REVIEW ARTICLE

Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 53-63

Recent changes in guidelines on programmatic management of drug resistant tuberculosis in India 2019: a paradigm shift in tuberculosis control

Arunabha Datta Chaudhuri
Professor, Department of Respiratory Medicine, R.G. Kar Medical College, Kolkata, West Bengal, India

Correspondence Address:
Prof. (Dr.) Arunabha Datta Chaudhuri
Designation - Professor, Department of Respiratory Medicine R.G. Kar Medical College, Kolkata, Residence - BF-130, Sector - I, Salt Lake City, Kolkata - 700064
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jacp.jacp_47_20

The new version of guidelines of programmatic management of drug resistant tuberculosis in India 2019 by Revised National Tuberculosis Control Programme, Central TB Division, Directorate General of Health Services, Ministry of Health & Family Welfare, Nirman Bhawan, New Delhi, integrates use of the shorter MDR TB regimen and all oral longer MDR TB regimen with new drugs under RNTCP with opportunity to modify the regimen based on DST results. There are mammoth and comprehensive changes in the guidelines on programmatic management of drug resistant tuberculosis in India 2019.

Keywords: DRTB, DRTB 19, PMDT 19, PMDT guideline 2019

Introduction

Causes of drug resistance

• Microbial: As a result of genetic mutation. Caused by random chromosomal mutations at predictable frequencies. (H resistant bacilli 1 in 10⁶, R 1 in 10⁸, HR 1 in 10¹⁴)
• Essentially drug resistance is a man-made phenomenon
• Providers/Programmes: Inadequate regimens, Unsupervised treatment, Absence of guidelines or inappropriate guidelines, non-compliance with guidelines, Inadequate training of health staff, No monitoring of treatment, Poorly organized or funded TB control programmes.
• Drugs: Inadequate supply, non-availability of certain drugs (stock-outs or delivery disruptions), poor quality, poor storage conditions, wrong dosages or combination.
• Patients: Inadequate drug intake, unobserved treatment (Poor DOT), poor adherence, lack of information, non-availability of free drugs, adverse drug reactions, social & economic barriers, malabsorption, substance abuse disorders.

• Strong systems to detect early, successfully treat and ensure long-term disease-free status of TB patients.
• Systems for early detection and treatment of drug-resistant forms of TB be integrated into existing TB services.
• Health care facilities and congregate settings to focus on proper infection control measures
• Measures to prevent incidence and transmission of TB are also effective in prevention of drug-resistance.

• Program is committed to providing Universal Drug Susceptibility testing (UDST) for all notified TB patients.
• A range of rapid molecular tests are available for UDST: Cartridge Based Nucleic Acid Amplification Test (CBNAAT), Line Probe Assay (LPA), TruNAAT
• ToG 2016–as per revised diagnostic algorithm, selected presumptive TB patients tested on CBNAAT for reliable and early microbiological confirmation of TB and R resistance status is available as a byproduct
• Several additional DST technologies in the development pipeline, will be made available progressively as they are endorsed for use by WHO

• Concept of decentralized DR-TB Centres at district level.
• Previously, centralized PMDT treatment initiation in inpatient settings.
• This version, guidance on both in-patient and out-patient based treatment initiation.
• Decentralised drug supply chain management to the district level.

• Move to patient centric approach focussing patient’s needs and preferences for better adherence.
• Development of information communication technology (ICT) also gives an option of self-report drug consumption, monitored and supported by various levels simultaneously.
• Most appropriate modality of adherence monitoring may be used as a collective decision for the patient, treatment supporter and the Medical Officer (MO).

• Scale up plan of all oral regimen and shorter MDR-TB regimen.
• There are newer drugs like Bedaquiline (Bdq) and Delamanid (Dlm) currently approved to be used under the programme only.
• Drugs are reclassified based on the evidences to manage the patient and recommended for use in the management of DR-TB.
• few shorter MDR-TB regimens are being studied worldwide using combination therapy with newer drugs.

1. State-level structure − State PMDT Committee
2. Nodal DR-TB Centre − Nodal DR-TBC Committee
3. District DR-TB Centre − District DR-TBC Committee

1. Pre-treatment evaluation,
2. Counselling to Patient and Family Members,
3. Treatment initiation of DR-TB patients,
4. Coordination with C-DST labs and districts,
5. Nikshay entries and periodic reporting,
6. Travel enablers
7. Follow up monitoring, Management of adverse drug reactions,
8. Providing clinical decision, referral, management support and training to districts,
9. AIC measures, nutritional assessment, mental health and palliative care,
10. Submit regularly reports to the State TB Cell and State PMDT committee [Figure 1].

    Figure 1 Overall PMDT Structures and Roles Click here to view

1. Rapid molecular Drug Resistance Testing (DRT) − Genotype
   1. Nucleic Acid Amplification Test (NAAT)
      1. cartridge based Gene-Xpert platform,
      2. chip based TruNAAT platform
   2. Line Probe Assay (LPA)
      1. First line (H & R),
      2. Second line (Lfx, Mfx, Km, Cm, Am)
2. Growth-based phenotypic drug susceptibility testing (DST)
   1. First-line drugs: R, H, E, Z
   2. Second-line drugs: S, Lfx, Mfx, Km, Cm, Am
   3. Other drugs: Lzd, Cfz, Bdq, Dlm PAS etc.,

• Volume of 2-5 ml.
• Preferably mucopurulent and not heavily blood stained or contaminated.
• Collect the specimen in a sterile container (50 ml conical tube) after thorough rinsing of the mouth with clean water.
• Specimens should be transported to the NAAT or C-DST laboratory as soon as possible after collection.
• If a delay is unavoidable the specimens should be refrigerated to inhibit the growth of unwanted micro-organisms.

• All notified TB patients and non-responder to treatment and presumptive TB patients Offer NAAT.
• Based on the result, the patient would be classified as R resistant detected (RR TB) or R resistance not detected to guide decision of the appropriate treatment.
• For patients with NAAT result as M.tb detected (irrespective of R status), the second specimen will be transported to the C-DST lab in cold chain.
• In rare circumstances when the second specimen is used at NAAT lab itself to repeat the test, a fresh specimen is to be collected from the patient and transported in cold chain to the concerned C-DST lab. However, this may not be always possible for EP specimen.
• Reconfirmation of RR among the new TB patients will be carried out at C-DST lab by FL LPA with the second specimen sent from NAAT site.
• If Rifampicin Resistant detected then FL LPA, SL LPA (for FQ or SLI), DST to Mfx (1.0), Lzd, Cfz, Z, Bdq, Dlm (whenever available) will be set up on liquid culture using the decontaminated deposits only for RR TB patients (Base line SL DST).

Figure 2 DR-TB diagnostic algorithm Click here to view

1. history and physical examination,
2. height/weight,
3. random blood sugar (RBS),
4. chest X-ray and
5. HIV testing. No additional investigations are required for H mono/poly DR TB patients unless clinically indicated.

1. Complete Blood Count (Hb, TLC, DLC, Platelet count),
2. Blood Urea & S. Creatinine,
3. Audiometry (only if on injectable),
4. Liver Function Tests,
5. Thyroid Stimulating Hormone levels to assess the thyroid function (TSH levels alone are usually sufficient to assess the thyroid function of the patient),
6. Urine examination − Routine and Microscopic,
7. Psychiatric evaluation if required,
8. Serum electrolytes (Na, K, Mg, Ca) only for new drugs,
9. S. protein (Albumin, Globulin and total proteins) (only if on Dlm),
10. ECG (if on Mfx, Bdq, Cfz or Dlm),
11. urine pregnancy test (in women of reproductive age group),
12. Ophthalmologist opinion − rule out chorioretinitis/uveitis (only if on Linezolid),
13. Surgical evaluation should be done at appropriate time if required.

• In majority of MDR/RR TB patients, pretreatment evaluation can be done on an outpatient basis.
• The physician may decide for admission for initiation of treatment or get it done on an outpatient basis.
• A specialist consultation along with reports of pre-treatment evaluation tests can be arranged, if required.
• Must ensure that laboratory capacity and specialists for consultation are available, either in-house or through an outsourced mechanism
• For infection control purposes, a separate space for specimen and blood collection should be identified

CLASSES OF ANTI TB DRUGS RECOMMENDED FOR TREATMENT OF DR-TB

• In MDR/RR TB patients on longer regimens, all three Group A agents (Lfx/Mfx, Bdq &Lzd) and one Group B agent (Cfz &Cs) should be included to ensure that treatment starts with at least four TB agents likely to be effective, and that at least three agents are included for the rest of the treatment after Bdq is stopped.
• If only one or two Group A agents are used, both Group B agents are to be included.
• If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it.

Standard DRTB Regimen [Table 1]

Table 1 Standard DRTB regimen Click here to view

• Bdq/Dlm can be provided to the patient ≥ 18 yrs.
• Dlm can be provided to age group 6 to 17 years.
• Use of Bdq for 6 to 17 yrs and Dlm for 3 to 6 yrs may be considered only after approval of DCGI.
• non-pregnant females or females not on hormonal birth control methods are eligible. They should be willing to continue practicing birth control methods throughout the treatment period or have been post-menopausal for past 2 years; and
• patients with controlled stable arrhythmia can be considered after obtaining cardiac consultation.

• Pregnancy & lactating mother
• currently having uncontrolled cardiac arrhythmia that requires medication;
• QTcF interval characteristics at base line:
  1. QTcF ≥ 500 at baseline & normal electrolytes, ECG to be repeated after 6 hours and If both ECGs show QTcF>500 then the patient should not be challenged with cardiotoxic drugs.
• history of additional risk factors for Torsade de Pointes, e.g. heart failure, hypokalaemia, family history of long QT syndrome;
• If results of the serum chemistry panel, haematology or urinalysis are outside the normal reference range (including above listed parametres), the patient may still be considered if the physician judges that the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable.
• Hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to a patient receiving any QTc prolonging drugs.
• Bdq/Dlm is not added to a failing regimen in any MDR/RR TB patient

• Lzd may cause anaemia, thrombocytopenia, peripheral neuritis and optic neuritis. Adequate precaution may be taken accordingly.
• Cs should be used carefully in pre-existing seizure disorders not adequately control with medication. Neurologist consultation should be taken prior to initiation of Cs in such patients, also psychiatrist opinion should be taken in severe depression as Cs can cause depression and suicidal tendency.
• Cfz causes dark brown discoloration of the skin. Accordingly, the patient should be counselled prior to initiation of treatment with Cfz

Patient Flow for H mono/poly resistance [Figure 3] [Table 2]

Figure 3 Integrated drug resistant algorithm Click here to view

Table 2 Criteria for patients to receive standard DR TB regimen Click here to view

• If H is found to be resistant, the patient will be initiated on all oral H mono-poly DR TB regimen at the PHI level while awaiting the results of SL LPA
• Modify the regimen appropriately at the N/DDR TBC if Lfx/Mfx(h) resistance is detected on SL LPA.

• All oral longer MDR TB regimen can be initiated on outpatient basis if the patient is satisfying all following risk assessment criteria:
  • QTcF < 450 ms in males and <470 ms in females at baseline.
  • Normal serum K, Mg, Ca at baseline.
  • No history of structural cardiac abnormalities (LVH or RVH secondary to hypertension can also cause ECG changes, however mere presence of LVH need not be an exclusion criteria) or ECG abnormalities.
• Patients with QTcF between >450 to 500 ms in male and > 470 to 500 ms in female upto 500ms require daily monitoring of ECG for 3 days along with evaluation and correction of any electrolyte abnormalities. A cardiologist opinion may need to be taken.
• The first dose is given under supervision at the treatment initiating facility for ambulatory patients.
• Patient should be initiated from Monthly patient wise box
• Entire one-month box needs to be handed over at the time of discharge.

• Replacement of drugs required in following conditions: −1. adverse drug reaction, 2. poor tolerance, 3.contraindication, 4.resistance detected on baseline LC DST.

Table 3 Sequence of using replacement drugs to modify the regimen Click here to view

Table 4 Sequence of using replacement drugs to modify the all oral longer regimen Click here to view

• The regimen should preferably be fully oral. However, in certain circumstances, an Injectable may have to be used for the need of efficacy and side-effect profile
• Five drugs are to be used in IP and at least four drugs in the CP.
• Newer drugs (Bdq or DLm) should be given for 24 weeks only.
• Dlm and Am will not be used in CP.
• Replacement sequence: Z*, Am* , Eto*, PAS, E, Imp/ clm or Mpm with Amx/ clv in that order of preference (*Z if resistance not detected, Am if SL LPA suggest and Eto if no inh A mutation detected)

Table 5 Dosage of DR-TB drugs for adults Click here to view

Table 6 Duration of regimen Click here to view

• In patients with extensive disease;
• uncontrolled comorbidity;
• extra-pulmonary TB and
• if smear at the end of 4^th month is found positive; based on smear microscopy and clinical monitoring;

• Total duration of shorter MDR TB regimen is for 9-11 months
• IP should be given for at least four months. After fourth month of treatment, if the result of sputum microscopy is negative then CP should be initiated.
• If sputum smear microscopy does not become negative by the fourth month of treatment, subject the patient to FL LPA and SL LPA and culture DST.
• If no additional resistance is detected, the IP should be prolonged until sputum smear converts maximum till 6 months.
• If the intensive phase is prolonged, the injectable agent is only given three times a week.
• IP should be extended to 5th or 6th month based on smear results. This will be done for a maximum of 2 months
• If the patient remains smear positive at the end of 6th month of treatment, the patient will be declared as “Treatment Failure”, re-evaluated as per integrated DR TB algorithm and initiated on an appropriate modified regimen based on the extended DST.

• Total duration of all oral longer MDR TB regimen is 18-20 months.
• At the end of 6^th month, the dose of Lzd will be tapered to half if the 4th or 5th month culture result is negative.
• If the 4th or 5th month culture result remains positive, the regimen with same Lzd dosage need to be extended for 1 more month. However, new drug (Bdq or Dlm) is given for 24 weeks only.
• Decision for continuation of extended IP with Lzd (600/300 mg) beyond 7th month, is decided based on the culture results of 6th/5th month and the clinical/radiographic response.
• Extension of IP beyond 8^th month is not permitted and patient should be switched to CP. (i.e., total duration of treatment is not more than 20 months).
• If the patient continues to remain culture positive or reverts back to culture positive after 8 months of treatment, the patient is declared as “Treatment failed”, re-evaluated as per integrated DR TB algorithm and initiated on an appropriate modified regimen based on the extended DST.
• For XDR TB patients, all oral longer MDR TB regimen would be given for 20 months.

• After initiation of Rx from the DR-TB Centre, MO D/NDR TB center,
  • at monthly intervals during the IP, and
  • at 3-monthly intervals during the CP until the end of treatment
• Assess clinical, microbiologic, and radiologic response to treatment
• Measure weight
• Assess possible adverse drug reactions (ADR)
• Encourage the patient to continue treatment
• Verify treatment card

• Smear examination would be used on a monthly basis from 3^rd month onwards to guide the decision on moving from IP to CP in shorter MDR TB regimen and extension of treatment from 6 months to 9 months and treatment outcome for all oral H mono/poly regimen.
• For H mono/poly regimen,
  • positive smear result at 4^th month, treatment will be extended to 9 months.
  • Follow up positive at end of 5^th month, declare as treatment failed.
  • Follow up culture would be done at 3^rd, 6^th and 9^th month (if applicable). If found culture positive, DST will be done.
• For shorter MDR TB regimen,
  • If smear/culture remains positive at the end of IP and/or extended IP, a fresh specimen/culture isolate of that time will be subjected to FL/SL-LPA to check for amplification of resistance to FQ/ SLI or InhA mutation.
  • If the patient is found to be susceptible to both FQ and SLI at end of IP, the intensive phase will be extended on monthly basis up to a maximum of six months.
  • At end of extended IP or later, if any resistance is detected by SL-LPA OR InhA mutation detected on FL-LPA OR if found to be culture positive, the patient will be declared as treatment failure.
  • The patient is then re-evaluated for all oral longer MDR TB regimen with appropriate modification if required.

• Follow-up culture should be done using liquid culture.
• final treatment outcome of all MDR-TB patients will be declared on the basis of follow-up culture results only
• For all oral longer MDR TB regimen
  • In case of extension of IP, the follow-up culture months will shift by every month of extension of IP till maximum limit of IP for all regimen classes.
  • Extension of treatment is based on the follow up culture result of 5^th month or 4^th month culture result is negative at the end of 6 months of treatment, reduce the dose of Lzd for subsequent period of treatment. If 5^th month culture result is not available, decision should be based on the 4^th month culture result.
  • If the follow up culture result (5^th or 4^th month) is positive, continue the regimen for one more month and extend the total duration of treatment for one more month.
  • Extend the treatment maximum for 2 more months based on the follow up culture results of 6^th or 7^th month, beyond this, reduce the dose of Lzd to half for subsequent period in all the weight bands.
  • Patient should have received minimum 8 months of treatment before declaring the patient as treatment failed if the patient is not converted.

• Culture conversion: Patient is considered to have culture converted when two consecutive cultures, taken at least 1 month apart, are found to be negative. In such a case, the specimen collection date of the first negative culture is used as the date of conversion.
• Culture reversion: Patient is considered to have culture reverted when, after an initial culture conversion, two consecutive cultures, taken at least 1 month apart, are found to be positive. For the purpose of defining Treatment failed, reversion is considered only when it occurs in the continuation phase.
• Smear conversion: Patient is considered to have smear converted when two consecutive smears, taken at least 1 month apart, are found to be negative. In such a case, the specimen collection date of the first negative smear is used as the date of conversion.
• Smear reversion: Patient is considered to have smear reverted when, after an initial smear conversion, two consecutive smears, taken at least 1 month apart, are found to be positive. For the purpose of defining Treatment failed, reversion is considered only when it occurs in the continuation phase.

• Cured: A microbiologically confirmed patient at the beginning of treatment who was smear negative at the end of the complete treatment and on at least one previous occasion.
• Treatment completed: A patient who has completed treatment according to guidelines but does not meet the definition for cure or treatment failure due to lack of microbiological results.
• Treatment failed: A patient whose biological specimen is positive by smear at 5 months or later
• Died: A patient who has died due to any reason during the course of anti-TB treatment
• Lost to follow up: A patient whose treatment was interrupted for continuous 1 month or more.
• Not Evaluated: A patient for whom no treatment outcome is assigned. This includes former “transfer-out” & “still on treatment”
• Regimen Changed: A need for permanent discontinuation of existing regimen and initiation of new regimen with change of at least one or more anti-TB drugs prior to being declared as failed.

• Cured: A microbiologically confirmed MDR/RR TB patient who has completed treatment without evidence of failure and was culture negative at end of treatment and on at least one previous occasion.
• Treatment completed: A patient who has completed treatment according to guidelines but does not meet the definition for cure or treatment failure due to lack of microbiological results.
• Treatment failed: Treatment terminated or need for permanent regimen change of any anti-TB drugs in CP because of
  • lack of microbiological conversion by the end of extended IP or
  • microbiological reversion in CP after conversion to negative or
  • evidence of additional acquired resistance for drugs in regimen or
  • adverse drug reactions (ADR).
• Died: A patient who dies for any reason during the course of anti TB treatment.
• Lost to follow-up: A patient whose treatment was interrupted for continuous one month or more.
• Not evaluated: A patient for whom no treatment outcome is assigned, this includes former “transfer-out” & “still on treatment”.
• Regimen changed: A need for permanent discontinuation of existing regimen and initiation of new regimen with change of at least one or more anti-TB drugs prior to being declared as failed.

• Cured: A microbiologically confirmed MDR/RR TB patient who has completed treatment without evidence of failure and three or more consecutive cultures taken at least 1 month apart from 8 months onwards are negative including culture at the end of treatment.
• Treatment completed: A patient who has completed treatment according to guidelines but does not meet the definition for cure or treatment failure due to lack of microbiological results.
  • Treatment failed: Treatment terminated or need for permanent regimen change of at least two or more anti-TB drugs from 8^th months onwards because of lack of microbiological conversion by the end of the 8^th month of treatment or
  • microbiological reversion in the 8^th month or later after conversion to negative or
  • evidence of additional acquired resistance for drugs in regimen or
• Died: A patient who dies for any reason during the course of anti TB treatment.
• Lost to follow-up: A patient whose treatment was interrupted for one month or more for any reasons prior to being declared as failed.
• Not evaluated: A patient for whom no treatment outcome is assigned, this includes former ‘transfer- out’ & “still on treatment”.

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