Breaking News:Understanding Drug-Resistant Tuberculosis– What Just Happened

Abstract

Drug-resistant tuberculosis (DR-TB) poses a significant threat to India’s goal of eliminating tuberculosis, particularly in the context of the country’s high disease burden and its  substantial contribution to the global MDR/RR-TB caseload. DR-TB encompasses various resistance patterns including rifampicin-resistant, isoniazid-resistant, multidrug-resistant (MDR), pre-extensively drug-resistant (Pre-XDR) and extensively drug-resistant (XDR) TB, each defined by specific drug resistance profiles. Early and accurate diagnosis through rapid molecular tests such as CB-NAAT, Truenat, line probe assays (LPA) and culture-based drug susceptibility testing is critical for timely initiation of appropriate therapy and prevention of transmission. Treatment strategies under the National TB Elimination Programme (NTEP) include the BPaLM regimen, 9–11 months shorter oral regimen, 18–20 months longer oral regimen and specific regimens for isoniazid mono/poly resistance, tailored according to resistance patterns and patient eligibility. Strengthening program management, ensuring close monitoring for adverse events and treatment response and expanding specialised DR-TB services are essential steps towards achieving sustained control and eventual elimination of TB.

Keywords: Drug-resistant tuberculosis (DR-TB); Multidrug-resistant TB (MDR-TB); Line Probe Assay (LPA); BPaLM regimen.

Introduction

Tuberculosis (TB) has been haunting mankind, causing suffering and death since time immemorial. India’s organised fight against TB started in the early 20^th century, with radical changes coming in during the mid-1900s in the form of the first National Program in 1962. It has since then gone through several major changes to reach its present-day status, with hopes of ending the reign of terror caused by the disease, as echoed by the renaming of the program to the National TB Elimination Program (NTEP). In 2023, 25.52 lakh patients were diagnosed with TB, with 24.38 lakh (95.5%) patients put on treatment⁽¹⁾.

In the midst of a high disease burden, the emergence of drug resistance poses a major threat to the efforts to end TB, both nationally and globally. Worldwide, the estimated proportion of new TB cases with Multidrug- Resistant TB (MDR-TB)/ Rifampicin-Resistant TB (RR-TB) is 3.2% (95% UI: 2.5-3.8%) and of previously treated TB cases is 16% (95% UI: 9.0-24%)⁽²⁾. India is the biggest contributor of MDR/RR-TB patients, with 27% of the global population of diseased individuals living here. Hence, it is the need of the hour to address the issue of drug resistance for the successful elimination and eradication of the disease.

What is Drug-Resistant TB?

Drug-resistant TB refers to infection by tubercle bacilli that are resistant to one or more first or second-line anti-tuberculous drugs. First-line TB drugs – rifampicin (R), isoniazid (H), ethambutol (E) and pyrazinamide (Z) are used to treat drug-susceptible TB, whereas second-line TB drugs are those agents that are reserved for the treatment of DR-TB (isoniazid, ethambutol and pyrazinamide may also be used in MDR-TB regimens). Several definitions for DR-TB exist based on the specific drug or drug combinations to which the bacilli are resistant. These include:

• Rifampicin-resistant TB (RR-TB): A TB patient, whose biological specimen is resistant to rifampicin, detected using phenotypic or genotypic methods, with or without resistance to other anti-TB drugs.
• Isoniazid-resistant TB (HR-TB): A TB patient, whose biological specimen is resistant to isoniazid and susceptible to rifampicin, has been confirmed.
• Mono-resistant TB (MR-TB): A TB patient whose biological specimen is resistant to one first-line anti-TB drug only.
• Multidrug-resistant TB (MDR-TB): A TB patient, whose biological specimen is resistant to both isoniazid and rifampicin, with or without resistance to other first-line anti-TB drugs.
• Poly-drug resistant TB (PDR-TB): A TB patient, whose biological specimen is resistant to more than one first-line anti-TB drug, other than both H and R.
• Pre-extensively drug-resistant TB (Pre-XDR-TB): TB caused by Mycobacterium tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any
• Extensively drug-resistant TB (XDR-TB): TB caused by tb strains that fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone (levofloxacin or moxifloxacin) and at least one additional Group A drug (presently to either Bedaquiline or linezolid [or both]).

Diagnosing DR-TB

Rapid identification of DR-TB is important to initiate appropriate treatment and to prevent the spread of the disease as early as possible, since an inadequate or poorly administered treatment regimen allows drug-resistant mutants to become the dominant strain. Methods for identifying drug resistance are broadly classified into two:

Drug resistance testing (DRT): These are also known as rapid molecular diagnostic methods or genotypic tests. They detect specific genetic mutations that are associated with drug resistance.

• The Xpert MTB/RIF is a cartridge-based nucleic acid amplification test (CB- NAAT) that simultaneously detects TB and RR-TB by detecting specific DNA sequences for M. tb complex and rifampicin resistance. The turnaround time is 2 hours. It requires minimal technical training for operation but necessitates air conditioning and UPS to operate.
• The Truenat MTB and Truenat MTB-Rif Dx are chip-based, micro real-time polymerase chain reaction (PCR)-based NAAT used for TB detection and rifampicin resistance detection, respectively. The turnaround time is 1 hour each for the two tests and they can be performed at the point of care as they do not need air conditioning or UPS to operate.
• Line probe assay (LPA) uses PCR and reverse hybridisation methods for the detection of mutations associated with drug resistance. First-line LPA (FL LPA) detects resistance for isoniazid and rifampicin, whereas second-line LPA (SL LPA) detects resistance for fluoroquinolones and second-line injectable drugs (amikacin, kanamycin and capreomycin). Turnaround time for LPA is 1-3 days. They are available only at state-level Intermediate Reference Laboratories (IRL).

Growth-based drug susceptibility testing (DST): These are phenotypic tests that depend on conventional DST on solid or liquid culture media. Liquid culture is preferred due to a higher rate of M. tb isolation and shorter turnaround time. The Mycobacteria Growth Indicator Tube (MGIT) liquid culture system is the preferred method for DST.

The first test of choice for the diagnosis of TB in all populations is NAAT. Upfront NAAT is offered for all presumptive TB patients in areas that have transitioned from smear microscopy to molecular tests for diagnosis⁽⁴⁾. For all patients with M. tb detected in NAAT, a second specimen is to be sent for FL-LPA, irrespective of the status of rifampicin resistance. If resistance to either rifampicin (by NAAT or FL-LPA) or isoniazid (by FL-LPA) is detected, a second specimen is sent for SL-LPA and liquid culture DST (not feasible sometimes, especially in the case of extrapulmonary TB). Repeat testing for resistance may be done at the point of treatment if there is suspicion of non-response to treatment. Treatment is then initiated based on the integrated algorithm.

Treatment of DR-TB

The anti-TB drugs recommended for treatment of MDR/RR-TB patients are classified into three groups (Table 1) based on efficacy, experience of use and drug class, as per WHO Consolidated Guidelines for TB Module 4: Treatment of Drug-Resistant TB (2020)⁽³⁾.

Table 1: Grouping of anti-TB drugs and steps for designing a longer MDR/RR-TB regimen

Treatment for drug-resistant TB mainly comprises four regimens: BPaLM regimen, 9-11 months shorter oral MDR/RR-TB regimen, 18-20 months longer oral M/XDR-TB regimen and H mono/poly DR-TB regimen.

BPaLM Regimen

BPaLM regimen, represents a major advancement in MDR/RR-TB management. Current guidelines increasingly recommend it as the preferred regimen in eligible patients, with other regimens as alternatives when BPaLM is not feasible.

BPaLM regimen consists of bedaquiline, pretomanid, linezolid and moxifloxacin. It is the first choice of treatment in eligible patients with MDR/RR-TB regardless of their fluoroquinolone status or HIV status⁽⁵⁾.

1. Age ≥ 14 years;
2. Previous intake to Bdq, Lzd and/or Pa <1 month or >1 month history of  intake with documented sensitivity to these drugs;
3. QTcF in ECG 450ms in males and 470ms in females;
4. Non-pregnant, non-breastfeeding women.

• Doses of drugs: Bdq 400mg once daily for the first two weeks, followed by 200mg thrice weekly, Pa 200mg daily, Lzd 600mg once daily and Mfx 400mg daily.
• Duration: 26-39 weeks. (extended to 39 weeks if the dose of Lzd has to be reduced to 300mg due to any serious toxicity).

In case the treatment cannot be continued due to intolerance, serious side effects or the emergence of drug resistance to any of the component drugs except fluoroquinolones, the treatment must be shifted to a longer oral M/XDR-TB regimen.

9-11 Months Shorter Oral MDR/RR-TB Regimen

Whenever a patient of MDR/RR-TB is not eligible for the BPaLM regimen, the next choice is the 9-11 months shorter oral regimen (Table 2). It is preferred over the 18-20 months longer M/XDR-TB regimen in both adults and children. Fluoroquinolone resistance must not be present to start this regimen. Previously, ethionamide (Eto) was part of the regimen and hence it was contraindicated in pregnancy. Currently, Eto has been replaced by linezolid, hence it can be given to pregnant women irrespective of the gestational age. In non-lactating women, non- pregnant women and pregnant women with <20 or <24 weeks of gestation who are willing for medical termination of pregnancy, the regimen with Eto may be used.

(H^h– High-dose isoniazid)

Table 2: 9-11 months shorter oral regimen with Lzd or Eto

If sputum smear microscopy is positive by the end of the 4^th month, then FL-LPA and SL-LPA, culture & DST should be offered and the duration of the IP phase can be extended (to a maximum of 6 months). Accordingly, the total duration of treatment may be extended to 11 months.

18-20 Months Longer Oral M/XDR-TB Regimen

This regimen consists of the following: (6 or longer) Bdq (18-20) Lfx Lzd Cfz Cs.

It is given for patients who cannot be initiated on BPaLM or a 9-11 months shorter oral MDR/RR-TB regimen due to reasons of ineligibility, additional resistance, intolerance, non- availability of any drug in use or emergence of exclusion criteria. The regimen is constituted such that all the Group A and Group B agents (from Table 1) are 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 if bedaquiline is stopped (WHO recommendation, but adopted as above in India for operational ease). There is no intensive or continuation phase in this regimen. In case any of the component(s) needs to be replaced due to intolerance or resistance, it is replaced with Group C drugs in the order of – delamanid, amikacin, pyrazinamide, ethionamide, PAS, ethambutol and penems.

Isoniazid (H) Mono/Poly Drug-Resistant TB Regimen

This regimen consists of 6 months of levofloxacin, rifampicin, ethambutol and pyrazinamide with no separate intensive/ continuation phase. The duration can be extended to 9 months in certain conditions, including extensive disease and uncontrolled comorbidity. The patients who are failing to respond with this regimen will be considered as ‘probable MDR-TB cases’ and will be further evaluated for treatment with one of the above MDR-TB regimens.

All the above-mentioned regimens have specific pre-treatment evaluation and follow-up monitoring that further determine any changes during the course of treatment. Since all the regimens contain multiple drugs taken for long durations, close monitoring is of utmost importance to look for the development of adverse effects as well as to identify a failing regimen. All the services for DR-TB are carried out through the Programmatic Management of Drug-Resistant TB (PMDT) under NTEP, with the support of a nationwide network of DR-TB centres, NTEP staff, general health system staff, community volunteers and the private health facilities. To further improve the quality of care offered by the DR-TB centres, difficult-to-treat TB clinics (DT3C) are established at the state and national levels. Altogether, the best efforts are being put forward against DR-TB by the nation in this age-long battle with the ultimate goal of the elimination of the disease.

Conclusion

Drug-resistant tuberculosis (DR-TB) poses a huge hurdle to India’s goal of eliminating tuberculosis. India contributes substantially to the global MDR/RR-TB burden. Early and accurate diagnosis through rapid molecular tests and culture-based drug susceptibility testing followed by timely initiation of appropriate therapy is the key to eradication and prevention of transmission. Treatment strategies under the National TB Elimination Programme (NTEP) include the BPaLM regimen, 9–11 months shorter oral regimen, 18–20 months longer oral regimen and specific regimens for isoniazid mono/poly resistance, tailored according to resistance patterns and patient eligibility. These strategies with monitoring for adverse events and treatment response and expanding specialised DR-TB services are ways to eventual elimination of TB in India.

References:

1. Central TB division, Ministry of Health & Family Welfare, Government of India TB Report 2024. [Internet]. 2024.
2. World Health Organization. Global TB Report 2024. https://who.int [Internet]. 2024.
3. WHO Consolidated Guidelines on Tuberculosis: Module 4 – Treatment [Internet]. https://www.who.int/2020.
4. Central TB Division, Ministry of Health & Family Welfare, Government of India. Guidelines for Programmatic Management of Drug-Resistant TB in India 2021 [Internet].
5. Central TB Division, Ministry of Health & Family Welfare, Government of India. National Guidelines for Management of Drug-Resistant TB 2024 [Internet].

¹Specialist, Corresponding author: ²Senior Consultant, Dept. of Pulmonology, Baby Memorial Hospital, Calicut, Email: [email protected]