Can DR-TB Regimens be Sometimes Given to Select Drug Sensitive Cases?- A Clinician’s Perspective

INTRODUCTION National TB Elimination Programme (NTEP) has fixed 2HREZ/4HRE regimen for all drug-sensitive (DS-TB) cases, comprising of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z). These potent first-line drugs, i.e., HREZ, are the backbone of DS-TB treatment for last many decades. The success rate of the DS-TB regimen has always remained high and the latest reported is around 87%.[1] The treatment for drug-resistant TB (DR-TB) was incorporated in to Revised National TB Control Programme (RNTCP) as DOTS plus regimens. These regimens involved use of less potent second-line drugs which were at least 5 and up to 7 in number based on grouping of medicines, and were required to be taken for a longer duration, often ranging from 12–24 months.[2] Later, these were modified as conventional MDR regimen, shorter MDR regimen, XDR regimen, and INH monoresistant TB regimen.[3] Individualization of these regimens based on drug sensitivity testing (DST) reports and for adverse events, was later allowed as RNTCP adopted a flexible policy for concerns on the fixed nature of DR-TB regimens.[4] The DR-TB treatment success rate in India, however, remained low, for example, 48% and 30% for MDR and XDR-TB, respectively, as reflected in the Global TB report 2019.[5,6] The main reason for using a larger number of drugs and for longer duration in DR-TB regimens is the low potency of the second-line drugs. There is no evidence that DR-TB strains are more virulent than DS-TB strains. Rather, drug resistance is associated with a fitness cost, leading to a slower growth rate of mycobacteria.[7] Under the national strategic plan 2017–25, NTEP omitted second-line injectable drugs (SLIs) from the DR-TB regimens and rolled out all oral shorter (9–11 months) and longer (18–20 months) regimens involving bedaquiline (Bdq) and linezolid (Lzd), two promising second-line drugs with good potency.[8,9] These have led to improvement in DR-TB treatment success rate, reaching 75% by year 2022 in comparison to 49% in year 2017.[1] Based on recommendations by the national technical expert group, a further shorter regimen BPaLM has been rolled out that includes Bdq, Pretomanid (Pa), Lzd, and Moxifloxacin (Mfx); after strong recommendation from WHO.[10] The NIX-TB trial with Bdq, Pa, and Lzd [BPaL regimen] as well as the TB PRACTECAL trial with the six-month BPaLM regimen, comprising Bdq, Pa, Lzd, and Mfx, have demonstrated high efficacy (treatment success rate 88.7%) and safety.[11,12] With introduction of BPaLM regimen, further better DR-TB treatment outcome is therefore expected. THE CORE ISSUE As per the NTEP guidelines, these new regimens (all oral longer, shorter, and BPaLM) are recommended for microbiologically proven DR-TB either by cartridge-based nucleic acid amplification test or line probe assay or DST on culture, and are typically reserved for Rifampicin-resistant (MDR/RR) TB, as INH monoresistant TB (Hr-TB) has non-bedaquiline regimen in place that includes levofloxacin (Lx), rifampicin (R), ethambutol (E), and pyrazinamide (Z) (LxREZ regimen).[8] Standardized HREZ regimen for DS-TB has well-documented efficacy, and therefore, individualized regimens are not allowed under NTEP. There is, however, a provision to modify the regimen for cases with drug adverse reactions (ADRs). At the program level, minor ADRs are to be managed by transient drug withdrawal or using replacement drugs from existing first/second-line drugs and serious ADRs are expected to be referred to higher centers.[13] There is, however, no provision in such cases to use new second-line drugs like Bdq, Pa, or Delamanid (Dlm) as replacement drugs, in view of their cost and possibly fear of indiscriminate use which may lead to acquired resistance. These drugs are available only as part of DR-TB regimens. There is no provision to switch such cases to a DR-TB regimen either.[13] In some cases, however, first-line drugs, including rifampicin, are required to be permanently discontinued, when attempts of rechallenge fail or are not advisable. Such scenarios include drug hypersensitivity, severe and prolonged ADRs, concomitant medication, and comorbidities. This may lead to regimen modification, extended treatment duration, and treatment interruption.[14] Drug-induced liver injury (DILI), in particular, is a common adverse reaction and it may be prolonged, recurrent on rechallenge and requires discontinuation of H, R, and Z.[15] In such cases, the standard HREZ regimen needs to be transiently and sometimes permanently modified and often second-line drugs, such as quinolones and SLIs, are introduced empirically to replace the first-line drugs, especially when DST pattern is not known. When standardized DR-TB regimens or individual new potent second-line drugs, such as Bdq, Pa, or Dlm, cannot be used, such select cases are treated with individualized regimens consisting of weak second-line drugs that are often given for undefined extended duration. This denies the patient a chance to receive a standardized potent drug regimen with shorter duration and proven higher efficacy rate. This becomes more relevant when such patient has extensive TB or is seriously ill, thereby raising an ethical concern. A rare compassionate use of newer potent drugs may be justified in such select cases.[16] PROPOSED POLICY MECHANISM UNDER NATIONAL TB ELIMINATION PROGRAMME More elaborate guidelines regarding the management of severe ADRs are required for DS-TB treatment, especially in patients with comorbidities. A precise protocol for rechallenge of offending drugs and a protocol for desensitization in case of drug allergy need to be laid down. For cases where reintroducing the offending drugs fail, the order of preference of replacement drugs needs to be defined and the duration of treatment extension, when needed, also needs to be defined. Only an advice of referral to higher center is not enough.[13] Modifying regimens may be a real challenge in cases of severe DILI or drug hypersensitivity.[17-19] Currently, switch from a DS-TB to a DR-TB regimen is rarely allowed when there is treatment failure, even when proof of resistance is lacking, especially in extrapulmonary cases. Such a decision to initiate the DR-TB regimen can be taken by the nodal DR-TB center (NDR-TBC) or district DR-TB center (DDR-TBC) in consultation with the respective N/DDR-TBC committee and advice from TB experts. Similarly, selective DS-TB cases, who do not tolerate first-line drugs despite transient replacement and rechallenge, also deserve a chance to get treated with new potent drugs or switch to DR-TB regimen, though technically they are not MDR-TB or RR-TB cases. What matters here is not the drug resistance but the inability to use potent first-line drugs as discussed above. These patients may then stand a better chance to cure than that on the modified regimen without new potent drugs.[1,5,6] The regimen nomenclature in the guidelines as “M/XDR-TB regimen” is misleading as it gives an impression that these regimens have been defined as per the resistance status of mycobacteria.[13] These are indeed second-line drug regimens that should be available to any patient for whom first-line regimen cannot be used. Such provision may therefore be considered as per the flexibility policy which has always been a strength of NTEP. Switch to a well-defined and randomized controlled trial tested regimen, such as BPaLM, would be preferred rather than randomly allowing the use of new drugs as replacement drugs to individualized weak regimens. On a downside, such provision has a potential risk for indiscriminate use of these potent drugs. Such decisions on case-to-case basis may therefore be allowed only after careful consideration and discussion with TB experts and the N/DDR-TBC committee. A clear treatment decision-making algorithm would ensure that new second-line regimens are indeed needed and it is not possible to formulate an effective individualized regimen with existing first-line or replacement drugs. Such a conditional policy provision will not cause additional burden on the program as such select cases are rare. This is a practice perspective from a clinician who often feels unsure about the treatment outcome when the DS-TB treatment regimen has to be modified with weak second-line drugs. These patients deserve a better chance to cure when more potent drug regimens are available with NTEP. Though NTEP has to think with a broader view, a clinician thinks for each patient individually. A conditional policy provision would be a good relief. CONCLUSION NTEP may consider to make these potent second-line drug regimens available to select DS-TB cases who cannot be appropriately treated with standard first- or second-line drugs or where an effective individualized regimen cannot be formulated, regardless of the drug-resistant status of the mycobacteria. Author contribution These are the views of the author based on his on-ground clinical observations. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest to declare.