the continuation phase of treatment.
3. Chemotherapy for Drug-resistant TB: Two-phased chemotherapy varying from 9 - 24 months in patients having demonstrated resistance to drugs used in standard chemotherapy. The regimen varies with the drug to which the resistance is present, however, each regimen contains a mix of second-line anti-TB drugs including injectables.   

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Tuberculosis Infectiousness and Host Susceptibility, The Journal of Infectious Diseases, Vol. 216, suppl_6, 2017.
• Tuberculosis chemotherapy: Current Drug Delivery Approaches, Respiratory Research 7, Article no. 118, 2006.
• Tuberculosis Case-finding and Chemotherapy: Questions and Answers, K. Toman.

 Assessment

As TB is an airborne infection, TB bacteria are released into the air when someone with infectious TB coughs or sneezes. The risk of infection can be reduced by taking simple precautions:

Figure: Measures for control and prevention of tuberculosis

TB Preventive Treatment(TPT) also has a very important role in prevention of TB. Presently, household contacts of sputum-positive TB patients are given TPT upon confirmation of TB infection and ruling our active Tuberculosis.

Resources:

• Technical and Operational Guidelines for TB Control in India 2016

The National Tuberculosis Control Program (NTP) of India was launched in 1962. It relied on BCG, X-ray based diagnosis and Streptomycin and INH based treatment centralized at district level.  

Based on a review of the NTP, and WHO recommendations of the DOTS Strategy, Government of India then revised the NTP and launched new program with the title Revised National Tuberculosis Control Program (RNTCP) in 1997. It used Sputum microscopy at DMC(Designated Microscopy Centres) for diagnosis, and multi-drug Short Course Anti-TB Therapy,  decentralized to the TU (TB Unit) level. 

In recognition of the rising drug resistance problem the DOTS Plus/ PMDT (Programmatic Management of Drug Resistant TB) was launched in 2006 and scaled up to the entire country by 2012. 

Further to strengthen the monitoring and supervision system - a case based notification system - Nikshay was introduced in 2012. The same year Tuberculosis was added as a notifiable disease at the point of diagnosis by all health care providers.

Other key milestones from 2012 to 2020 were the availability of the Standards of TB Care in India (STCI) in 2014, introduction of the Daily weight band wise Fixed Dose combination (FDC) in 2016 and new drugs like Bedaquilline  and Delaminid were started in 2017 and 2018 respectively. 

To emphasise the commitment of the Government of India and to accelerate the efforts towards TB elimination, RNTCP was renamed as "National Tuberculosis Elimination Programme (NTEP)" in 2020.

Figure: Key milestones under NTEP

Resources:

• TBC India Website
• National Stratergic Plan for Tuberculosis Elimination 2017 - 2025

The Government of India has committed to achieving the Sustainable Development Goals(SDG) targets related to ending TB by 2025 (5 years ahead of the global target).  This would mean that in 2025, the 2030 target of achieving 80% reduction in incidence, 90% reduction in deaths due to TB compared to that of 2015, is to be achieved.

Table: India's commitment to End TB by 2025.

Resources:

• National Strategic Plan (NSP) - 2017 - 2025
• Global TB report 2021
• END TB Strategy

NSP 2012 - 2017 had the aim of achieving universal access to quality diagnosis and treatment. The NSP 2017-2025 which builds on the success and learnings of the last NSP, and articulates the bold and innovative steps required to move towards TB elimination. In 2020, RNTCP was renamed to "National Tuberculosis Elimination Programme" with the following objectives:

Figure: Objectives of NTEP

Resources:

• TBC India Website

National Tuberculosis Elimination Programme (NTEP) is a centrally sponsored programme being implemented under the aegis of National Health Mission.

National Level: Managed by Central TB Division (CTD), the technical arm of the Ministry of Health and Family Welfare (MOHFW)

State Level: State TB Cell coordinates the overall TB elimination programme in state under the guidance of State Health Society. The training ,supervision, monitoring and evaluation NTEP at state level are looked after by STDC (State TB Training and Demonstration Centre).

District TB Centre (DTC) is the nodal point for all TB elimination activities in the district under the guidance of the District Health Society.

Tuberculosis Unit (TU) Level: NTEP activities at block/sub-district level are implemented through TU which comprises Designated Medical Officer (MO) supported by two full-time NTEP staff - STS (Senior Treatment Supervisor) & STLS (Senior TB Lab Supervisor).

PHI (Peripheral Health Institute): PHI is a health facility manned by a Medical Officer (MO). Some of the PHIs are also the Tuberculosis Diagnostic Centres, which are the most peripheral level laboratories in the NTEP structure. All the Private Health Facilities like Private Practitioners / Private Hospitals / Clinics / Nursing Homes are also PHI.

Figure: Organisational structure of NTEP

Resources:

• TB India Report 2021
• Technical and Operational Guidelines for TB Control in India 2016

The State TB Cell or STC is the state-level implementing structure of the National TB Elimination Program (NTEP). It is the leading institution for management of NTEP activities at the state level. 

The STC is a State Government entity that acts as the bridge between the Central and State Governments for implementing the NTEP. It works under the guidance of the Central TB Division (CTD), and it oversees the program implementation at the districts.

1. The State TB Cell is supported by the State TB Training and Demonstration Centre (STDC) for its technical functionalities. STDC mainly supports training, supervision and monitoring.
2. The nodal laboratory for the State is the Intermediate Reference Laboratory (IRL). This supports quality assurance of the smear microscopy network and laboratory services in the state.
3. The STC has a fully operational State Drug Store (SDS) which is responsible for the effective management and uninterrupted supply of good-quality of medicines and other logistics.

Human Resources at the State TB Cell are:

1. State Tuberculosis Officer (STO). A dedicated official from the state health system, at the rank of a Joint Director is designated as the STO and heads the implementation of the NTEP at state level.
2. Medical Officer STC (MO-STC): A medical officer from the state health system assists the STO in overseeing various activities.
3. State DRTB Coordinator​: Assist the STO in DRTB activities monitoring across the districts
4. TB - HIV Coordinator: Assist the STO in overseeing TB comorbidities across the district.
5. State PPM Coordinator: Looks at the private sector engagement
6. State IEC Officer/ACSM Officer: Oversees the implementation of advocacy, communication and social mobilisation activities across different districts.
7. STC - Epidemiologist: Assist the STO and STDC Directors by analyzing state-level data and preparing review materials
8. Other support staff at the STC include
   1. Accounts Officer
   2. Technical Officer-PSM
   3. Secretarial Assistant
   4. Data entry operators/Nikshay operator

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Training Modules (5-9) for Programme Managers and Medical Officers, 2020.

Assessment

The State Tuberculosis (TB) Cell (STC) is supported by the State TB Training and Demonstration Centre (STDC) in many states through its three units – Training Unit, Supervision and Monitoring Unit and an Intermediate Reference Laboratory (IRL). This relationship is shown in the figure below.

1. Training Unit: It is involved in estimating the training load, organizing state level training (Induction and Refresher) and evaluating the performance of those who undergo training.
2. Supervision and Monitoring Unit: It consists of a team which is dedicated to the supervision of TB elimination activities through supervisory visits, periodic desk review of Nikshay and Nikshay Aushadhi data, and plans state internal evaluations apart from assisting in other supervision and monitoring activities of National Reference Laboratories, Central TB Division and other national/international monitoring missions.
3. Intermediate Reference Laboratory: This supports an effective quality assurance system of the sputum smear microscopy network and laboratory services for the programmatic management of drug-resistant TB (molecular drug resistance and culture and drug susceptibility testing) in the state.

The STDC is also involved in operational research.

Human Resources in the STDC

• The STDC functions under the leadership of STDC Director. 

Training and Supervision & Monitoring Units:

• 1 Epidemiologist
• 1/more Medical Officer
• 1 Nikshay Operator
• 1 Secretarial Assistant

Intermediate Reference Laboratory (IRL):

• 1 Microbiologist
• 1 Microbiologist- External Quality Assistance (EQA)
• 1 Senior Laboratory Technician- EQA

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Training Modules (5-9) for Programme Managers and Medical Officers, 2020.

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The key level for the management of public health services is the district​ level. The District Tuberculosis Centre (DTC) is the nodal point for tuberculosis (TB) control activities in the district​.

Functions of the DTC

The primary role of the DTC is a managerial one. The DTC is the central program management unit of the district responsible for all activities related to National TB Elimination Programme (NTEP) implementation such as:

• Advocacy
• Active case finding
• Diagnosis, treatment (both for drug-susceptible and drug-resistant TB cases) and follow up
• Managing comorbidities
• Service delivery
• Maintaining diagnostic and treatment infrastructure
• Setting up Drug-resistant TB (DR-TB) centres
• Ensuring community engagement and TB forums
• Multi-sectorial involvement for drug management, and supervision and monitoring
• Financial management
• Drugs, logistics and supply chain management.

Components of the DTC

1. District Drug Store (DDS)
2. Nucleic Acid Amplification Test machine (Cartridge Based NAAT or TrueNAT)
3. Designated Microscopic Center (DMC)
4. Treatment Support Center
5. Drug Resistant TB (DR-TB) Center
6. X-Ray Unit

With expansion of TB services and ongoing collaboration with various national programs, the structure of DTC is highly integrated as part of general health system and some components may cater to non-TB patients as well e.g., the DMC may be a part of general laboratory, and X-ray unit can be functional for all departments and not just chest/TB section.

Human Resources Deployed at the DTC

The Chief District Health Officer (CDHO) / Chief District Medical Officer (CDMO) / Civil Surgeon or an equivalent functionary in the district is responsible for all medical and public health activities including control of TB.

A full-time District TB Officer (DTO), trained at the national level and based at the DTC, is responsible for planning, training, supervising and monitoring the programme in the district. The DTO is assisted by other technical and secretarial staff:

1. Medical Officer- District TB Center
2. District DR-TB-HIV Coordinator
3. District Public Private Mix Coordinator
4. District Program Coordinator
5. District Drug Store Pharmacist
6. District Data Entry Operator-Nikshay
7. District Accountant
8. Senior TB laboratory Supervisor
9. Senior Treatment Supervisor
10. Laboratory Technicians for DMC and NAAT site
11. Counsellor for District DR-TB center
12. TB Health Visitors

While the National TB Elimination Program (NTEP) approves the above positions through National Health Mission NTEP Project Implementation Plan, the district always has the flexibility for additional resource deployment based on the need and existing epidemic. The DTO and his/her team are supported by various other program officers/staff and non-governmental organizations working in the field for Tuberculosis and Health.

Resources

• NTEP Training Modules 1-4 for Programme Managers & Medical Officers, 2020.
• NTEP Training Modules 5-9 for Programme Managers & Medical Officers, 2020.

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Tuberculosis (TB) unit (TU) is the sub-district level supervisory unit of National TB Elimination Program with the following organogram:

Figure: Organogram of a TB Unit

(PHI: Peripheral Health Institution)

TUs are based mainly on National Health Mission (NHM) health blocks with the aim of aligning with the NHM Block Programme Management Unit (BPMU) for optimum resource utilization and appropriate monitoring.

The TUs have been created based on a population of 1 per 2,00,000 (range 1.5 – 2.5 lakh) for rural and urban populations and 1 per 1,00,000 (0.75 – 1.25 lakh) population in hilly/tribal/difficult areas.

The TU consists of a designated Medical Officer-Tuberculosis Control (MO-TC), as well as one full-time supervisory staff - Senior Treatment Supervisor (STS). However, one Senior TB Laboratory Supervisor (STLS) will be there in every 5 lakh population (one per 2.5 lakh population for tribal/hilly/difficult areas), mostly covering 2-3 TUs.

TB Unit manages the provision of TB services (Diagnosis, Treatment, Prevention, etc.) and programme management in the assigned geographical area. 

Resources

• RNTCP Technical and Operational Guidelines for TB Control in India 2016.
• Training Modules (1-4) for Programme Managers & Medical Officers, 2020.

Under the National Tuberculosis Elimination Programme (NTEP), a Peripheral Health Institute (PHI) is a health facility that is manned by at least a Medical Officer (MO), where diagnosis and management of Tuberculosis (TB) are done.

At this level, there are dispensaries, Primary Health Centres (PHCs), Community Health Centres (CHCs), referral hospitals, major hospitals, speciality clinics or hospitals (including other health facilities), TB hospitals, Anti-retroviral Treatment (ART) centres and medical colleges within the respective district.

All health facilities in the private and Non-government Organisation (NGO) sectors participating in NTEP are also considered PHIs. Some of these PHIs also function as Designated Microscopy Centres (DMCs).

Role of PHIs in Program Management for TB Elimination

• PHIs undertake tuberculosis case-finding and treatment activities as a part of the general health services.
• In situations where more than one MO is posted in any of the PHC, one of them may be identified and entrusted with the responsibilities of the NTEP.
• Additionally, NTEP provides 1 TB Health Visitor (TBHV) per one lakh urban population to support the urban TB control activities in urban settings/ medical colleges.

Resources

• NTEP Training Modules 1-4 for Programme Managers & Medical Officers, 2020.
• NTEP Training Modules 5-9 for Programme Managers & Medical Officers, 2020.

Image

DRUG STORE

Central TB Division, MoHFW, has

Under NTEP, there is a large network of drug stores across the country to ensure a regular and uninterrupted supply of drugs and consumables. The Drugs and consumables are procured at the Central level and supplied at Central warehouses (GMSDs & CMSS); further drugs and consumables are supplied to the State Drug Stores and further dissemination to district and sub-district levels following the stocking norms to ensure uninterrupted supply of drugs and consumables to the patient.

To provide overall policy guidance and coordination, the Procurement and Supply Chain Management (PSM) Unit has been established at Central TB Division (CTD), MoHFW, for procurement and Supply Chain Management of all types of anti-TB drugs, diagnostics and consumables.

The Standards for TB Care in India (STCI), which is a locally customized version of the International Standards of Tuberculosis Care, mentions 26 standards that every citizen of India should receive irrespective of the sector of treatment. 

STCI were developed based on a series of discussions involving various stakeholders including clinicians, public health specialists, community workers and patient advocates. 

STCI represent what is expected for quality TB care from the Indian healthcare system including both public and private systems. 

It was first published in 2014 and outlines standards across the four themes of TB diagnosis, TB treatment, public health action and social inclusion.

Following are the list of the 26 Standards:

Table 1: Categorisation of the Standards for TB Care in India, Source: Standards for TB Care in India, World Health Organisation, pp. 13-23

Resources

• Standards for TB Care in India, World Health Organisation, 2014

Assessment

Those who are suspected of having TB disease are first screened for symptoms like cough and fever for more than 2 weeks, blood stained sputum and weight-loss. If found positive on screening, then TB patients are referred for testing to the nearest health facility. If diagnosed with TB, then they are subsequently initiated on treatment. The TB patients initiated on treatment are regularly monitored with the help of field staff or digital interventions like 99DOTS and MERM (Medication Event Reminder Monitor) technology. NTEP staff also ensures that the TB patients are regularly followed up on monthly basis till their treatment completion.

Figure: Patient Flow

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National Tuberculosis Elimination Programme (NTEP) strives for all presumptive TB patients to be microbiologically confirmed. Under NTEP, the acceptable methods for microbiological diagnosis of TB are: 

Rapid diagnostic molecular test: Rapid molecular tests that use techniques like NAAT are very specific. They amplify the genomic material in the patient sample and hence enhances detection

• Nucleic Acid Amplification Test (NAAT) e.g., GeneXpert, TrueNat

  

  Figure: Genxpert Machine for CBNAAT

  

  Figure:  Truenat Machine

• Line Probe Assay

Microscopy is a TB diagnostic technology that utilizes the acid-fastness property of Mycobacterium tuberculosis to visualize it under a microscope. Results of sputum smear microscopy can either be smear-negative, or smear-positive (with various grades). 

Advantages:

• It is currently the most accessible and cheapest TB diagnostic test available under National TB Elimination Programme (NTEP) in India.
• It has the shortest turnaround time for diagnosis.
• It has high specificity. 

Limitations:

• Low sensitivity. It becomes positive only when more than 5000 bacilli/ml of sample are present. Hence, cases would be missed in early disease, or when an inappropriate biological specimen is provided, where bacterial load in sputum is less.
• It is unable to differentiate between M. tuberculosis and Non-tuberculous Mycobacteria (NTM). This is predominantly an issue in geographies with lower burden.

There are two types of microscopies used in NTEP: Ziehl-Neelsen (ZN) Microscopy and Fluorescence Microscopy (FM). These vary in the type of stain and microscope used. FM is newer of the two types and is currently recommended for use over ZN.

Resources

• WHO Policy Statement - Fluoresence Light-emitted Microscope for the Diagnosis of TB, 2010.

Cartridge Based Nucleic Acid Amplification Test (CBNAAT) is a rapid molecular diagnostic test. It is used for diagnosis of Tuberculosis (TB) and Rif-resistant Tuberculosis (RR-TB) in NTEP. Results are obtained from unprocessed sputum samples in about 2hours which helps in early detection and treatment of TB patients. 

India has vast number of CBNAAT laboratories which are utilized for TB/RR-TB detection and Universal Drug Susceptibility Testing (UDST) under the National TB Elimination Program (NTEP).  

Figure: CBNAAT Cartridge and Machine in Use (Image courtesy: USAID supported Challenge TB Project)

The CB-NAAT system detects DNA sequences specific for Mycobacterium tuberculosis complex and rifampicin resistance by Polymerase Chain Reaction (PCR). It concentrates Mycobacterium tuberculosis bacilli from sputum samples, isolates genomic material from the captured bacteria by sonication and subsequently amplifies the genomic DNA by PCR. The process identifies clinically relevant rifampicin resistance-inducing mutations in the RNA polymerase beta (rpoB) gene in the Mycobacterium tuberculosis genome in a real-time format using fluorescent probes called molecular beacons.

Video: Cartridge-Based Nucleic Acid Amplification Test [CBNAAT] - GeneXpert Technology 

Resources

• Training Module (1-4) for Program Managers and Medical Officers, NTEP, MoHFW, 2020.
• India TB Report 2021, National TB Elimination Program (NTEP), MoHFW, 2021.

Assessment Questions

TrueNAT MTB and TrueNAT MTB Rif Dx Assay are intended to be used for detection of Mycobacterium tuberculosis bacteria (for TB diagnosis) and to detect resistance to rifampicin (Rif), respectively.

Positioning of TrueNAT MTB and TrueNAT MTB Rif Dx Assay

TrueNAT MTB and TrueNAT MTB Rif Dx Assay are suitable as point-of-care tests for use in peripheral laboratories and microscopy centres due to the following operational features:

• Biosafety requirements similar to smear microscopy
• Sample pre-treatment and preparation kits stable at 2-40°C, while TrueNAT chips stable between 2-30°C
• Test reagents with shelf life of 2 years
• Operates up to 8 hours on fully-charged batteries
• Temperature controlled operation, like air-conditioning, not required (operates up to ≤ 40°C)
• Operates under a wide relative humidity range (10-80%) & dusty conditions
• Portable and comes with a carrying case.

Target population

National TB Elimination Programme (NTEP) has defined the use of Nucleic Acid Amplification Test (NAAT) like Cartridge Based Nucleic Acid Amplification Test (CBNAAT) and TrueNAT as upfront tests for diagnosis of TB in presumptive paediatric TB, presumptive extra-pulmonary cases, People Living with HIV (PLHIV), smear negative X-ray suggestive of TB, contacts of Drug Resistant TB (DR-TB), treatment non-responders, TB affected patients retrieved after loss to follow-up and other vulnerable groups.

Resources

• Guidelines for Programmatic Management of Drug resistant Tuberculosis (PMDT) in India, 2021.
• Practical Guide to Implementation of TrueNAT Tests for the Detection of TB and Rifampicin Resistance.

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Line Probe Assay (LPA) is a rapid molecular test available at centralised laboratories.

The assay is based on Polymerase Chain Reaction (PCR) that can simultaneously detect Mycobacterium tuberculosis complex as well as drug sensitivity to anti-TB drugs.

Figure 1: The GenoType MTBDRplus Molecular LPA Procedure; Source: Molecular Detection of Drug-resistant Tuberculosis by Line Probe Assay.

Advantages of LPA

• Rapid molecular test. (Turnaround time: 3-5 days)
• Highly sensitive and specific.
• Performed directly from sputum smear-positive specimens and on isolates of M. tuberculosis complex grown from smear-negative and smear-positive specimens.
• Detects multiple gene mutations in anti-TB drugs.
  • First-line LPA detects mutations to rifampicin and isoniazid
  • Second-line LPA detects mutations to fluoroquinolones and aminoglycosides.
• Suitable for low and high-throughput labs.

Disadvantages of LPA

• Cannot be used as a point-of-care test.
• Requires appropriate laboratory infrastructure, equipment and biosafety precautions.
• Different rooms (DNA extraction, pre-amplification, amplification, post-amplification/ hybridization) are required to perform different steps (Figure 2).
• Requires trained manpower to perform tests and interpret test results.
• Stringent internal quality control is required to prevent contamination.

Figure 2: Amplification (A) and Post-amplification Laboratory (B) for LPA; Source: Molecular Detection of Drug-resistant Tuberculosis by Line Probe Assay.

Resources

• Guidelines for PMDT in India, 2021.
• Molecular Detection of Drug-resistant Tuberculosis by Line Probe Assay.

Assessment

Culturing TB Bacilli is well known and historic method for detection/ confirmation of Tuberculosis. It is a highly sensitive and specific phenotypic test; it can detect even a few viable bacilli in the sample (Upto 10 Colony Forming Units- CFUs). TB bacilli multiply in the culture and form colonies of TB bacilli which can are easily be identified.

Based on the growth media used Culture is divided in to two types, Solid and Liquid Culture methods. Types Culture:

• Solid Culture on Lowenstein Jensen media : Historic gold standard culture test. Results take usually upto 2 months (60 days).
• Modern Liquid culture systems: (e.g. BACTEC MGIT 960, BacT Alert or Versatrek etc.) Results take usually up to 42 days. 

Uses

1. Solid culture is the gold standard diagnostic test for TB. But it is not used for the purpose of TB diagnosis due to the long turn around time of 2 months. It is largely used for research purposes where it is used as the baseline test on which the sensitivity and specificity of other tests are calculated.
2. Liquid Culture is being used for follow-up monitoring of patients on drug resistant TB treatment to detect treatment failure. Liquid culture is also used for long term follow up patients who have successfully completed treatment to detect recurrence.
3. Liquid culture is used as a previous step to grow bacilli and obtain isolates prior to Drug Susceptibility Testing.
4. Liquid cultures are also used in TB prevalence surveys for its high sensitivity and specificity

Resources

• Guidelines for Programmatic Management of Drug Resistant Tuberculosis in India 2021

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Culture Drug Susceptibility Testing (CDST) is a growth-based phenotypic method used to check the susceptibility of Mycobacterium tuberculosis strains to various first and second line anti-TB drugs. Mycobacterial resistance to a particular drug is identified if there is growth observed in culture in presence of that drug.

In NTEP CDST is the standard method to detect resistance in samples of patients who have tested positive on followup. While CDST is possible on both Solid and Liquid culture, currently, the NTEP utilizes only liquid culture as a method for DST, due to faster Turn around times.

CDST testing services are available under NTEP in designated, specialized laboratories called CDST Labs both in public and private sector. Currently there are 80 such laboratories (60 certified for First Line and 49 for Second line drugs). Such designated laboratories are subject to regular external quality assessment, often by the National Reference Laboratory at that region.

Quality assured DST to R, H, Z, Mfx, Lfx, Lzd, Am, Km and Cm are available across the country. 

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, 2021.
• Training Manual for Mycobacterium tuberculosis Culture & Drug Susceptibility Testing, NTEP, 2009.
• RNTCP Laboratory Network Overview, CTD, 2009.

Screening for active tuberculosis (TB) a process to filter out people who are less likely to have TB, from a group. Screened positive people are likely to have TB and are confirmed subsequently using a TB diagnostic test. This will allow finite diagnostic testing resources to be used on the remaining.

Screening in TB may be performed ​using simple field tools (4 Symptom complex) and tests such as Chest X-ray, or a combination of both. ​Combination of both is the most effective, but is often not applied due to the practical difficulties in making a chest X-ray conveniently available.

Screening is an integral part of any general case finding effort. It is also applied systematically in specific situations.

1. At health care facilities (intensified case finding): Here those visiting are screened using the 4 symptom complex, often at the point of entry to the facility. Those screened positive may be fast-tracked to TB Diagnostic testing.
2. In vulnerable populations in active case finding efforts: Here the entire population identified for active case finding are screened using the pre-decided protocols by going door to door. 

Resources

• Systematic Screening for Active Tuberculosis; Principles and Recommendations, WHO 2013.
• National Strategic Plan for Tuberculosis Elimination 2020–2025.

Systematic screening of all individuals of a defined population is known as active case finding.  It is applied outside of health facilities at the community level by the health system.

Objective of ACF is to:

1. identify cases early, initiate prompt treatment, reduce risk of poor treatment outcomes and reduce risk of further transmission of TB
2. to provide access to diagnosis services to populations that would have been otherwise unreached

It is effort intensive and is recommended only in population groups where there is estimated high case load. In NTEP, ACF is recommended only to be performed in Key / vulnerable population.

ACF can also be clubbed with suitable ACSM campaigns to create awareness about the signs and symptoms and about TB in the target population/ community. It can also be combined with other health activities/ campaigns (such as Pulse Polio/ Leprosy screening/ population based screening for NCDs) for increased efficiency.

Resources

1. Training Modules for Programme Managers and Medical Officers.
2. Active TB Case Finding, Guidance Document.
3. WHO recommendations for Systematic Screening for Active Tuberculosis

Assessment

The goals of tuberculosis treatment are:

• Rendering the patient non-infectious, breaking the chain of transmission and decreasing the infection​ pool

• Decreasing case fatality and morbidity by ensuring relapse-free cure

• Minimising and preventing the development of drug resistance.  ​

To meet the goals of treatment, the regimens should be:

• Safe, easy to administer and aid treatment adherence
• Long enough to achieve the long-term cure of the disease, and short enough to increase patient compliance.

Any treatment regimen which reduces the pill count but increases the overall treatment success is an ideal regimen to meet the goals of tuberculosis treatment.  

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.

Assessment

​

Under the National TB Elimination Programme (NTEP), strategies adopted in the treatment of TB are based on the available scientific and operational researches. These strategies are combined to ensure better treatment outcomes for the TB patients. The main strategies include:

Domiciliary Treatment

• This is a strategy that allows for the treatment of TB in a patient’s home.
• Domiciliary chemotherapy proved to be as effective as sanatoria treatment (which was the historical way of treating TB) and achieved higher cure rates.
• The patients having the social benefits of being at home. 

Short Course Chemotherapy (SCC)

• Chemotherapy of TB underwent revolutionary changes in the 70s owing to the availability of two well-tolerated and highly effective drugs – rifampicin and pyrazinamide.
• These drugs allowed for SCC and made it possible to simplify treatment and reduce its duration without reducing the therapeutic effect.
• Now with SCC regimens, it is possible to treat and cure TB patients in 6 months.
• When given daily, these regimens are effective, achieve high cure rates, prevent the emergence of drug resistance and minimize relapses.
• The shorter duration also contributes to improvement in treatment adherence.

Directly Observed Treatment (DOT)

DOT is a method whereby a trained healthcare worker or another trained designated person (treatment supporter) watches a patient swallow each dose of anti-TB drugs and document it.

• DOT can reduce the development of drug resistance, treatment failure, or relapse after the end of treatment.
• Many patients who do not receive directly observed treatment stop taking drugs once they feel better.
• Hence, by providing DOT, the NTEP ensures that patients receive the right drugs, in the right doses, at the right intervals and for the right duration.

The modern treatment strategy is based on standardized short-course chemotherapy regimens largely administered on a domiciliary basis, utilising the DOTS strategy and proper case management to ensure completion of treatment and cure.

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Treatment of Tuberculosis Disease, CDC, 2006.
• Guide on Tuberculosis Control for Primary Health Care Providers, WHO, 2015.
• Treatment of Tuberculosis: Guidelines for National Programmes, WHO, 2003.

Assessment

Tuberculosis treatment and its different regimens have scientific backgrounds for their formulations. To understand this, we need to know about the mode of action of each anti-TB drug first.

Mode of Action of Anti-TB Drugs

Anti-TB drugs have the following three actions:

1. Early bactericidal activity: Killing of actively growing bacilli (in the phase of rapid multiplication and uninhibited metabolic activity).
2. Sterilizing activity of persisting bacilli, i.e., metabolically inhibited organisms in a quasi-dormant state.
3. Ability to prevent the emergence of drug resistance.

The ranking of first-line drugs with respect to their type of activity is indicated in Table 1 below.

Table 1: Ranking of first-line anti-TB drugs used in the treatment of drug-sensitive TB, based on the mode of action and activity

Thus, each drug has unique characteristics and drug combinations will make the regimen more effective.

Need for Long Duration of Treatment of TB

• Anti-TB drugs mostly kill actively multiplying tubercle bacilli.
• When bacilli have low metabolic activity, i.e., when bacterial growth has almost come to a standstill and the organisms are “dormant”, they are not killed by otherwise bactericidal drugs. Such organisms are referred to as persisters*.
• Though they may survive in the presence of drugs, behaving as if they were drug-resistant, they are in fact susceptible to the drugs.
• Thus, if for some reason these organisms regain their ability to multiply freely, they would be killed by the very drugs that had not harmed them before.
• When dormant bacilli again become metabolically active and start multiplying during effective chemotherapy, they are soon killed.
• Once chemotherapy has been completed, the revived bacilli may continue to multiply and thus cause relapse.
• This explains why conventional chemotherapy needs to be of long duration.

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Tuberculosis Case-finding and Chemotherapy: Questions and Answers, K. Toman.

 Assessment

Standard TB Treatment is divided into two phases

• Intensive Phase(IP): In this phase,
  • Kills most of the TB bacteria during the first 8 weeks of treatment, but some bacteria can survive longer
  • Therefore, more drugs are administered to kill the bacteria and reduce the severity of disease.
  • Treatment in this phase usually is of short duration(2 to 6 Months or more) in comparison to Continuation Phase(CP)

• Continuation Phase(CP): In this phase,
  • All the remaining TB bacteria are in the dormant stage i.e., stage when growth and development of bacteria are temporarily stopped.
  • Therefore, fewer but powerful antibiotics are administered to kill those bacteria. 
  • Treatment in this phase usually lasts longer than Intensive Phase(IP)(4 to 18 Months or more)

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Fixed-dose combinations (FDCs) are drug formulations where two or more drugs are combined physically into one formulation such as a tablet or pill.

This is more convenient to the patients taking medicines and it also simplifies the supply chain.

Resources:

• Technical and Operational Guidelines for TB Control in India 2016

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Fixed-Dose Combination(FDC) provides a simple approach to deliver the correct number of drugs at the right dosage as all the necessary drugs are combined in a single tablet. By altering the number of pills according to the patient’s body weight, complete treatment is delivered without the need for calculation of dose

Figure: Advantages of Fixed Dose Combination(FDC)

A regimen means a prescribed systematic form of treatment for a course of drug(s). For TB treatment, Multi drug combination of regimen is followed. 

All TB drug regimens have an initial intensive phase(IP) followed by a continuation phase(CP). 

Following are some of the main TB drug regimens used based on the drug resistance pattern detected for TB patients.

• First-Line Anti TB Drugs(Prescribed for Drug Sensitive TB DS-TB)
  • Daily weight band wise FDC

• Second-Line Anti TB Drugs (Prescribed for Drug Resistance TB - DR-TB)
  • H Mono Poly Regimen
  • Shorter oral Bedaquiline containing MDR-TB regimen
  • Longer oral Bedaquiline containing regimen
  • Shorter injectable containing MDR-TB regimen

To know the TB treatment response and to determine that if patient is cured, TB patients are clinically evaluated at the end of every four weeks of treatment, and they are also followed up by performing sputum test at end of each treatment phase (i.e. Intensive phase and Continuation phase)

TB patients during clinical evaluations are assessed to

• Identify possible adverse reactions to medications;
• Check for any comorbid conditions;
• Weight change;
• monitor adherence; and determine treatment efficacy by observing their symptoms

Although each patient responds to treatment at a different pace, all TB symptoms should gradually improve and eventually go away.

Patients whose symptoms do not improve during the first 2 months of treatment, or whose symptoms worsen after improving initially, should be re-evaluated for adherence issues and development of drug resistance.

After completion of TB treatment, all patients should be followed up at the end of

• 6 months,
• 12 months,
• 18 months &
• 24 months

TB patients at the follow up should be screened for any clinical symptoms and/or cough. If found positive on screening, then sputum microscopy and/or culture should be considered. This is important in detecting the recurrence of TB at the earliest.

After completion of TB treatment, if the patient has not developed any clinical symptoms and/or cough and also if the microscopy remains negative during their follow up, then the patient is considered as “Relapse Free Cure from TB.”

When a TB patient consumes all the doses under the prescribed regimen, then Treatment Outcome is declared for a Patient.

Treatment success is considered when a TB patient either Cured or Treatment completed is accounted in treatment success

Adverse Drug Reactions(ADR) are unwanted or harmful reactions experienced following the use of a drug or combination of drugs and are suspected to be related to a drug. Severity of adverse effects varies from tolerable and mild ADRs to serious and life threatening ADRs.

Figure: Various Adverse Drug Reactions

Common ADR Symptoms:

• Pain in upper abdominal area, with loss of appetite
• Nausea – Uneasy feeling with inclination to vomit, after having the drugs
• Gastritis – Burning sensation in lower chest region, bloating sensation, sourness in mouth
• Diarrhoea - Loose stool(2-3 in a day)

Adverse Drug Reactions(ADR) are classified into serious and non-serious ADR depending upon the intensity of symptoms experienced by the patient. Below is the brief overview

1. Counsel and reassure the patient as the common occurring adverse effects usually resolve with time.
2. Advise the patient to take all the drugs together.
3. Advise patient to take light meal (biscuits, bread, rice etc.) before taking drugs.
4. Inform patients that they may take drugs embedded in banana or at the bedtime to reduce their associated side effects.
5. Encourage patients to keep themselves hydrated by increasing fluid intake.
6. Provide ORS (Oral Rehydration Solution) to counter dehydration due to loose motion and vomiting.

Figure: Referral to PHI for ADR

Resources:

• Training Guide for Peripheral Health Workers on Adverse Drug Reactions

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The Tuberculosis Treatment Card is a paper-based recording form that is kept in the institution treating the TB patient under the National TB Elimination Programme (NTEP). It is a pre-requisite documentation related to treatment services offered to TB patients under NTEP.

Uses of the TB Treatment Card

The TB treatment card is primarily used for:

1. Documenting administered drugs with their dosages
2. Documenting follow-up investigation results
3. Monitoring adherence to treatment
4. Recording adverse events
5. Recording treatment outcomes

There are two pages in the TB treatment card and details in each page is delineated in the table below.

Important Points to Note

• The TB treatment card is filled at the Peripheral Health Institution (PHI) when a patient is initiated on treatment.
• The original TB treatment card is kept at the PHI and updated fortnightly.
• A duplicate treatment card is to be given to the treatment supporter for documentation of daily events. 
• The treatment supporter should be trained on how to record the treatment card. 
• Details on the patient’s HIV status are not included in the treatment supporter’s copy to maintain confidentiality.

The figure below shows the 1^st page of the TB treatment card. Click here to access the full form in the NTEP Training Modules 1-4 for Programme Managers & Medical Officers, p. 223.

Figure: First Page of the TB Treatment Card; Source: NTEP Training Modules 1-4 for Programme Managers & Medical Officers, p. 223

Resources

• NTEP Training Modules 1-4 for Programme Managers & Medical Officers, 2020.

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In the National TB Elimination Programme (NTEP), the ‘NTEP TB identity card’ is provided for their identification and record of clinical follow-ups.

The identity card is completed for each patient who has a Tuberculosis (TB) Treatment Card, and it is kept with the patient. Information from the TB Treatment Card is used to complete the identity card.

There are 3 parts in the NTEP TB identity card and details in each part is delineated in Table 1.

The information contained in this card will help to continue treatment in case the patient is transferred or admitted to any other health facility any time during the treatment period. The TB identity card is shown in Figure 1.

Figure 1: NTEP TB Identity Card; Source: NTEP Training Modules 1-4 for Programme Managers & Medical Officers, 2020

Resources

• NTEP Training Modules 1-4 for Programme Managers & Medical Officers, 2020

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TB patients may not stay in one place throughout the treatment duration. When they move from one place to other, there should be a mechanism to hand over the responsibility of continuing the patient's treatment in a facility near the new place of the patient. This is the concept of patient transfer and can be easily managed in Nikshay portal.

• The transfer module in Nikshay enables transfer requests of patients between Health Facilities (HFs) across the country.
• Provision of shifting of patient from one HF to another is possible if the patient changes his/her residence for the purpose of treatment.
• The requests are of two types: “Transfer In” and “Transfer Out”.
• All transfer requests needs to be accepted by the “District/ TB Unit (TU)/ Peripheral Health Institute (PHI)” where the transfer request is made in order for it to take effect.
• Transfer requests can be made to even the District/ TU level. However, it can be completed only once the “Transferred to PHI” has been assigned.

Figure: Transfer Management in Nikshay; Source: Nikshay Zendesk, Nikshay Knowledge Base, Advanced Transfer in Web.

Steps in Transfer of TB Patient

1. In Nikshay, the referring HF updates details from the current HF of patient to the HF where patient is being transferred.

2. The receiving HF gets the intimation about the transfer.

The patient transfer module also provides the provision to pull the patient belonging to another HF to the recipient HF. The accountability of the transferred patients is now with the receiving HF and the treatment initiating facility.

A separate transfer register is also available to get details about various transfers from and to a given district, which can be downloaded from Nikshay reports.

Resources

• Nikshay Zendesk, Nikshay Knowledge Base, Advanced Transfer in Web.
• Guidelines for PMDT in India, 2021.

Assessment

​The management principles of Extrapulmonary Tuberculosis (EPTB) are shown in the figure below.

Figure: Ten principles about what every EPTB patient in India needs as a basic standard of care

Abbr: CBNAAT:Cartridge-based Nucleic Acid AMplification Test; PTB: Pulmonary TB; NTEP: National TB Elimination Programme

Diagnosis of EP-TB

• All efforts need to be made to get a microbiological confirmation whenever a sample is available. 
• Clinical diagnosis can be made by treating physician based on the clinical features, lab investigations, imaging studies and by ruling out other causes

Treatment Regimen and Duration for EPTB

The treatment regimen and schedule for EPTB cases will remain the same as for pulmonary TB (2HRZE/ 4HRE). However, the duration of the continuation phase in EPTB may be extended in special situations such as TB Meningitis, bone and spine TB etc.

Role of Surgery in EPTB Cases

• Surgery is sometimes required for the diagnosis of EPTB. It is reserved for management of late complications of the disease.

Monitoring Treatment Response

• Response to treatment in EPTB may be best assessed clinically. Clinical follow-up is the most important criterion for the follow-up of EPTB patients. The clinician can assess the patient’s condition by checking weight gain and a decrease/ increase in presenting clinical symptoms.
• Investigations such as Acid-fast Bacilli (AFB) microscopy, chest X-ray, liver function tests, serum creatinine, and USG-abdomen can be used to monitor the treatment status.

The treatment support and other monitoring activities remain the same as for pulmonary TB.

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Index TB Guidelines on Extra-pulmonary Tuberculosis for India, Central TB Division, 2016.

Assessment

Treatment interruption is defined as a patient-initiated episode in which the patient discontinues TB treatment. All efforts must be made to ensure that TB patients do not interrupt treatment or are not lost to follow-up. Action should be taken to promptly retrieve patients who fail to come for their daily dose by the treatment supporter

The management of treatment interruptions is made based on the following criteria:

i. Type of case: Whether new, relapse or failure

ii. Duration of treatment taken: Less than one month/ more than one month. This helps in assessing the risk of the presence of drug resistance.

iii. Duration of Interruption: Less than one month/ more than a month.

If treatment interruption is more than one month, the outcome is declared as ‘lost to follow up’.

If a patient returns to the health facility after interrupting treatment for more than one month, the patient sample needs to be subjected to Drug Susceptibility Testing (DST) to determine resistance/ sensitivity status to anti-TB drugs.

In case the interruption is for less than one month, the same treatment regimen is completed to complete all doses.

Modes of Retrieval

TB treatment is supervised by a trained treatment supporter (a health worker, family member or community volunteer). The residential address is verified for all TB patients by home visits. However, in case of treatment interruption, patient retrieval action is required.

Retrieval can be done by the following modes:

1. Retrieval of patients interrupting treatment within 24 hours of discontinuation is done by the Treatment Supporter (TS) or Accredited Social Health Activist (ASHA)/ Auxilliary Nurse Midwife (ANM)/ Multipurpose Worker (MPW). The reason for interruptions should be reviewed carefully and efforts made to counsel and bring the patient back for treatment.

2. If the TS is not successful in retrieving such patients, it should be reported to the next higher level of supervisors, like Senior Treatment Supervisor (STS), and they should take all efforts to counsel and retrieve the patient.

3. If the patient interrupts treatment on more than one occasion, the Medical Officer of the Peripheral Health Institute (MO-PHI) should visit the patient’s home. The MO-PHI should give intensive counselling to the patient and may provide additional support to continue the treatment without interruption.

4. Innovative use of information and communication technologies for treatment adherence monitoring through 99 DOTS, Medication Event Reminder Monitor (MERM), etc. are also beneficial in finding missed doses and initiating retrieval action by the health staff.

Resources

1. Training Modules (1-4) for Programme Managers and Medical Officers.

2. Guidelines for PMDT in India, 2021.

Assessment

There are five principal ways to prevent Drug-resistant Tuberculosis (DR-TB), as given in the figure below.

Image

 Figure: Five Principal Ways to Prevent DR-TB; Source: Guideline for PMDT in India, 2021.

• Drug resistance cannot be prevented by mere diagnosis and treatment of DR-TB.
• Basic TB diagnostic and treatment services should receive priority for the prevention of drug resistance.
• Systems for early detection and treatment of DR-TB should be integrated into the existing TB services and the general health system.
• Healthcare facilities and congregate settings should be provided with proper infection control measures.
• Transmission should be prevented by addressing non-specific determinants like access to care, comorbidities and awareness.

Resources

• Guidelines for PMDT in India, 2021.
• Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-resistant Tuberculosis.

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The suggested treatment regimen covering maximum non-Mycobacterium Tuberculosis (NTM) mainly Mycobacterium Avium Complex (MAC) is as follows: 

• Rifampicin (R) 450-600 mg OD
• Ethambutol (E) 800-1200 mg OD
• Clarithromycin (Clr) 1 gm OD (split into two doses)
• Add injection Amikacin (Am) 750 mg – 1 gm thrice weekly for the first 2-3 months

Intensive Phase (IP) is for 3 months and can be extended to a maximum of 6 months with all four drugs. 

Continuation Phase (CP) of treatment will be with the same drugs except for injectable. This should be continued for 12 months after sputum culture conversion. Drugs will be given as per the standard weight bands.

If the patient does not culture convert by end of 3 months, then species identification and Drug Susceptibility Testing (DST) are required for further management. 

Management of complicated/ invasive TB disease:

• Recommended initial regimen for most patients with nodular/ bronchiectatic MAC lung disease:
  • Thrice-weekly regimen including Clarithromycin 1000 mg or Azithromycin 500 mg, Ethambutol 25 mg/kg, and Rifampicin 600 mg administered three times per week.
• Recommended initial regimen for fibro-cavitary or severe nodular/ bronchiectatic MAC lung disease: 
• Clarithromycin 500-1000 mg/day or Azithromycin 250 mg/day, Ethambutol 15 mg/kg/day, and Rifampicin 10 mg/kg/day (maximum, 600 mg). 

Points to Note

• Intermittent drug therapy is not recommended for patients who have a cavitary disease, patients who have been previously treated, or patients who have moderate or severe disease.
• The primary microbiologic goal of therapy is 12 months of negative sputum cultures while on therapy; therefore, sputum must be collected from patients for Acid-fast Bacilli (AFB) examination throughout treatment on monthly basis in IP and quarterly basis in CP after culture conversion is achieved.
• Given these complexities, the treatment of NTM will be the prerogative of the Nodal Drug-resistant TB Centres (NDR-TBCs).

Resources

• Training Modules (1-4) for Programme Managers & Medical Officers (NTEP), 2020.
• British Thoracic Society Guidelines for the Management of Nontuberculous Mycobacterial Pulmonary Disease, 2017.
• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.

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Daily Regimen is prescribed for Drug Sensitive TB patients (DSTB), where the patient needs to consume the FDC formulation daily.

Daily Regimen comprises the first line Anti TB drugs based on

• Age: Adult/ Pediatric
• Weight of the patient: Weight Bands

Age: Based on age, patients are categorized into

• Adults: The patient's age should be greater than 19 years
• Paediatrics: Patient's age up to 19 years and weight less than 39 Kgs

Weight Bands: 

• Treatment dosages are based on TB patients’ weight.
• A weight band category is defined for Adults and Pediatric patients separately, and FDC are issued based on that weight category.

Intensive Phase(IP): Consists of eight weeks (56 doses) of HRZE in daily dosages as per weight of patient.

Continuation Phase(CP): Consists of 16 weeks (112 doses) of HRE in daily dosages as per weight of patient.

For adults, there are five weight bands, as shown in the table below. The table also indicates the number of FDC tablets that have to be consumed in each weight band

Regular monthly follow up of the patient needs to be done and if patient loses or gains approx. 5 kg weight and if weight band changes during the treatment, then the dose of the patient needs to be recalculated.
 

Intensive Phase (IP)

Consists of eight weeks (56 doses) of HRZ in daily dosages as per weight of patient.

Ethambutol (E) is given separately for children to monitor ophthalmic side effects.

Continuous Phase (CP)

Consists of 16 weeks (112 doses) of HRE in daily dosages as per the weight of the patient.

In Pediatric, there are six weight bands’s as shown in the table below. The table also indicates the number of FDC tablets  that has to be consumed in each weight band

Regular monthly follow-up of the paediatric patient needs to be done and if the patient weight crosses the range of the weight band during the treatment, then the weight band of the patient should be changed immediately.

Children above 39 kg shall usually be adolescents, the drug dosage requirement for them would be similar to adults

Resources:

• Technical and Operational Guidelines for TB Control in India 2016

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Community Health Volunteers(CHVs) have to refer the presumptive cases identified based on the r symptom screening to the nearest NTEP health facility for further investigation. Once Diagnosed with TB, the TB patients are initiated on the first-line TB treatment. Patients are also offered NAAT within a maximum of 15 days to rule out any drug resistance. If no drug resistance is detected, then the patient continues on the first-line TB treatment. TB patients are then clinically evaluated every month to check the progress of TB treatment. 

The treatment duration of TB is divided into two phases - The Intensive Phase(IP) and the Continuation Phase(CP). Post-treatment completion, patients are then evaluated at intervals of 6,12,18 and 24 Months to ensure a relapse-free TB cure for the patient.

Figure: DSTB Treatment Flow

What is Drug-Resistant Tuberculosis?

• Drug-Resistant TB occurs when bacteria become resistant to the drugs used to treat TB. This means that the drug can no longer kill the TB bacteria.

• Multidrug-resistant TB (MDR TB) is a type of DR-TB where TB bacteria is resistant to both Isoniazid and Rifampicin, the two most potent anti-TB drugs.

                               Figure: High Risk for Drug-Resistant Tuberculosis (DRTB)

Resources:

• Guidelines for Programmatic Management of Drug-Resistant Tuberculosis in India, March 2021 
• WHO Consolidated Guidelines on Tuberculosis: Module 4-Treatment: Drug resistant TB Treatment, 2020

Goals of Drug-resistant Tuberculosis (DR-TB) treatment under the National Tuberculosis Elimination Program (NTEP) are as follows:

Image

Figure: Goals of DR-TB Treatment; Source: Guidelines for PMDT in India, March 2021, p41.

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• Technical and Operational Guidelines for TB in India, 2016. 

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All patients diagnosed with TB should have universal access to rapid DST for at least Rifampicin and further DST for at least Fluoroquinolones among all TB patients with rifampicin resistance, i.e. UDST. 

UDST tests are offered preferably before treatment initiation to a maximum within 15 days from diagnosis. Based on the UDST test result, if Rifampicin resistance is detected, the patient is shifted to DR-TB Treatment Regimen. If Rifampicin resistance is not detected, then first-line anti TB treatment is continued, and the patient is screened further on their follow-ups. If tested positive in sputum examination during any patient follow up, then sputum is sent for further drug resistance testing, and the patient is referred to PHI for follow-up.

Figure: Screening of patient for initiating DRTB Treatment from DSTB Treatment

Resources:

• Guidelines for Programmatic Management of Drug Resistant Tuberculosis in India, March 2021 
• WHO Consolidated Guidelines on Tuberculosis: Module 4-Treatment: Drug resistant TB Treatment, 2020

Depending upon type of drug resistance, there are four broad DRTB Treatment regimen.

1. H Mono/Poly Treatment Regimen(6-9 months)
2. Shorter oral Bedaquiline containing MDR/RR-TB regimen(9-11 months)
3. Shorter injectable containing regimen(9-11 months)
4. Longer oral M/XDR-TB regimen(18-20 months)

Drugs administered for DRTB Regimen:

• Drugs are decided based on the drug resistance detected for a patient and will be informed by the medical officer.
• Injections might also be administered to the admitted patient.
• H Mono/Poly Regimen can be initiated at any health facility, while the other two regimen need to be initiated at N/DDR-TB Centre

Figure: Patient wise boxes(PWB) for DRTB Treatment

PTE Objective

Drugs used for the treatment of drug-resistant TB have significant adverse effects. Hence, there is a need for PTE to rule out any underlying condition at the baseline, like co-morbid conditions, radiological abnormalities, Electrocardiogram (ECG) changes, or biochemical derangements. 

PTE is essential to identify:

• The patient's eligibility for initiation of a particular regimen
• Patients who require special attention during treatment
• Regimen modifications from the beginning of treatment

Important Points 

• In the majority of Multidrug-resistant (MDR)/ Rifampicin-resistant Tuberculosis (RR-TB) patients, PTE can be done on an outpatient basis.
• The District TB Officer (DTO) and Medical Officer of the TB Unit (MO-TU) can arrange for PTE at the Nodal and District DR-TB Centre (N/DDR-TBC) or at the sub-district level health facility, wherever feasible.
• No additional investigations are required for H Mono/ Poly DR-TB patients unless clinically indicated.
• The PTE carried out at the time of treatment initiation can be considered valid for 1 month from the date of the test result and the patient can be re-initiated on a subsequent regimen considering the previously conducted PTEs.
• Active Drug Safety Management and Monitoring (aDSM) treatment initiation forms are required to be completed for all DR-TB patients at the time of initiation of each new episode of treatment.
• PTE should include a thorough clinical evaluation by a physician and expert consultation as per the need. 
• Laboratory-based tests should be performed based on the drugs used in the treatment regimen.
• Pre-treatment evaluation should be made available free of charge to the patient.​

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• WHO Consolidated Guidelines on Tuberculosis: Module 4 -Treatment: Drug-resistant TB Treatment, 2020.

The anti-TB drugs recommended for treatment of Multi- and Extensively Drug-resistant (M/XDR) TB patients are grouped into three groups –  A, B and C (Figure below).

Figure: Groups A, B and C of Anti-TB Drugs used in Treatment of M/XDR-TB Patients

Grouping of drugs is done based on their efficacy, experience of use and drug class. This grouping is intended to guide the design of individualized, longer M/XDR-TB regimens (the composition of the recommended shorter MDR/RR-TB regimen is largely standardized).

Resources

• Guidelines for Programmatic Management of Tuberculosis in India, 2021.
• WHO Consolidated Guidelines on Tuberculosis, Module 4 - Treatment: Drug-resistant TB Treatment, 2020.

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Figure: Sirturo 100 mg Bedaquiline Tablets

Newer anti-TB drugs are needed to improve the treatment outcomes of DR-TB, shorten the duration of treatment, address the problem of drug resistance, and have less toxic drugs. Five decades after the discovery of Rifampicin, two newer drugs with anti-TB effects were approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the Central Drugs Standard Control Organization (CDSCO). These are: Bedaquiline (Bdq) Delamanid (Dlm) In July 2020, the Drug Controller General of India (DCGI) also approved a third newer drug - Pretomanid (Pa) to use under the Conditional Access Programme (CAP) under the National Tuberculosis Elimination Program (NTEP).

Resources

• The Use of Bedaquiline in the Treatment of Multidrug-resistant Tuberculosis, Interim Policy Guidance, WHO, 2013.
• The Use of Delamanid in the Treatment of Multidrug-resistant Tuberculosis in Children and Adolescents, Interim Policy Guidance, WHO, 2016.
• WHO Consolidated Guidelines on Tuberculosis, Module 4: Treatment- Drug-resistant TB Treatment.  
• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.

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The dosage for Drug-resistant TB (DR-TB) drugs used in the regimen by weight bands for adults are enumerated in the table below.

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-resistant Tuberculosis, 2014.

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The principles of designing Drug-resistant TB (DR-TB) treatment regimens (Shorter or longer oral Multi (M)/ Extensively Drug-resistant TB (XDR-TB), and H mono/ poly DR-TB regimens in children are similar to adults:

• Children, aged 5 years to less than 18 years of age and weighing at least 15 kg, are eligible for both longer oral and shorter oral Bedaquiline-containing Multidrug-resistant (MDR)/ Rifampicin-resistant TB (RR-TB) regimens.​
• Management of H mono/ poly DR-TB in children will be the same as in adults and child-friendly formulations can be used.
• The drug doses should be used as per paediatric weight bands.
• Bedaquiline (Bdq) tablets suspended in water have been shown to have the same bioavailability as tablets swallowed whole and therefore, should be used to treat DR-TB in children until a child-friendly formulation becomes available.​
• Delamanid (Dlm) is already approved for treating M/XDR-TB under the National TB Elimination Programme (NTEP) for children from 6 years onwards.​
• As in adults, the extension of Bdq beyond 6 months and concomitant use of Bdq and Dlm in special situations will apply to children as well. ​
• Treatment can be directly extended to 9 months in certain conditions like extensive disease, extrapulmonary TB, uncontrolled comorbidity, smear-positive cases at the end of the 4th month and when the regimen is modified.
• Shortening the total treatment duration to less than 18 months may be considered in children without the extensive disease.​
• For children under 5 years of age, where neither Bdq nor Dlm is approved yet, the longer oral M/XDR-TB regimen should be suitably modified as per the replacement drug. A suitable regimen can be designed considering child-friendly formulations where Bdq can be replaced with Amikacin (Am), Pyrazinamide (Z) or Ethionamide (Eto) in the initial phase.​
• Children below 5 years are not excluded from short-course regimens, instead receive short course injectables till further evidence on the use of Bdq is available.
• The use of injectable agents in children should be exceptional and limited to salvage treatment and be monitored for early detection of ototoxicity. 
• Meropenem is the preferred drug over imipenem in TB meningitis considering the risk of seizures in children due to Imipenem.

Additional Information

• Achieving an appropriate dose in children aged 3-5 years will be easier when the special formulation dispersible 25 mg tablet used in trials in these age groups becomes available.​
• The recent data review for the World Health Organization (WHO) guidelines suggested that there are no additional safety concerns for concurrent use of Dlm with Bdq.​
• For treatment and management of adverse drug reactions in children, there should be provision for treatment in consultation with a specialist. 

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• Consolidated Guidelines on Tuberculosis: Module 4 - Treatment: Drug-resistant TB Treatment, 2020.

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Common Adverse events to second line treatment are as below

Figure: Adverse Drug Reaction to Second line drugs

Adverse events should be identified, monitored and be referred to

• Nearest treating doctor for minor symptoms or
• District DR-TB Centres for major symptoms

If required, hospitalization can be done at the District DR-TB Centers where inpatient facility is available or referred to a Nodal DRTB Centre for admission

Resources

• Guidelines for Programmatic Management of Drug Resistant Tuberculosis in India, March 2021
• Ready reckoner for Medical Officer -Adverse Drug Reactions Associated with Anti-TB Drugs identification and Management, 2019

Based on the World Health Organization (WHO) treatment guidelines, 2020 recommendations, the National TB Elimination Programme (NTEP) have decided to transition from the current shorter injectable-containing Multi-drug Resistant (MDR)/ Rifampicin-resistant TB (RR-TB) regimen to the shorter oral bedaquiline-containing MDR/RR-TB regimen in the year 2021.​

Salient Features of the Shorter Oral Bedaquiline-containing MDR/RR-TB Regimen

• This regimen will be used in patients >5 years of age weighing 15 kg or more.​
• The regimen will be expanded in a phased manner starting with selected states to gain programmatic experience to guide future expansion within 2021.​
• The regimen consists of an initial phase of 4 months that may be extended up to 6 months and a continuation phase of 5 months, giving a total duration of 9-11 months. Bdq is used for a duration of 6 months.​

​

Figure 1: Regimen and duration of shorter oral Bdq-containing MDR/RR-TB regimen

Abbr: Bdq - Bedaquiline, Lfx- Levofloxacin, Cfz- Clofazamine, Z- Pyrazinamide, E- Ethambutol, H^h- High-dose Isoniazid, Eto- Ethionamide​

Points to Note

• From the start to the end of 4 months these drugs are used: Bedaquiline, Levofloxacine, Clofazamine, Pyrazinamide, Ethambutol, high-dose Isoniazid, Ethionamide
• From the start of 5 months to the end of 6 months (If IP not extended): Bdq, Lfx, Cfz, Z, E
• From the start of 7 months to the end of 9 months: Lfx, Cfz, Z, E

If the IP is extended up to 6 months, then all 3 drugs Bdq, Hh and Eto are stopped together

Resources​​

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• WHO Consolidated Guidelines on Tuberculosis, Module 4 - Treatment: Drug Resistant TB Treatment. 

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The total duration of treatment in this regimen is 9-11 months with Intensive Phase (IP) at least 4 months and Continuation Phase (CP) for 5 months. Treatment extension of IP is done up to 2 months based on follow-up results and is indicated in the algorithm presented in the figure below.

Figure: Treatment Extension/ Regimen Change Based on Follow up Smear/ Culture/ DST Results

Abbr: FL & SL- LPA- First Line & Second Line- Line Probe Assay, C&DST- Culture and Drug Susceptibility Test, Z- Pyrazinamide,  Cfz- Clofazimine, FQ- Fluoroquinolone, N/DDR-TBC- Nodal/ District DR-TB Centre

Resources

• Guidelines for Programmatic Management of Tuberculosis in India, 2021.
• WHO Consolidated Guidelines on Tuberculosis: Module 4 – Treatment: Drug-resistant TB Treatment, 2020.

Drug dose administration for shorter/ longer oral Bedaquiline (Bdq)-containing Multidrug-resistant (MDR)/ Rifampicin-resistant (RR)-TB regimen depends on the factors described below.

• The dosage of second-line anti-TB drugs would vary as per the weight of the Drug-resistant TB (DR-TB) patients.​ There are five weight bands in adult patients (≥ 18 years): <16 kg, 16-29 kg, 30-45 kg, 46-70 kg and >70 kg. The weight bands of adult patients for Drug-sensitive TB (DS-TB) patients are different compared to DR-TB patients.
• All morning doses should be supervised by the treatment supporter via Directly Observed Treatment, Short-course (DOTS).​
• In patients with drug intolerance, Cycloserine (Cs), Ethionamide (Eto) and Sodium (Na) Para Aminosalicylic Acid (PAS), can be given in two divided doses.​ Pyridoxine should be provided as part of the regimen till the end of treatment for all patients. ​​

Change in Weight Bands during Treatment​

• For adult DR-TB patients whose weight increases or decreases by 5 kg or more compared to baseline weight and crosses the current weight band during the course of the treatment, the weight band must be changed at the time of issuing next month's box to the treatment supporter of the patient.
• For paediatric patients, the drug dosage should be adjusted immediately once the weight of the patient crosses the range of the weight band. Counsel the patient about the change in dose.

​Key Considerations for Newer Drugs ​

• Avoid milk-containing products with drugs: The calcium in the milk can decrease the absorption of Fluoroquinolones (FQs)​.
• Avoid large fatty meals: Fat impairs the absorption of anti-TB drugs (Cs, Isoniazid (H), etc.).​

Resources

• Guidelines for Programmatic Management of Tuberculosis in India, 2021.
• The Use of Bedaquiline in the Treatment of Multidrug-resistant Tuberculosis: Interim Policy Guidance, 2013

In adults, the dosage of drugs for a shorter oral Bedaquiline (Bdq) - containing Multi-drug Resistant (MDR)/ Rifampicin-resistant Tuberculosis (RR-TB) regimen, varies according to their weight. 

The table below provides drug dosages for adult patients, according to their weight bands, in a shorter oral Bedaquiline-containing MDR/RR-TB regimen.

Resources​

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• The Use of Bedaquiline in the Treatment of Multidrug-resistant Tuberculosis: Interim Policy Guidance, 2013.

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Drugs that are part of the shorter Bedaquiline (Bdq)-containing regimen have some typical side effects which need close monitoring of Drug Resistant-TB (DR-TB) patients while providing the treatment.

Resources​

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021. 

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Longer oral Multi (M)/ Extensive Drug-resistant (XDR) -TB treatment is specified with a definite regime and duration.

Regimen: (18-20) Levofloxacin (Lfx), Bedaquiline (Bdq) (6 months or longer), Linezolid^# (Lzd), Clofazimine (Cfz), Cycloserine (Cs)​​ (^# dose of Lzd will be tapered to 300 mg after the initial 6–8 months of treatment)​

• Duration: 18-20 months
• No separate Intensive Phase (IP) and Continuation Phase (CP).
• Bdq will be given for 6 months and extended beyond 6 months as an exception.
• Pyridoxine should be given to all Drug-resistant TB (DR-TB) patients as per the weight bands.
• For Extensively Drug-resistant TB (XDR-TB) patients, the duration of a longer oral XDR-TB regimen would be for 20 months.

Resources

• Guidelines for Programmatic Management of Drug-Resistant Tuberculosis in India, March 2021.
• WHO Consolidated Guidelines on Tuberculosis: Module 4 – Treatment: Drug-resistant TB Treatment, 2020.

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The total duration of a longer oral Multidrug/ Extensively drug-resistant TB (M/XDR-TB) regimen is 18–20 months. ​

Image

Figure: Protocol for Treatment Extension in Longer Oral M/XDR-TB Treatment Regimen

Extension of Bedaquiline (Bdq) beyond 6 months is to be considered in patients in whom an effective regimen cannot otherwise be designed.

• If any additional resistance to Group A, B or C drugs in use is detected, the patient needs to be reassessed at the Nodal/ District Drug-resistant Tuberculosis Centre (N/DDR-TBC) for modification of a longer oral M/XDR-TB regimen immediately on receiving the report.
• A treatment duration of 15–17 months after culture conversion is suggested for most patients. The duration may be modified according to the patient’s response to treatment.

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021. ​
• WHO Consolidated Guidelines on Tuberculosis: Module 4 – Treatment: Drug-resistant TB Treatment, 2020. 

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The table below showcases the adverse drug events that may be caused by drugs used for longer oral Multi (M)/ Extensively Drug-resistant TB (XDR-TB) regimen. In these situations, replacement drugs are used instead of these drugs.

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• WHO Consolidated Guidelines on Tuberculosis: Module 4 - Treatment: Drug Resistant TB Treatment, 2020.

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It is important to know the dosages of Multi (M)/ Extensively Drug-resistant TB (XDR-TB) drugs for adults on a longer oral M/XDR-TB regimen.​

The table below shows the M/XDR-TB regimen drugs for adults weight band-wise, used in longer oral M/XDR-TB regimen customized for India by national experts.

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• WHO Consolidated Guidelines on Tuberculosis: Module 4 – Treatment: Drug-resistant TB Treatment, 2020.

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Isoniazid (H) mono/ poly Drug-resistant TB (DR-TB) regimen has the following regimen, duration and dosage of drugs.

Regimen: (6 or 9) Lfx R E Z

Dosage

• The dosage of drugs would vary as per the weight of the patients.
• Adult patients (≥ 18 years) would be classified in weight bands of <16 kg, 16-29 kg, 30-45 kg, 46-70 kg and 70 kg. The drug dosages by these weight bands are shown in the table below.
• All drugs in the regimen are to be given on a daily basis under observation.

Duration

• H mono/ poly DR-TB regimen is for 6 or 9 months with no separate Intensive Phase (IP)/ Continuation Phase (CP).
• In exceptional situations of unavailability of loose drug R or E or Z, the use of 4 FDC (HREZ) with Levofloxacin (Lfx) loose tablets may be considered as an option rather than not starting the H mono/ poly DR-TB patients on treatment.

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.
• WHO Consolidated Guidelines on Tuberculosis: Module 4 - Treatment: Drug-resistant TB Treatment, 2020.

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he potential adverse drug events that can occur when using drugs in the H mono/ poly DR-TB regimen are tabulated below:

Resources

• Guidelines for Programmatic Management of Drug Resistant Tuberculosis in India, March 2021.
• WHO Consolidated Guidelines on Tuberculosis: Module 4 - Treatment: Drug resistant TB Treatment, 2020.
• Technical and Operational Guidelines for TB in India, 2016.

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• TB Infection (or previously known as Latent TB infection) is a stage in between uninfected and having active TB. In this stage the person has no symptoms and can only be identified using laboratory tests.

• The vast majority of infected people may never develop TB disease. However, to achieve TB elimination, it is important to treat TB infection in people at risk of developing active TB disease.

• It is a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifested active TB.

• There is no single acceptable/reliable test for direct identification of Mycobacterium tuberculosis infection in humans. Tuberculin Skin Test (TST) and Interferon-gamma release assay (IGRA) are commonly used tests for identifying TB infection.

Resources:

• Latent Tuberculosis Infection Guideline

• Guideline for Programmatic Management of Tuberculosis Preventive Treatment in India

For TB infection, there are two recommended tests which can be used to identify such patients.

Tuberculin Skin Test (TST)

The skin test is done by injecting a small amount (0.5 ml) of TB antigens into the top layer of skin on your inner forearm. If one has ever been exposed to TB bacteria (Mycobacterium tuberculosis), there will be a reaction indicated by the development of a firm red bump (induration) >= 10 mm at the site within 2 days.

Image

Figure: Tuberculin Skin Test

Interferon-gamma release assay (IGRA)

IGRA is a Blood test. If one has been exposed to TB bacteria, the white blood cell in the blood will release a substance called gamma interferon when the cells are exposed to specific TB antigens.

Image

Figure: Interferon-gamma release assay (IGRA)

Resources:

• Latent Tuberculosis Infection Guideline
• Guideline for Programmatic Management of Tuberculosis Preventive Treatment in India

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TPT treatment options recommended under NTEP include:

• 3-month weekly Isoniazid and Rifapentine (3HP)
• 6-months daily isoniazid (6H)

Table 1: TPT Options for Target Population; Source: (Guidelines for Programmatic Management of Tuberculosis Preventive Treatment)

Table 2: TPT dosage based on age and weight band recommended by NTEP; Source: Guidelines for Programmatic Management of Tuberculosis Preventive Treatment

Resources

• Guidelines for Programmatic Management of Tuberculosis Preventive Treatment
• National Strategic Plan for TB Elimination

Assessment

The NTEP has prioritized the target population for TPT based on elevated risk of progression from infection to TB disease or increased likelihood of exposure to TB disease. 

The target populations have been divided into two groups:

1. Household contacts of bacteriologically confirmed pulmonary TB patients notified in Nikshay from public and private sector.

#Chest X Ray (CXR) and TBI testing would be offered wherever available, but TPT must not be deferred in their absence

*Bacteriologically confirmed pulmonary TB patients to be prioritized for enumeration of the target population for TPT

2. Expanded to other risk groups

Several medical conditions are risk factors for TB and poor TB treatment outcomes. Similarly, TB can complicate the course of some diseases. Therefore, it is important to identify these comorbidities in people diagnosed with TB to ensure early diagnosis and improved outcomes. When these conditions are highly prevalent in the general population, they can significantly contribute to the TB burden. Consequently, reducing the prevalence of these conditions can help prevent TB.

TB shares underlying social determinants with many of these conditions. Addressing the social determinants of health is a shared responsibility across disease programmes and other stakeholders within and beyond the health sector. 

Figure: Various comorbid and special situation related with tuberculosis

The primary impact of HIV on TB is that the risk of developing TB becomes higher in patients with HIV. Overall, HIV-infected persons have an approximately 8-times greater risk of TB than persons without HIV infection. 

Screen TB PLHIV patients for symptoms of TB and HIV

Figure: Screening steps for TB - HIV patients

Treatment for TB HIV Patients​

• All TB patients who have been diagnosed and registered under NTEP should be referred for screening for HIV.
• Referral of TB patients for screening for HIV and its recording & reporting is the responsibility of the Peripheral Health Institutions(PHI) where TB treatment is initiated.
• TB patients diagnosed with HIV will receive the same duration of TB treatment with daily regimen as non-HIV TB patients.
• TB patients must be referred to the nearest ART(Anti - Retroviral Treatment) centre for management of HIV.

As a consequence of urbanization as well as social and economic development, there has been a rapidly growing epidemic of Diabetes Mellitus(DM). India has the second largest number of diabetic people in the world.

Screen TB patients for symptoms of diabetes

Figure: Screening steps for TB - Diabetic Patients

Treatment for TB Diabetes Patients​

• All TB patients who have been diagnosed and registered under NTEP will be referred for screening for Diabetes.
• Referral of TB patients for screening for DM and its recording & reporting is the responsibility of the Peripheral Health Institutions(PHI) where TB treatment is initiated.
• TB patients diagnosed with diabetes will receive the same duration of TB treatment with daily regimen as non-diabetic TB patients.
• TB patients must be referred to the nearest healthcare facility for management of DM.
• Regular monitoring of blood sugar levels is advised.

Malnutrition refers to deficiencies, excesses or imbalances in a person’s intake of energy and/or nutrients. The term malnutrition covers 2 broad groups of conditions.

• One is ‘undernutrition’—which includes stunting(low height for age), wasting(low weight for height), underweight(low weight for age) and micronutrient deficiencies or insufficiencies(a lack of important vitamins and minerals).
• The other is overweight, obesity and diet-related non communicable diseases (such as heart disease, stroke, diabetes, and cancer).

Screen TB Malnutrition patients for nutritional needs

Figure: Screening Steps for TB - Malnutrition patients

Treatment for TB Malnutrition Patients

Cases of TB with SAM and moderate undernutrition should be referred to the nearest health facility of NTEP for further management. Special focus should be given to the following categories:

• Children below five years
• School-age children and adolescents(Up to age 18 years)
• Adults, including pregnant and lactating women, with active TB and SAM

About 10% TB deaths globally have been attributed to alcohol as a risk factor(WHO, Global TB Report 2017). Alcohol abuse is associated with threefold increase in risk of contracting tuberculosis.

Side effects of anti TB drugs in this situation might get aggravated.

Figure: Impact of Alcoholism on TB patients

Treatment for Alcoholic TB Patients:

• Patients with TB and a history of alcohol use should be referred to the nearest health facility of NTEP to manage TB and alcoholism.
• While registering as a TB case, the status of alcohol use should be recorded in the patient records. If the TB patient is an alcohol user, he/she should be counselled to quit it. If the patient doesn't quit alcohol, s/he may be referred to the nearest alcohol de-addiction facility.
• The patient should be assessed at every follow-up visit for TB and the status of use of alcohol.
• At the end of treatment, his/her status of alcohol use should be recorded on the treatment card. If the patient has not quit alcohol, he/she should be referred to the nearest alcohol de-addiction facility and Alcohol Anonymous wherever available.

Almost 38% of TB deaths are associated with the use of tobacco. The prevalence of TB is three times higher among ever-smokers as compared to that of never-smokers. Mortality from TB is three to four times higher among ever-smokers as compared to never-smokers. Smoking contributes to 50% of male deaths in the 25-69 age group from TB in India.

Figure: Impact of Tobacco on TB patients

Treatment for TB - Tobacco Patients:

• While registering as a TB case, the status of tobacco use is recorded on the TB treatment card.
• If the TB patient is a smoker or tobacco user, he/she is counselled to quit tobacco use. The patient is assessed at every visit for follow up for TB and the status of tobacco use.
• At the end of treatment, his/her status of tobacco use is recorded in the treatment card. If the patient has not quit tobacco use, he/she will be referred to the nearest Tobacco Cessation Clinic(TCC) or Quit Line or M-Cessation Initiative.

Silicosis is a progressive and disabling interstitial lung disease caused by inhalation and deposition in the lungs of particles of free silica.

Mutual Risk of TB and Silicosis

• TB is a clinical complication of silicosis, called silico-tuberculosis. Silica-exposed workers with or without silicosis are at increased risk for TB. There is also an increased risk of extrapulmonary TB in individuals exposed to silica.
• The risk of a patient with silicosis developing TB is 2.8 – 3.9 times higher than a healthy individual.
• The risk of TB relapse in patients with silicosis is approximately 1.5 times higher than in patients without silicosis.

The presence of silica particles in the lung and silicosis may:

• Facilitate initiation of TB infection and progression to active TB
• Exacerbate the course and outcome of TB, including prognosis and survival

Diagnosis

The diagnosis of silicosis is made based on a history of exposure to silica accompanied by a clinical and radiological profile consistent with the disease.

Under the Integrated Management Algorithm for TB disease and TB infection released by the National TB Elimination Programme (NTEP), patients with silicosis are first screened according to the four-symptom complex to rule out/in active TB and tested for TB accordingly. 

If active TB is ruled out >> Refer for Tuberculin Skin Test (TST)/ Interferon Gamma Release Assay (IGRA) >> Positive test >> Evaluate with Chest X-ray (CXR) >> Commence TB Preventive Therapy (TPT) irrespective of CXR results.

CXR often indicates TB in silicosis patients earlier than the clinical symptoms, and regular radiographic screening is required for early TB detection. Radiographic comparison of serial films is done with particular attention to:

• Rapid appearance of new opacities, symmetric nodules or consolidation and the finding of pleural effusion or excavations.
• Cavitation is the strongest indicator of probable silico-tuberculosis.

Other diagnostic tools that can help in diagnosis are:

• Chest Computed Tomography (CT) scan
• Bronchoscopy with bronchoalveolar lavage in conjunction with transbronchial biopsy
• Spirometry

Treatment and Follow-up

To keep the disease from getting worse, all silicosis patients need to eliminate any more exposure to silica. Supportive measures include the use of cough medicines, bronchodilators, oxygen therapy and pulmonary rehabilitation.

TB treatment in patients with silicosis is challenging, perhaps due to impairment of macrophage function by free silica and/or poor drug penetration into fibrotic nodules. Usual anti-TB drugs with directly observed therapy are recommended but for an extended duration of at least 8 months, to reduce the chances of relapse.

Follow-up of patients with silicosis and TB follow the same schedule as is in prevailing guidelines.

Prevention

TB prevention in silicosis patients is essential and includes:

• Active surveillance of vulnerable groups including workers
• Adoption of measures to reduce exposure to silica dust
• Patients with silicosis are eligible for TPT after ruling out active TB

NTEP is in the process of engaging with the Ministry of Labour and Mining to identify high priority districts with stone crushing units/ mining industry. Specific guidelines will be developed to support persons with an occupational risk for TB and provide access, diagnosis and treatment services from the programme.

Resources

• NTEP at a Glance; Comprehensive Clinical Management Protocol of Tuberculosis, 2022.
• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Silico-tuberculosis, Silicosis and Other Respiratory Morbidities Among Sandstone Mine-workers in Rajasthan - A Cross-sectional Study, Saranya Rajavel et al., 2020.
• Mini-review: Silico-tuberculosis; Massimiliano Lanzafame et al, 2021.
• Immunity to the Dual Threat of Silica Exposure and Mycobacterium tuberculosis, Petr Konečný et al., 2019.

Assessment

​

Relationship between Cancer and Tuberculosis (TB)

TB and malignancy may be related in the following four ways:

1. TB as a marker for occult cancer: Occult cancer may lead to locally-reduced infection barriers and/or generalised immunosuppression, rendering a cancer patient susceptible to TB infection/ reactivation.
2. TB as a risk factor for cancer: TB may increase the risk of cancer locally and systemically through chronic inflammation, fibrosis and production of carcinogenic molecules.
3. Shared risk factors for TB and some cancers: Shared risk factors such as smoking, alcoholism, Chronic Obstructive Pulmonary Disease (COPD) and immunosuppression, including HIV, may lead to both TB and cancer, affecting both prevalent and subsequent cancer risk.
4. Treatment of cancer-fueling TB: Many cancers are treated with immunosuppressants or steroids. These drugs might induce immunosuppression in the patients undergoing treatment for cancer and hence, a flare-up of TB.

Mutual Risk of Cancer and TB

• TB patients are 2-11 times more likely than non-TB patients to develop lung cancer, according to studies.
• After cancer diagnosis, the incidence of TB also increases, both in the short term and long-term.
• All types of cancer increase the risk of the development of active TB, but with varying degrees. Haematologic cancer patients had the highest rates of active TB, followed by head and neck cancers, lung cancer and breast cancer patients.

There is intrinsic immunosuppression due to the cancer itself, immunosuppressive effects of chemotherapy, or other host factors (e.g., smoking, malnutrition) that may increase the susceptibility to both cancer and TB. Thus, there is increased incidence of TB in cancer patients, and vice-versa.

Diagnosis of TB in Cancer Patients: Under the Integrated Management Algorithm for TB disease and TB infection released by the National TB Elimination Programme (NTEP), cancer patients are first screened according to the four-symptom complex to rule out/in active TB and all presumptive TB cases need to undergo testing for TB.

Co-existence of TB and cancer poses a diagnostic challenge since clinical and radiological presentations between TB and cancers are similar, hence the need for bidirectional screening. E.g., if biopsy specimens reveal infiltration by malignant cells, still send sample for microbiological confirmation of M. tuberculosis. Thus, allowing for accurate diagnosis and initiation of anti-TB treatment instead of attributing clinical deterioration to chemotherapy complications and progression of underlying malignancy.

Diagnosis of lung cancer in TB patients is usually done in consultation with a clinical specialist and can include examination of induced sputum specimens for malignant cells, as well as use of other diagnostic tools such as Computed Tomography (CT) scans, bronchoscopy, Positron Emission Tomography (PET) scans, Magnetic Resonance Imaging (MRI), histopathology and the use of biological markers.

Treatment

TB treatment in cancer patients uses the standard DS-TB/DR-TB regimens and course, except that the treating physician should assess the drug interactions between anti-TB and anti-cancer drugs. For cancer treatment, drugs may have to be modified to accommodate anti-TB treatment and to aid better prognosis of the TB outcome. However, all decisions must be taken by a competent specialist after examining the individual case.

Curative resection, chemotherapy and radiation therapy are the mainstay treatment options for cancer in TB patients. Co-existence of TB in cancer patients necessitates anti-TB treatment with extended duration, if required. Follow-up during and after treatment also follows prevailing guidelines.

Prevention

Under the NTEP, TB prevention in cancer patients is essential and includes:

• Regular screening for signs and symptoms of TB infection among all patients on immunosuppressive therapy and anti-Tumour Necrosis Factor (TNF) medicines.
• Education and referral of patients who do not have TB symptoms for TB infection testing/assessment of their eligibility for TPT.

Resources

• NTEP at a Glance; Comprehensive Clinical Management Protocol of Tuberculosis, 2022.
• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Tuberculosis and Risk of Cancer: A Danish Nationwide Cohort Study, D. F. Simonsen et al., International Journal of Tuberculosis and Lung Diseases, The Union, 2014.
• Increased Risk of Active Tuberculosis after Cancer Diagnosis, Dennis F. Simonsen et al., Journal of Infection, 2017.
• Pulmonary Tuberculosis as Differential Diagnosis of Lung Cancer; MLB Bhatt et al., South Asian Journal of Cancer, 2012.

Assessment

The presence of tuberculosis disease during pregnancy, delivery, and postpartum is known to result in unfavourable outcomes for both pregnant women and their infants. These outcomes include a roughly two-fold increased risk of preterm birth, low birth weight, intrauterine growth restriction, and a six-fold increase in perinatal death.

Screen TB patients in Pregnancy & Lactating Patients

Figure: Screening Steps in special situation - Pregnancy and Lactating TB Patients

Treatment for TB - Pregnant & Lactating Patients

• Cases of pregnant/lactating women with active TB should be referred to the nearest health facility of NTEP for further management.
• They should be continued on iron and folic acid and other vitamins and minerals to complement their maternal micronutrient needs.
• In situations when calcium intake is low, calcium supplementation is recommended as part of antenatal care.

Tuberculosis and COVID-19 are infectious diseases which primarily attack the lungs. They present with similar symptoms of cough, fever and difficulty in breathing, although TB disease has a longer incubation period and a slower onset of disease.

Screen patients for symptoms of TB and COVID-19

Figure: Screening steps for TB - COVID 19 Patients

Management of TB & COVID-19 Patients

People with TB are likely to be at increased risk of COVID-19 infection, illness and death. So, TB patients should take precautions as advised by health authorities to be protected from COVID-19 and continue their TB treatment as prescribed.

Prevention: While both TB and COVID-19 are spread by close contact between people, the exact mode of transmission differs. Thus, the patient should be explained the following measures to control disease spread.

• Apart from that keeping rooms well ventilated, avoiding crowds and Respiratory precautions are thus important in the control of COVID-19 and TB Disease

Tuberculosis(TB) is curable if patients are treated with effective, uninterrupted anti-tuberculous treatment. Treatment adherence is critical for curing individual patients, controlling the spread of infection in the community, and minimizing the development of drug resistance.

Adherence to treatment means that a patient follows the recommended course of treatment by taking all the prescribed medications for the entire length of time, as necessary. In other words, “right dose for the right duration”.

In Drug Sensitive Tuberculosis(DSTB), a TB patient completes 168 doses of TB treatment and adheres to TB treatment.

Adherence to tuberculosis(TB) treatment is important for promoting individual and public health. Poor adherence to TB treatment results in:

• More individual suffering and death,
• Costly treatment as treatment regimens lengthen and
• Increases the risk for Drug Resistant Tuberculosis

Proper treatment of all forms of TB is critical to reducing individual morbidity and mortality and to interrupting transmission among family and community members.

Recording of Treatment Adherence can be done as

• Manually by DOT/Health Care Provider in TB Treatment Card of a patient.
• Self-reported by Patient using digital tools for reporting adherence using 99 DOTS and MERM technologies.

Monitoring Treatment Adherence:

All TB patients should be monitored to assess their response to TB treatment. Nikshay Adherence calendar has a colour legend for various doses taken by a patient

Figure: Sample Nikshay Adherence Calendar in web and Mobile App

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Figure: DSTB Treatment Card (Paper)
 

99DOTS is a low-cost digital adherence technology built-in Nikshay that uses inexpensive packaging(envelopes or stickers) with medication that enables people taking medication to engage with their treatment daily. This packaging, distributed to TB patients taking medications, has a hidden number behind perforated flaps on the external envelope; in some cases, the number may be fixed outside the medication blister or pill bottle. This number can be a toll-free number that can be called to register daily adherence or a code sent by SMS, USSD, or other communication channels. Calling or messaging the number is free!

Figure: 99 DOTS Envelope

MERM: The Medication Event Reminder Monitor(MERM) is a digital pillbox that provides daily pill-taking reminders and facilitates remote monitoring of medication adherence. This system provides visual and audible reminders for both daily dosing and refill,.transmits this data to a server so that healthcare providers can remotely visualize patients’ dosing histories to support enhanced adherence counselling. 

Figure: MERM Box

Manual recording of Adherence in Nikshay:

in Nikshay, Adherence can only be recorded only if there is corresponding dispensation being issued to a Patient 

Figure: Steps to record manual dose in Nikshay

Recording in Patient Treatment Card:

Figure: Filled Treatment card for TB Patient

Missed Dose recording in Nikshay:

For recording missed doses in Nikshay, following steps should be followed:

A person affected by TB requires support throughout the course of treatment and beyond that. The support to a TB patient is essential to ensure that s/he completes the treatment without affecting her/his quality of life (QoL). Keeping the patient as the central figure in the continuum of care, and ensuring social and personal circumstances are supportive (not only meeting immediate requirements of medical treatment) is the key to treatment support.

Figure: Key Components of Treatment Support

Resources

National Strategic Plan for Tuberculosis Elimination 2017–2025, RNTCP, 2017.

A Patient-centred Approach to TB Care, WHO, 2018.

Assessment

A Treatment Supporter can be any person such as a Medical Officer, MPWs, community volunteers working with the program etc. Even a patient’s relative or family member can be a Treatment Supporter.

As per NTEP guidelines, salaried NTEP/General Health System staff may also be assigned as treatment supporters for a patient.  However, they will not be eligible for any honorarium.

A patient can only be linked to one treatment supporter at a time in Nikshay.

Supply Chain Management (SCM) is the handing of flow of goods and material from point of origin to point of consumption, with the objective to ensure that the supplies are present for utilization without any interruption. It covers everything from procurement and sourcing of raw materials to delivery of final product to the consumer, along with the related logistics. It will also include the related information systems that enable monitoring and exchange of information.

Effective SCM ensures the following:

• Continuous availability of quality-assured medicines/ products at the right time and at all healthcare levels.
• Minimizes wastage by preventing expiry of drugs at all levels, maintenance of adequate stock levels and accurate records.
• Maximizes patient care by coordination in all departments and by minimizing human errors/ medication errors.
• Economically viable by minimizing monetary loss (e.g., through pilferage) and optimizing cost via bulk purchasing or according to consumption needs.

Robust supply chain management systems have two main components:

1. Physical flow: Involved the movement and storage of supplies
2. Information flow: Allows the various stakeholders to coordinate and control the flow of supplies

Resources

• NTEP Training Modules 1-4 for Programme Managers & Medical Officers, 2020.
• NTEP Training Modules 5-9 for Programme Managers & Medical Officers, 2020.
• Guidelines for Programmatic Management of Drug-resistant TB, 2021.

Assessment

Under the National TB Elimination Programme (NTEP), the anti-TB drugs are procured at the centre level by the Central TB Division (CTD), Ministry of Health and Family Welfare (MoHFW), and supplied to the central warehouses.

From the central level warehouses, the drugs are supplied to different State Drug Stores (SDS) and further distributed to District Drug Stores (DDS) and sub-district level (TB Unit (TU) Store and Peripheral Health Institute (PHI)).

This movement of drug flow is monitored in real-time through Ni-kshay Aushadhi.

Figure: Flowchart Showing the Overview of Distribution of Drugs

Abbr: CMSS: Central Medical Services Society; GDF: Global Drug Facility; CTD: Central TB Division; GMSD: Government Medical Store Depot; SDS: State Drug Store; DDS: District Drug Store; TU: TB Unit; PHC: Primary Health Centre; PHI: Peripheral Health Institute.

Resources

• Standard Operating Procedure Manual Procurement & Supply Chain Management, CTD, MoHFW, India, 2018.
• Procurement, Supply Chain Management & Preventive Maintenance, Module 6, CTD, MoHFW, India.

Various stocks are maintained at different levels. To facilitate the monitoring of the quantity of these stocks, these are classified as follows:

1. Active Stock: It refers to those stocks which have passed all quality parameters and those which are ready to use/ dispatch for consumption. This is the heart of a warehouse and mostly uses the major chunk of storage. The First Expiry First Out (FEFO) principle will apply to this section of the drug stock.
2. Quarantine Stock: The stock which is pending for quality testing or not yet prepared for active usage is called quarantine medicines. This stock is kept in a separate area that is called the quarantine area and is not to be disbursed for usage until they are declared as active stock.
3. Safety Stock: Buffer stock or safety stock is the amount of stock or medicine set aside to meet the requirements of the facility/ store at the time of an emergency like unforeseen demand or depleting stock. However, this stock should be frequently checked for expiry and replenished at right time to prevent its expiry.
4. Damaged Stock: The medicines or stocks which are found damaged during the delivery at a particular facility/ warehouse in terms of packaging/ leakage/ broken, are to be identified and kept separately as damaged stock. The idea is to return them to the supplier with the proper Damage Stock Report Form. The pharmacist needs to mark such damaged stock in the delivery challan at the time of the receipt.
5. Substandard Stock: Substandard medicines/ items are products that do not meet the quality standards and specifications. These items should be kept separately to avoid their use. These stocks need to be reported to the parent store. As per the directions, these stocks either need to be returned to the supplier or disposed of in accordance with the biomedical waste management guidelines.
6. Lost in Transit Stock: It refers to the stock which is either misplaced/ lost during transportation. The pharmacist needs to report such stock in the delivery challan at the time of the receipt and the same needs to be reported to the supplying store immediately.
7. Expired Stock: Ideally, the warehouse should not have an expired medicine/ item if a proper FEFO mechanism is adopted for dispatch. However, in certain situations, drugs/ items may get expired and may not be suitable for usage as recommended by the manufacturer. Such stock is called Expired Stock. These expired drugs/ items need to be kept separately in a demarcated area and are labelled as expired drugs/ items and are to be disposed of, in accordance with the prevailing biomedical waste disposal guidelines after obtaining necessary approvals.

Resources

• Operational Guidelines for TB Services at Health & Wellness Centres, MoHFW, GoI, 2020.

Assessment

Minimum Stock

 A minimum stock level is a threshold value that indicates the level below which actual medicine stock should not normally be allowed to fall.

In other words, a minimum stock level is a minimum quantity of a particular drug/ medicine that must be kept at all times.

The main factors to consider when fixing the minimum stock level are:

• Average consumption
• Time needed to procure/ receive from supplies/ reporting facility, i.e., Lead time
• Reorder level (a fixed stock level between the maximum and minimum stock levels, at which a request for supply will be placed)

The minimum stock level can be calculated by applying the following formula:

Minimum Stock Level = Reorder level - (Average consumption per time period under consideration x Time taken for delivery)

(time period may be day/ week/ month/ quarter)

Maximum Stock

A maximum stock level is the upper limit of stock that should not be exceeded under normal circumstances without the prior agreement of the management.

The aim of setting a maximum stock level is to maintain the inventory level at the warehouse.

The main factors to consider when fixing the maximum stock level are:

• Average consumption
• Availability of storage space
• Economic order quantity
• Time needed to procure/ receive from supplies/ reporting facility
• Cost of carrying inventory or cost of storage

The maximum stock level can be calculated by applying the following formula:

Maximum Stock Level = Reorder level + Reorder quantity - (Minimum consumption per time period under consideration x Minimum time taken for delivery)

Figure: Stock Re-ordering Level; Source: Inventory Management.

Resources

• Maximum STock Level in Inventory Management, Interlake Mecalux.
• Inventory Management.

Assessment

The principle of First-Expired, First-Out (FEFO) means that the drugs which are due to expire first, are to be issued first. 

The FEFO principle ensures that the product with the shortest expiry date is utilised at the earliest within its shelf-life. 

Following the FEFO principles, the stocks need to be placed/ arranged/ stacked in a sequential manner. 

Steps Followed for Implementing FEFO

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1. Check Expiry Date
   • The expiry date of the stock need to be checked at the time of receipt of supplies with the release order/issue voucher. 
   • The ‘Expiry Dates’ should be marked in bold letters, 3” to 4” in size, on the drug cartons with a marker pen, for easy identification and control of drugs immediately on their arrival.
   • The pharmacist need to record for expiry date of the stock in the Ni-kshay Aushadhi or in stock register.
      
2. Storing Supplies with Different Dates of Manufacture and Expiry in Different Batches
   • Different batches of supplies with different dates of manufacture and expiry should be stored separately.
   • Supplies that are past their date of expiry should never be stored with the items which are still being used and the storekeeper should ensure that there is no stocking of supplies beyond their date of expiry.
      
3. Checking the Utilisation Pattern Before Issuing Drugs
   • The storekeeper should strictly follow FEFO principles to ensure that all short-expiry drugs should be distributed to  the State/ District/TU/ Peripheral Health Institute based on the utilisation pattern of each.
   • The storekeeper is also expected to install appropriate tools to periodically monitor controls over the expiry position of drugs held in stocks mainly through storage of drugs of a particular description at one place, expiry-wise stacking and marking expiry dates on cartons/ drug boxes with marker pens.
   • The Pharmacist need to check for Expiry date from the physical stock and Ni-kshay Aushadhi prior to issue.
   • In case of short-expiry supplies, the distribution should be on the rational basis keeping in view the utilization pattern to ensure judicious consumption.
      
4. Frequent Checks/ Physical Verification
   • Frequent check and physical verification to be carried out by the supervisory officer on regular basis. This ensures that the older drugs are being used first and that none of the drugs are past their date of expiry.

Resources

• Module for STS - Part 2: Ensuring Proper Registration and Reporting, CTD, MoHFW, India.
• Training Modules (5-9) for Programme Managers and Medical Officers, CTD, MoHFW, India.

Assessment

The short expiry drugs are the drugs which are left with a short shelf-life and need to be utilised immediately to avoid their expiry. 

Shelf-life of a drug is defined as a period during which the drug will last without deterioration, provided all precautions for good storage practices have been undertaken. The shelf-life of anti-TB drugs ranges from 3-5 years after which the chances of losing efficacy and probability of side effects increase rapidly. Therefore, it is important to ensure that appropriate steps are taken as soon as the drugs reach the critical stage to ensure their usage well within their shelf-life.

Identification of Short Expiry Drugs 

• Short expiry depends on two main factors, duration of the treatment and the time taken for transit from one level to the next lower level, i.e., from State Drug Stores (SDS) to the District TB Centre (DTC) --->Tuberculosis Unit (TU) ---> Peripheral Health Institute (PHI).
• Whenever the drugs are dispatched,  the transit duration (approx.3 months), possible treatment interruption (approx. 1 month), a probable extension of the Intensive Phase (1 month) and the buffer stocking norm under each facility should be taken into account, to calculate if the drug is expiring shortly.

Principles of Management of Short Expiry Drugs 

• For the drugs whose expiry date is mentioned only as month and year, the last day of that particular month should be considered as the date of expiry.
• Expiry-wise stacking of the drugs, marking of expiry dates on cartons/ drug boxes with marker pens and periodic monitoring of the expiry position of the drugs.
• The expiry date should be highlighted in yellow to flag attention to the drugs facing the risk of expiry.
• First-Expiry-First-Out (FEFO) principle should be strictly followed in the case of short-expiry drugs which means the drugs near to expiry should be issued first.
• All the details about the drug quantity and expiry date should be recorded and reported in Ni-kshay Aushadhi.
• A review of drug adequacy should be conducted monthly/quarterly by the officer in charge to identify any stock imbalances or excessive short expiry drugs and implement corrective measures accordingly.
• The distribution of short expiry drugs on a rational basis, keeping in view the utilisation pattern of each district to ensure timely consumption of close to expiry drugs.

Resources

• Standard Operating Procedure Manual Procurement & Supply Chain Management, CTD, MoHFW, India, 2018.
• Procurement, Supply Chain Management & Preventive Maintenance, Module 6, CTD, MoHFW, India.

Assessment

Buffer stock refers to a reserve that is used in unforeseen emergencies. It is also known as strategic stock or safety stock. This mandates close monitoring of drug stocks and maintaining buffer stock at all levels following the stocking norms to ensure an uninterrupted supply of drugs.

Importance of Maintaining Buffer Stock

1. To cover for delays/ disruptions (if any) in the supply chain.
2. To manage instances where more patients are initiated on treatment than the actual expected patients in a particular month.
3. To ensure that no patient is sent back due to a shortage of drugs at any point in time.
4. For smooth functioning of the programme on a national level.

Buffer stock to be maintained at different levels under NTEP

Resources

• Standard Operating Procedure Manual Procurement & Supply Chain Management, CTD, MoHFW, India, 2018.
• Guidelines for PMDT in India, 2021. 

Assessment

Lead time is defined as the time interval between the order generation for a product and its receipt/ availability for use. Lead time for a product depends upon the type of product, quantity available in the market/ manufacturer and the weather conditions in which it is transported.

In supply chain management lead time plays a very important role as it is mandatory to place reorders in time to avoid stocking out the product. Poorly managed lead time can lead to stock out and leads to delays in supplying the product to clients or end users.

Lead Time = Reordering delay (Time period) + Supply Delay (Time period)

Figure: Lead Time in Supply Chain Management

Benefits of Reduction in Lead Time

• Minimises stock-outs 
• Helps to get medicines/ items on time
• Reduces the wastage of inventory
• Gives the estimation of demand

How to Reduce the Lead Time

• Stop ordering surplus inventory
• Keep an eye on the inventory level
• Cut out as many steps as possible
• Maintain the inventory as per the storage capacity
• Continuous follow-up with the supplier or the facility

Resources

• Strategies to Reduce lead Time in Your Supply Chain.

Assessment

N-ikshay platform has a module for drug dispensation to patients. This feature is used for:

• Adding details of the product and quantity of drugs issued to patients.
• Printing and downloading the details of drugs dispensed as a prescription to share with the patients.
• Saving the time spent in repetitive data entry by copying previous dispensation details.
• Logging details of drugs that are returned by patients.
• Ensuring timely dispensation of drugs to patients by accessing the list of patients whose refill is due through the ‘Refill Due Task List’.

The stepwise details of adding dispensation are shown in the figure below.

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Figure: Workflow for "Add Dispensation" on Ni-kshay; Source: Ni-kshay Portal.

Steps for Dispensation to Patients in Ni-kshay

1. Click on the ‘Add Dispensation’ button.
2. Search by episode ID or dispensation ID.
3. Enter dispensation details:

• Enter the “Date of Prescription”.
• The type of regimen gets auto-populated based on the test results.
• Enter the “Date of  Dispensation”.
• “Weight Band” is getting auto-populated. 
• The phase also gets auto-populated based on the test.
• Enter the “Current Weight”.

4. Enter drug issuing facility details.

• Select the State.
• Select the District.
• Select the “Drug Issuing Facility Type”.
• Select the “Drug Issuing Facility Name”.

5. Enter Product Details.

• Click on “Add” if required to add more product(s).
• Select the “Source” from the list.
• Select the prescribed product name from the drop-down option, it is a mandatory field.
• It is an auto-populated field based on the chosen product.
• Enter the “Quantity” as per the prescription, it is a mandatory field.
• Select the quantity less than or equal to the available quantity.

6. Enter Refill Details.

• Enter the dosing start date as per the prescription, it is a mandatory field.
• Enter the number of days of dispensation as per the prescription, it is a mandatory field.
• Enter remarks, if any.

In case a patient returns drugs, the same can be recorded under Return Dispensation. 

Resources

• Ni-kshay Portal.

Assessment

Inventory Management (IM) is a systematic approach to ordering, receiving, storing, issuing and reordering drugs and other commodities. IM is a critical element in supply chain management which ensures the availability of the right products in the right place at the right time.

Image

Figure: Overview of Inventory Management in NTEP

Abbr: SDS: State Drug Store; DTC: District Tuberculosis Centre, NTEP: National Tuberculosis Elimination Programme.

Under the National TB Elimination Programme (NTEP), IM refers to the activities carried out by the officer-in-charge of logistics and includes the following:

1. Determination of Stock Status at the SDS and DTCs/ Subordinate Stocking Points: The pharmacist will determine the drug stock status of their store and of all the sub-units up to PHIs through Ni-kshay Aushadhi.
2. Review of Adequacy of Stock: The Pharmacist will analyse the adequacy of stocks on the basis of the available stock and estimated consumption as per the stocking norms.
3. Correction of Imbalances through Transfers: Based on the review of drug adequacy, the officer-in-charge will flag all the sub-stores that are significantly under or overstocked.
   1. The needs of sub-stores flagged as understocked will be addressed through the Additional Drug Request (ADR) or Drug Transfer Advice (DTA) mechanism.
   2. The stocks at the sub-stores flagged as overstocked or with close to expiry drugs will also be corrected by the DTA mechanism.
   3. These transfers will only be authorised by the State TB Officer (STO)/ District TB Officer (DTO)/ officer-in-charge and should be recorded in Ni-kshay Aushadhi.
4. Replenishment of Stock: The stocks at the stores are replenished on a quarterly basis, pursuant to the review and validation of the reports available in the Ni-kshay Aushadhi.

Resources

• Standard Operating Procedure Manual, Procurement & Supply Chain Management, Central TB Division, Ministry of Health and Family Welfare, Government of India.

Assessment

National TB Elimination Programme (NTEP) has established a robust supply chain management to ensure an uninterrupted supply of drugs and consumables across the country.

The drugs, diagnostic equipment, etc., are procured mainly through the central level and the states are granted permission to procure some consumables through the local state or district level while abiding by the NTEP guidelines.

1. Anti-TB Drugs

The various type of anti-TB drugs are classified as follows:

Image

2. Consumables

Various consumables used are:

Image

Resources

• Standard Operating Procedure Manual Procurement & Supply Chain Management, CTD, MoHFW, India, 2018.
• Procurement, Supply Chain Management & Preventive Maintenance, Module 6, CTD, MoHFW, India.
• Guidelines on Programmatic Management of Drug-resistant TB (PMDT) in India, NTEP, CTD, MoHFW, India, 2021.

Assessment

Under the National TB Elimination Programme (NTEP) a comprehensive supply management system is maintained through Ni-kshay Aushadhi wherein all the stocking points and implementing health facilities are required to update the stock utilisation, consumption, requirement and expiry on a near to real-time basis. The requirement of all items at all levels is then calculated based on the data reported.

Injectables under NTEP

• The injectables used in TB treatment under NTEP are as follows:
  • Amikacin
  • Streptomycin
  • Kanamycin
  • Capreomycin
• Amongst these, Amikacin and Streptomycin, have been downgraded to Group C under the World Health Organisation's (WHO) reclassification of anti-TB drugs and are not included if an adequate regimen can be built without them.
• Kanamycin and Capreomycin are also no longer recommended for use.
• They are currently used only in special situations where the regimen cannot be completed and are supplied as Type B boxes.
• The District TB Officer (DTO) is responsible for issuing the injectables and the Peripheral Health Institute Medical Officer (PHI-MO) along with the Directly Observed Treatment (DOT) provider is responsible for making suitable arrangements during the intensive phase of the treatment for daily injections.

Other Related Supplies

• The other supplies required whenever the injectable TB treatment regimen is used are as follows:
  • Water container
  • Disposable tumblers
  • Sterile water
  • Disposable needles and syringes
  • Cotton
  • Methylated spirit
• In order to ensure accurate DOT, the DOT centre should have all the related supplies matched to the number of injection vials that are stocked in the centre.
• There should also be a sufficient number of disposable needles and syringes for giving injections along with cotton and methylated spirit to ensure that the injections are always given under sterile conditions.
• An adequate supply of sterile water, with enough water containers and disposable tumblers, must be ensured.

Procurement Injectables and Related Supplies under NTEP

The procurement of second-line drugs under the programme is done centrally depending on the policies and funding mechanism either through the Central Medical Services Society (CMSS) or through the Global Drug Facility (GDF). These are then distributed to implementing levels via State Drug Stores (SDS), District Drug Stores (DDS), Tuberculosis Unit (TU) and PHI. Other treatment-related supplies can also be procured at the state/ district level following NTEP guidelines/ General Financial Rules (GFR).

Resources

• Standard Operating Procedure Manual Procurement & Supply Chain Management, CTD, MoHFW, India, 2018.
• Procurement, Supply Chain Management & Preventive Maintenance, Module 6, CTD, MoHFW, India.
• Guidelines on Programmatic Management of Drug-resistant TB (PMDT) in India, CTD, MoHFW, India, 2021.

Assessment

The National TB Elimination Programme (NTEP) laboratory network is composed of National Reference Laboratories (NRLs) at the national level, at the state level Intermediate Reference Laboratories (IRLs) and Culture & Drug Susceptibility Testing (C&DST) laboratories and at the peripheral level Designated Microscopy Centres (DMCs).

Each of these laboratories is responsible for performing various functions at its own levels.

Figure: Flowchart of Laboratory Consumables

Table: Laboratory Consumables

Resources

• Training Module (1-4) for Programme Managers and Medical Officers, NTEP, MoHFW, 2020.
• Procurement, Supply Chain Management & Preventive Maintenance, Module 6, CTD.
• Module for Laboratory Technicians, CTD, MoHFW, India, 2005.
• Standard Operating Procedure Manual Procurement & Supply Chain Management, CTD, MoHFW, India, 2018.

99 DOTS

99 DOTS is an IT-enabled ‘pill-in-hand’ adherence monitoring system implemented by the National TB Elimination Programme (NTEP) for all Drug-sensitive TB (DS-TB) patients on a daily regimen.

Mechanism of 99 DOTS

• In this system, the medicine blister packs (Figure 1) are wrapped with envelopes which have unique toll-free phone numbers printed on them.
• Each time a patient dispenses the pills, they break through perforated flaps on the back of the envelope, revealing a hidden phone number.
• The patient is expected to give a call to this toll-free number from his/her registered mobile number to report that they have consumed the medication.
• This is documented and updated against the patients’ adherence record in Ni-kshay.
• The sequence of hidden numbers cannot be predicted by patients but is known by the system for each month of medication prescribed.
• If the call is not received from the patients by 3:00 p.m., an SMS reminder is sent to the patients on their registered mobile number.
• If the patient still does not consume medications, the issue is escalated to the authority chain till corrective action is taken.
• Additionally, the patient can also be remotely followed up with help of Call Centres or using an Interactive Voice Response (IVR).

Printing of 99 DOTS Envelopes

• Specification for the printing of 99 DOTS envelopes is provided by Central TB Division (CTD) to all states and the envelopes are printed at the state level and then distributed to the districts.
• The cost of printing and distribution of these envelopes should be budgeted in the state Programme Implementation Plan (PIP).

Advantages of 99 DOTS

• Enables the NTEP staff to prioritise patients who need to be visited and counselled.
• Empowers patients to be able to take charge of their own treatment.

                                                       Figure1: 99-DOTS Blister Pack

Figure 2: Colour-coded adherence calendar output of 99-DOTS patients based on calling

Medication Event Reminder Monitor (MERM) Box

The Medication Event Reminder Monitor (MERM) Box is an electronic pill box specially designed to monitor Multidrug-resistant TB (MDR-TB) treatment.

Mechanism of MERM

• Medications are dispensed in blister packs and each drug is placed in a different partitioned compartment within the pillbox.
• The MERM box contains a removable electronic battery-powered module when triggered by a magnetic sensor captures and stores data each time the container is opened, as a proxy for medication ingestion.
• The MERM is programmed to provide audio-visual reminders to the patients to take medications at a specific time of the day.
• The visual reminder consists of:
  • Green light: Corresponds to a label encouraging the patient to take a dose.
  • Yellow light: Alerts patients about the need to refill medications.
  • Red light: Indicates a low battery and the need to replace the MERM’s battery.

• The audio reminder consists of a ringing sound that would occur at the same time as the visual dose-taking reminder.

• The data from the MERM boxes is transmitted every 72 hours using cellular networks and recorded on a computer server.
• Each patient’s adherence history is presented as a colour-coded calendar (Figure 2) in which:
  • Green suggested that the MERM was opened on a given day: Suggesting probable medicine was consumed.
  • Red suggested that the device was not opened: Suggesting that medicine was probably not consumed.
• In case there is a series of possible missed doses, i.e., red-coloured calendar days, it would result in automated SMS notifications to the patients and also prompt the system to address the interrupting patients who are potentially at higher risk for unfavourable outcomes.

Advantages of MERM box

• Facilitates the identification of high-risk patients and prompt intervention by the system to improve adherence.
• Facilitates storage and organisation of the multiple medications of the MDR-TB regimens.
• Reduces the required frequency of patient visits to a health facility in comparison to facility-based DOT.

Figure 3:Medication Event Reminder Monitor (MERM) Box

Resources

• Procurement, Supply Chain Management & Preventive Maintenance, Module 6, CTD, MoHFW, India.
• 99DOTS: A Low-Cost Approach to Monitoring and Improving Medication Adherence. In Tenth International Conference on Information and Communication Technologies and Development (ICTD ’19), Cross et al., Ahmedabad, India, 2019.
• 99 DOTS. International Journal of Contemporary Medical Research, 2016;3(9):2760-2762.

Information Education and Communication (IEC) Materials

• The purpose of the IEC materials is to create awareness and disseminate information about the disease (signs and symptoms) diagnosis, and treatment to increase accessibility and utilisation of services among the general population.
• IEC material also encourages the build-up of health-seeking behaviour among the masses in keeping with the focus on promotive and preventive health.
• Under IEC, posters, flyers, leaflets, brochures, booklets, etc. are printed and circulated. It is the responsibility of the state to print IEC material in various languages and distribute it among the general population.
• The surplus material is stored at the State Drug Store (SDS) for further distribution as and when required.

Printed Materials

As per the National TB Elimination Programme (NTEP) norms, the districts must use several forms and registers to record the diagnostic and treatment activities. In addition to these, the districts should maintain an adequate supply of printed material for the latest programmatic guidelines. These include the following:

Forms

• NTEP request for examination of biological specimens: Used to request tests such as sputum smear microscopy, Nucleic Acid Amplification Test (NAAT), Line Probe Assay (LPA), culture and Drug Susceptibility Test (DST).
• Treatment card (TB and Drug-resistant TB (DR-TB)): This card contains important information about a patient, such as their name, age, sex and address; type of disease; regimen prescribed; duration of treatment; etc.
• Patient’s identity card (TB and DR-TB patients): The front part of the ID card has patient information, name and address of the TB Unit (TU)/ district and treatment details of the patient including disease classification, type of patient, sputum results, category and information on the date of starting treatment. The back portion of the ID card has the results of the follow-up sputum examination, appointment dates for visits for drug administration and treatment outcome.
• Referral form for treatment (TB and DR-TB): Used when referring patients for treatment to other peripheral health institutions.
• Transfer form: This form is to be used when transferring registered patients on treatment from one reporting unit to another.
• TB notification forms

Registers

• Tuberculosis laboratory register: Used to record the results of sputum smear examinations at the microscopy centres
• Culture and DST laboratory register: Used to record the results of NAAT, LPA, culture and drug sensitivity testing
• Tuberculosis notification register: Contains information on all TB patients registered in the area
• Stock register: Used for recording the information on the stock of drugs and consumables received and issued by the health unit
• Reconstitution register: Used for recording the receipt of drugs of patients who have defaulted, died, failed treatment or transferred out
• Referral for treatment register: Maintained in all big hospitals and medical colleges where large numbers of cases are expected to be diagnosed and referred for treatment to other reporting units

Tablets

NTEP has provided tablet computers to all the key staff with the objective to support the system of capturing important information on a real-time basis. Distribution and storage of these tablet computers is another activity of the drug stores.

Programmatic guidelines

• Technical and Operational Guidelines 
• National Guidelines on Programmatic Management of Drug-resistant TB
• National Guidelines on Partnerships
• Desk Reference (Charts on diagnostic algorithm, dosage of anti-TB drugs, any other)
• Laboratory Manual for Sputum Smear Microscopy and NTEP Laboratory Network guidelines for Quality Assurance of smear microscopy for diagnosing TB
• Guidance document on Nutrition Support to TB patients
• Other relevant documents/ guidelines/ circulars circulated by the Central TB Division (CTD).

It is the responsibility of the state to determine once a year the number of forms and registers that would be needed during the following year. The states must ensure that there is an adequate supply of all the forms, registers and guidelines within the state and that sufficient funds are available for the same.

Once printed, all the forms, registers and guidelines are stored at the SDSs from where they are further distributed to the districts and other health units.

Resources

• Technical and Operational Guidelines for Tuberculosis Control, Central TB Division, Ministry of Health and Family Welfare, Government of India, 2005. 
• Training Modules (5-9) for Programme Managers & Medical Officers. Central TB Division, Ministry of Health and Family Welfare, Government of India, 2020. 

Assessment