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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 143-147

Effectiveness of the shorter MDR regimen in the management of tuberculosis: Shortfall in the outcome of disease a multidimensional approach and evaluation for a better alternative


State TB Demonstration Cum Training Centre, Intermediate Reference Laboratory, Kolkata, West Bengal, India

Date of Submission11-Sep-2019
Date of Acceptance07-Oct-2019
Date of Web Publication17-Jun-2020

Correspondence Address:
Dr. Prasanta Kumar Das
State TB Demonstration Cum Training Centre, Intermediate Reference Laboratory, 2nd Floor, Dr. B. C. Roy Post Graduate Institute of Paediatric Sciences, 38, Badan Roy Lane, Kolkata 10, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_131_19

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  Abstract 


Background: Shorter multidrug-resistant (MDR) regimen has proved to be very effective in some of the developing nations such as Bangladesh and several African countries. Various shortcomings in the execution of long-term MDR regimen have prompted for adapting the shorter regimen in India. The study explored the experience of the programmatic management of tuberculosis by a shorter regimen in West Bengal, India. Materials and Methods: Retrospective analysis of the data included the outcome analysis of the cured, lost to followup, treatment completed, treatment failure, treatment regimen changed and died. These attributes were analyzed. Results: Of the total 203 cases, cure rate accounted for 44.3%. Lost to follow-up was found to be 13.7%, in which alternative dispute resolution accounted for the major cause. A substantial amount of INH resistance is seen among the follow-up culture positive cases speculating the role of ethionamide in the regimen.

Keywords: Adverse drug reaction, line probe assay, lost to follow-up, multidrug-resistant shorter regimen


How to cite this article:
Das PK, Ganguly SB. Effectiveness of the shorter MDR regimen in the management of tuberculosis: Shortfall in the outcome of disease a multidimensional approach and evaluation for a better alternative. Biomed Biotechnol Res J 2020;4:143-7

How to cite this URL:
Das PK, Ganguly SB. Effectiveness of the shorter MDR regimen in the management of tuberculosis: Shortfall in the outcome of disease a multidimensional approach and evaluation for a better alternative. Biomed Biotechnol Res J [serial online] 2020 [cited 2020 Jul 13];4:143-7. Available from: http://www.bmbtrj.org/text.asp?2020/4/2/143/286840




  Introduction Top


By definition, multidrug-resistant tuberculosis (MDR-TB) is a disease caused by Mycobacterium tuberculosis that is resistant to at least both rifampicin and isoniazid with or without resistance to other anti-TB drug.

The study was done from the routine samples received at Intermediate Reference Laboratory Kolkata under the Revised National Tuberculosis Control Program for the diagnosis and drug sensitivity of cases of TB, so the patient consent is implied.

The study was done under the ethical approval from the Central TB division for performing shorter MDR through State TB Cell, West Bengal, Vide No. HTB/Training-129/2012/460/1 (38) dated March 26, 2018. MDR-TB is a major public health challenge in developing nations.[1] MDR-TB strains are resistant to at least Isoniazid (INH) and rifampin.[2]

Rifampicin-resistant TB (RR-TB) is defined as TB caused by the M. tuberculosis complex strain resistant to rifampicin detected genotypically or phenotypically with or without resistance to other anti-TB drugs.

Due to poor management, drug-resistant TB MDR-TB/RR-TB has been emerging as a major problem.

The treatment of MDR-TB is very expensive, requires at least 2 years of treatment with potentially toxic drugs.[1],[2],[3],[4],[5],[6]

The Global TB Report of 2016 estimated that 3.9% newly diagnosed and 21% of previously treated TB cases had MDR-TB.

Ethionamide (ETH) is one of the most important second-line anti-TB drugs;[2] the chemical structure of ETH is similar to that of INH.[3] Both inhibit the biosynthesis of mycolic acid.[4]

Worldwide report on poor treatment outcomes was reported in most of the 2-year long conventional MDR treatment. The probable reasons include poor treatment adherence due to lengthy, expensive, and toxic regimens, leading to poor compliance.[6]

This prompted a shorter regimen, an MDR TB regimen of 9–12 months instead of the conventional 2 years duration. The WHO has recommended extensive use of second-line line probe assay (LPA) tests to see the status of resistance for fluoroquinolones and second-line injectables before starting a shorter MDR regimen which has both these drugs.

Recently, WHO-recommended shorter regimen has proven successful in developing countries like Bangladesh.[7]

India also started with the shorter MDR regime. The study explores the advantages and disadvantages of the regimen in the Indian demography. The study also explores the fallouts and deaths due to various reasons and the percentage contribution of the reasons for the attrition.

The molecular biology of INH resistance in M. tuberculosis has been thoroughly studied. INH is a prodrug which undergoes anin vivo transformation to its active form. Catalase-peroxidase (KatG) encoded by katG performs this function in M. tuberculosis,[7] and mutations in katG, at codon 315, confer INH resistance.[8] The activated INH has a primary target. It is an Nicotinamide adenine dinucleotide (NAD) + hydrogen (H)-dependent enoyl-acyl carrier protein reductase, designated InhA.[9]

Mutations within the inhA structural gene[10],[11],[12],[13] or within the inhA promoter[12],[14],[15],[16],[17] are associated with both INH and ETH resistance.[9],[14] INH resistance occurs due to missense mutations within the inhA structural gene by reducing the NADH and protecting the enzyme from INH inactivation.[18] The inhA promoter mutations upregulate the target expression, thereby rendering INH and ETH resistance.[9],[10] The structural similarity and shared molecular target of INH and ETH led to the conjecture that ETH, such as INH, undergoes activation.[19]


  Materials and Methods Top


This is a retrospective analysis of patients put of shorter MDR regimen as per the diagnostic algorithm of a programmatic management of drug-resistant TB under the Revised National Tuberculosis Control Program. The sample of these patients was initially tested at the peripheral unit by Cartridge based Nucleic Acid Amplfication Test. RR cases were selected for shorter MDR regimen as per the criteria by the WHO.

The patients selected for shorter MDR regimen are as follows:

Inclusion criteria

  • All pulmonary and extrapulmonary cases only pleural effusion and lymph nodes
  • RR TB or MDR TB patient regardless of patient age or HIV status.


Exclusion criteria

  • All pregnant mothers
  • Extrapulmonary cases other than pleural effusion and lymph nodes
  • Previous exposure of more than 1 month to fluoroquinolones and second-line injectable group of drugs.


Smear examination of the patient selected for shorter MDR is done on a monthly basis in the intensive phase to guide decision-making to move to continuation phase. Smear examination is continued in the extended intensive phase only if the previous month smear is positive up to a maximum of 6 months. Follow-up cultures are done at the end of intensive phase, extended intensive phase, and at the end of treatment regime, and if found positive are subjected to first- and second-line LPA for the assessment of resistance, and if found resistance, modification regime is offered to the patient.

The outcomes of the treatment for all patients are declared only on the basis of follow-up culture.

During the course of treatment, samples of the patient are tested at specified intervals as follow-ups to assess the prognosis and outcome of the disease. Samples received at IRL Kolkata


  Statistical Analysis and Results Top


This is a retrospective analysis of all the districts of West Bengal with a total of 203 cases which were subjected to shorter MDR regimen, of which 189 are pulmonary and 14 were extrapulmonary cases. Among these, 10 are reactive to HIV and are put on to antiretroviral therapy, 190 are nonreactive, and 3 are having unknown status. Of the 14 extrapulmonary cases, 6 are cases of tubercular lymphadenopathy (3 HIV reactive) and 8 are pleural effusion.

Among these, 35 patients are diabetic, of them 16 (45.7%) are having HbA1C >8% and are on oral hypoglycemic agents.

Of this, 27 (10 + 17) samples remain culture positive at the end of the intensive phase, of which 10 samples were declared treatment failure, and there were 17 cases in which treatment regimen were changed owing to several factors. Out of these cases 10 were having Isoniazid resistance either due to kat G or inhA. 4 cases among these group were sensitive to isoniazid by Line probe Assay. All these cases were however found to be resistant to rifampicin which were earlier confirmed by CBNAAT test prior to put on to shorter MDR regimen.

On further analysis it was found 6 follow up cultures (treatment ongoing samples) shows positivity in liquid culture. These cases were found sensitive to isoniazid. 4 of these cases were resistant to fluoroquinolones. 2 of these cases were found to be resistant to the second line injectables.


  Discussion Top


Twentyseven (10 + 17) samples remain culture positive at the end of the intensive phase, of which 10 samples were declared treatment failure and 17 cases were from the group of treatment regimen changed 8.37%. The outcomes of the patient were put on the shorter MDR regimen, Bangladesh, Uzbekistan, Cameroon, Nigeria, and other different countries of sub-Sahara African belt. Success rate does not match with our selection of cases in the specified duration which does not reflect the success rate, as 13.7% [Table 1] of the cases were lost to follow-up in the duration study as majority of the cases turned to lost to follow-up had probably migrated to a different state or to different nation of close proximity.
Table 1: Outcome of shorter multidrug-resistant regimen in the study (n=203)

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Adverse drug reactions added significantly to the lost to follow-up cases which was about 13.7% [Table 1]. Headache along with vomiting accounted for 21.0% [Table 2]. After headache and vomiting, drug fever and skin rashes accounted for 18.4% [Table 2]. Cure rate accounted for 44.3% [Table 1].
Table 2: Adverse reaction noted in different case with shorter multidrug-resistant regimen (n=38)

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INH inhibits the process of mycolic acid synthesis.[20] Mutations in the katG gene or the inhA regulatory regions leads to INH resistance.

INH is rendered ineffective for the treatment of M. tuberculosis if encountered mutation.[8] The inhA regulatory region which encodes the primary target of active INH is nicotinamide adenine dinucleotide-dependent enoyl-acyl carrier protein reductase.,[21],[22] ETH and prothionamide. inhA mutations cause low-level resistance to the molecule meaning that higher doses may be effective.[23],[24]

As ETH is a structural analog of INH, cross-resistance occurs between INH and ETH;[14],[19],[25] thus, ETH and low-level INH show cross-resistance. A clinical trial has shown adding high-dose INH systematically to a standard MDR-TB regimen which has been effective.[26] ETH is judiciously used in case of MDR- or XDR-TB strains with katG mutations.[25],[26]

Of those who had failed to get cured on shorter MDR regimes were further subjected to first-line LPA based on sputum microscopy, and those which were smear negative in between the course of treatment were put on liquid culture and subsequently subjected to first-line LPA.


  Conclusion Top


Initiating a MDR regimen requires a modified selection criteria. The criteria should exclude isoniazid resistant cases owing to its cross resistance wth Ethionamide. As ETH is one of the challenging drugs selected in the shorter MDR regime, a simultaneous detection of RR status by CBNAAT at periphery and putting these samples for first-line as well as second-line LPA needs to be implemented prior to the selection of shorter MDR regime.

Twelve percentage of cases which were culture positive after the initiation of treatment with shorter MDR regime found to be resistant to fluoroquinolones groups or second-line injectable class resistance or both and lead to modification of treatment. Furthermore to note that the patient receiving the regimen where compelled to change the injectable kanamycin due to intolerability in the initial course of therapy have varied symptoms.

Studies were conducted for determining newer drug targets. Even extensive studies are required for detecting the wellknown drug targets (new drugs for TB) such as InhA, RpoB, FabC, FabD, KasA, Ndh, Glf, EfpA, EmbB, ES31, Cyp125, and InhA. FASII enoyl-ACP reductase (InhA) is the only well-validated target of the TB drug INH and has been a target of the rational drug design.[27]

Generally, the cost per diagnosis of using GeneXpert has proved to be very cost-effective among the elderly,[28] but the study included project samples which were facilitated by free drugs and diagnostic services; the cost-effectiveness for the patients was not very significant.

It is evident that there is a substantial risk for developing even more resistant forms of TB due to the usage of suboptimal drugs.[29]

Earlier, it was observed that after the initiation of treatment starting treatment 48 had a successful outcome, 6 (12%) treatment failed, 19 (38%) died, and one (2%) interrupted treatment.[30]

In a study, MDR MTB was noted in 66/113 patients, including 20 CAT I failure, 19 CAT II failure, and 27 CAT II relapse cases. Resistance to isoniazid (H) was seen most frequently in 74% of the patients, followed by resistance to pyrazinamide (Z).[31]

Based on our study, we had concluded that shorter MDR regimen is probably not the concrete solution for the patient having rifampicin-resistance status due to multifactorial events and nonadherence to the treatment on the patient part. Furthermore, studies are needed to evaluate the impact of shorter MDR regimen in different geographical region globally.

To establish this, an injectable-free regime needs to be formulated for avoiding the noncompliance and nonadherent to the treatment and minimization of adverse reactions and also lost to follow-up.

Twelve percentage of cases which were culture positive after initiation of treatment with shorter MDR regime found to be resistant to fluoroquinolones groups or second-line injectable class resistance or both and lead to modification of treatment

More similar studies should be explored in different geographical domains for similar cases with shorter MDR regimes to evaluate further the acceptability, tolerability, and compliance at the patient end to keep it as a definite regime in the management of drug resistance TB.

There are various studies in the developing and underdeveloped countries like Bangladesh and African countries where the outcome of a shorter MDR regimen is appreciably good in a range of 65%–85%. However, in our study, it turned to be 44.3% [Table 1], which is even less than the conventional regimen. Most studies need to be done in different provinces of our country with similar various dimensions related to shorter MDR regimen to establish the impact and outcome of regimen.

With the outcome of our study in the field of management of MDR TB, shorter MDR regimen is not appreciably good with multidimensional problems related to low cure rate, intolerability of the drugs included, and cross-resistance of isoniazid with ETH, an insight to be kept for a patient friendly regimen, preferably injectable free and good acceptability with high cure rate. This may be a strong pillar for the management of drug-resistant TB.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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