INTRODUCTION
Drug-resistant tuberculosis (DR-TB) is a chronic infectious disease requiring long-term treatment and complex regimens with serious adverse effects.[ 1 ] Bedaquiline and delamanid , two novel antituberculosis drugs, offer a high proportion of sputum conversion and cure rate in DR-TB patients.[ 2 , 3 ] They are included in a fully oral regimen.[ 4 ] Indonesia is one of the highest burden countries of DR-TB across the world. With support from the government, the Indonesia National Tuberculosis Program implemented bedaquiline and delamanid into programmatic use for the treatment of DR-TB, particularly in individual regimens.[ 5 ] Replacing second-line injectable drug-based regimens with bedaquiline - and/or delamanid -based therapies has proven to increase the effectiveness and safety of DR-TB treatment.[ 6 ]
Bedaquiline is administered orally and its pharmacological activity by inhibiting Mycobacterium tuberculosis ATP synthase. It has a high selectivity index for mycobacterial ATP synthase compared to eukaryotic cells. Therefore, bedaquiline does not interact with human ATP synthase.[ 7 ] Delamanid has a different mechanism from bedaquiline . Deazaflavin-dependent nitroreductase activates delamanid to intermediate products of nitric oxide and nitrous acid inhibiting the synthesis of methoxy mycolic acid, responsible for the survival of MTB either actively replicating or dormant.[ 8 ] Mycolic acid is an important component in the cell wall of MTB regulating permeability, acid-fast staining, viability, and virulence. The outer membrane also consists of trehalose glycolipids and phthiocerol dimycocerosates which adhere to mycolic acid and are responsible for interactions with the host and immune system. Therefore, inhibition of mycolic acid potently disrupts the cell wall of MTB and reduces inflammatory cell infiltration as a result of interaction between the host.[ 9 ]
Van Deun et al . proposed a core drug as the central component of a solid regimen, with moderate to high bactericidal and sterilizing activity and no evidence of cross-resistance to previous core drugs. Furthermore, two drugs with high bactericidal activity and two drugs with sterilizing activity are required to complete the regimens.[ 10 ] Bedaquiline was considered a core drug due to high bactericidal and sterilizing activity, and resistance prevention. Bedaquiline ’s bactericidal activity is initially weak and requires about a week to develop. To protect the variety of core drug-resistant mutants during the initial treatment days, companion drugs with high early bactericidal activity are necessary to reduce the bacillary load.[ 11 ] Delamanid and clofazimine can be used as companion drugs due to their high bactericidal and sterilizing effect, respectively.[ 10 ] Besides its high bactericidal, delamanid has an immunomodulatory property by increasing the Th1 cytokine, IL-12/23 p40, and decreasing the expression of Th2 cytokines, IL-6 and IL-10. Upregulating Th1 and downregulating Th2 by delamanid , enhances the bactericidal activity of macrophages.[ 12 ]
A recent study by Padmapriyadarsini et al . reported that after 24–36 weeks of treatment with regimens bedaquiline , delamanid , linezolid, and clofazimine, 91% of preextensively drug resistant-TB (XDR-TB) patients had favorable outcomes.[ 13 ] Regimens containing bedaquiline –delamanid are recommended to prevent acquired resistance and expected to reduce the resistance level, thereby increasing the cure rate. A recent study by Chesov et al . stated that at the beginning before treatment, all TB isolates were sensitive to bedaquiline . However, 15.3% of patients were resistant to bedaquiline during treatment and 3.8% were reinfected with bedaquiline -resistant strains.[ 14 ] Furthermore, a recent systematic review demonstrated that acquired bedaquiline resistance was 2.2% and 4.4% for phenotypic and genotypic, respectively.[ 15 ] A previous study by Pontali et al. , reported 81.4% of sputum culture conversion and 71.4% of treatment success after administration a regimen containing bedaquiline and delamanid . However, the limited number of studies with small number of patients was the limitation of Pontali et al. , and this result should be evaluated cautiously.[ 16 ]
According to the Ministry of Health of Indonesia Republic for the management of drug-resistant tuberculosis , for individual regimens, bedaquiline was given at a dose of 400 mg daily for 2 weeks and followed by 200 mg thrice weekly for 22 weeks, meanwhile delamanid was given at dose of 100 mg twice daily for 24 weeks.[ 17 ] Although previous studies have reported favorable outcomes with regimens containing bedaquiline –delamanid in DR-TB patients,[ 18–21 ] they have major differences in sample size, method and study design, comorbidity, HIV status, resistance profile, and tailored treatment. Therefore, they can’t be directly implemented in clinical settings. The aim of the present systematic review is to evaluate the efficacy or effectiveness of a regimen containing bedaquiline and delamanid to manage DR-TB. Our overall goal was to provide valuable information on the programmatic use of a regimen containing bedaquiline and delamanid . Hopefully, they can be included in clinical practice to manage DR-TB patients.
METHODS
Search strategy and study selection
This study is a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).[ 22 ] We used secondary data from articles published from 2017 up to October 2022 in PubMed and Science Direct databases reporting on the efficacy or effectiveness of individual regimens containing bedaquiline and delamanid in patients with drug-resistant tuberculosis . The search terms were: “drug-resistant tuberculosis ” (DR-TB),” “pre-XDR-TB,” “XDR-TB,” “MDR-TB,” “bedaquiline ,” “delamanid ,” “efficacy,” “effectiveness,” “culture conversion,” “sputum conversion,” and “favorable outcome.” Boolean operators with “OR,” “AND,” and “NOT” were used to combine these terms to search articles more specific.
Two reviewers (YS and SS) independently screened the articles by title or abstract and full text to exclude unrelated articles to the study objectives. The inclusion criteria to conduct this review were (a) articles written in English; (b) articles as original articles with randomized controlled trial, cohort, cross-sectional, or case–control study designs; patients diagnosed with drug-resistant tuberculosis including multidrug-resistant TB (MDR-TB), pre-XDR-TB, and XDR-TB; (c) patients concomitantly treated with regimens containing bedaquiline and delamanid ; (d) reporting success rate with smear sputum and/or culture conversion at least at the end of 6 months of treatment; and (e) DR-TB patients aged ≥18 years old. The exclusion criteria in our study were article written as a review, case report, letter to the editor, animal studies, and abstract proceeding or conferences. Articles in full text that meet the inclusion criteria will be summarized, extracted, and analyzed.
Outcome
Favorable outcomes were defined by sputum culture conversion within 6 months and cure rate at the end of treatment. The regimen was considered bedaquiline - and delamanid -containing based on what appeared in the method of the selected studies. We separated the treatment outcomes for experimental and observational studies. Optimized background therapy was concomitantly administered with bedaquiline and delamanid .
Data extraction
Two reviewers (YS and SS) extracted data from all eligible studies. The following data were extracted: author’s name, year of publication, study design, countries where study was conducted, sample size, treatment regimens and duration, drug resistance profile, culture conversion, and treatment outcomes.
Quality assessment
Two reviewers (YS and SS) examined the quality of each study using two different assessment tools (checklist) for observational and experimental studies. The third reviewer (SY) was included in case of inconsistencies between the two reviewers. We used the Newcastle–Ottawa Scale (NOS).[ 23 ] for observational studies and the Cochrane tool.[ 24 ] for experimental studies to assess the quality of the studies. The NOS consists of three domains including selection of participants, comparability, and outcomes. A study can be given a max of one point for each item within the selection and outcome and a max of two points for comparability. Studies were assigned as low, moderate, and high quality if scores of 0–3, 4–6, and 7–9, respectively. The Cochrane tool to assess the quality of experimental studies includes the use of random sequence; concealment to allocate participants; blinding of participants; blinding of outcome assessors; incomplete outcome data; selective reporting; and other bias. Each study was categorized as at low risk of bias if there was no concern regarding bias; as high risk of bias if there was no concern regarding bias; and unclear risk of bias if the information was incomplete.
Ethical statement
Since the present study was a systematic review, ethical approval was not applicable.
RESULTS
Study selection
A total of 381 records were identified in the initial search in two databases. After removing duplicate articles, 168 articles were screened for the title and abstract. Of these, 148 articles were excluded due to irrelevant and after full-text review, 20 full-text articles were assessed for eligibility. Of 20 articles, 6 of them were excluded, and finally, 14 articles met the inclusion criteria to be included in the systematic review, as shown in Figure 1 . Of 14 articles, 12 were observational and 2 experimental studies. The study period ranged from 2018 to 2022. Overall, 1407 DR-TB patients were included in bedaquiline - and delamanid -containing regimens. Only one study reported the treatment outcome at the end of 12 months. The summary of the characteristic of the included studies is shown in Table 1 .
Figure 1: PRISMA flowchart of study selection in the systematic review. PRISMA: Preferred reporting items for systematic reviews and meta-analyses
Table 1: Characteristic of studies included in the systematic review
Quality of included studies
The mean ± standard deviation score of the observational studies using NOS was 7.91 ± 0.27, indicating a high methodological quality and a low risk of bias, as shown in Table 2 . Of 2 experimental studies, one study by Dooley et al .[ 26 ] was categorized as a high risk of bias including allocation concealment, blinding of participants, and outcome blinding, as shown in Table 3 .
Table 2: Quality assessment of observational studies included in the systematic review
Table 3: Quality assessment of experimental studies included in the systematic review
DISCUSSION
Our study aimed to evaluate the favorable outcome of a regimen containing bedaquiline and delamanid together with optimized background regimen to manage DR-TB patients. Bedaquiline was used in short-term and individual regimens, meanwhile delamanid was approved for the latter. Bedaquiline and/or delamanid at treatment initiation and as part of an all-oral regimen improve successful treatment (culture conversion) and minimize side effects, such as hearing loss and renal dysfunction, related to the second-line injectable drugs.[ 37 ] Several studies have reported that adding bedaquiline and delamanid to DR-TB regimens effectively increases a culture conversion rate at 6 months. Bedaquiline in DR-TB treatment increase intracellular killing activity against MTB. A study by Giraud-Gatineau et al. , demonstrated an increase of autophagy and macrophage lysosomal activity, characterized by microtubule-associated protein light chain 3B and glycolisis.[ 38 ] However, some studies concerned about potential toxicity of bedaquiline and delamanid , especially when given together with other drugs prolonging the QT interval, such as fluoroquinolone and clofazimine.[ 6 , 39 ]
Sputum culture conversion is the most commonly used to evaluate the effectiveness after administering antituberculosis drugs. Sputum culture conversion was significantly associated with treatment outcomes. The study by Javaid et al . reported that to estimate cure, the sensitivity and specificity of sputum culture conversion at 6 months were 97.6% and 44.4%, respectively. Furthermore, the association of sputum culture conversion with cure was significantly greater at the 6th month (odds ratio [OR] = 32.10) than at 4 months (OR = 14.13).[ 40 ] Another study by Meyvisch et al . showed that conversion of sputum cultures at 24 weeks provided greater prognostic value for clinical outcome than sputum culture conversion at 8 weeks when assessing the outcome of adding a new drug for the DR-TB regimen.[ 41 ] Using sputum culture conversion at month 6 as a proxy marker to predict final outcomes can reduce the physicians’ waiting period to decide about regimen efficacy.
The overall sputum culture conversion at the end of the 6th month was 63.6%–94.7% for observational and 87.6%–95.0% for experimental studies. Resistance pattern did not affect the treatment outcome. Patients with fluoroquinolone resistance demonstrate favorable outcomes after initiation bedaquiline and delamanid . Furthermore, A Study by Kang et al. , reported that patients with MDR-TB, pre-XDR-TB, and XDR-TB, culture conversion at 6 months was 90.7%, 87.8%, and 90.6% (P = 0.952), and favorable outcome at 12 months was 87.1%, 82.7%, and 85.4%, respectively. Furthermore, resistance pattern including pre-XDR and XDR-TB was not associated with unfavorable outcome.[ 30 ] A study by Lee et al . reported significantly more prevalent lung cavities and bilateral lung disease in MDR TB patients who were resistant to fluoroquinolones than those who were sensitive.[ 31 ] The lung cavity provides an environment that facilitates the development of antituberculosis drug resistance due to high TB bacillary load, active bacterial replication, and potentially lower drug concentrations in the lung tissue.[ 42 ]
Pulmonary lesions in TB patients are a hypoxic condition characterized by induction of hypoxia-inducible factor-1a (HIF-1a) induction and synergistically increase collagenase activity leading to destruction and lung cavities. DR-TB patients with relapse cases have more lung lesions or cavities compared to those with new cases.[ 43 ] Delamanid is active against both replicating and dormant TB bacteria. They become dormant through decreased metabolism in hypoxic conditions, one of the factors for resistance. An in vitro study by Chen et al . reported that delamanid killed TB bacilli within hypoxic lesions of the lung.[ 44 ] In addition, regimens containing bedaquiline demonstrated radiological improvement in patients with XDR-TB.[ 45 ] It may explain the high efficacy of bedaquiline and/or delamanid in patients with pre-XDR and XDR-TB.
High efficacy of regimen containing bedaquiline and delamanid was demonstrated by low recurrence rate at 12 months after initation of the treatment.[ 34 ] Bedaquiline and/or delamanid could prevent relapsed in DR-TB patients. In a mouse tuberculosis model, Pieterman et al . reported culture negativity in the lungs was obtained after 8 and 20 weeks of bedaquiline /delamanid /linezolid and isoniazid/rifampicin/pyrazinamide/ethambutol (HRZE) treatment, respectively. After 14 weeks of treatment, only one mouse in the BDL group relapsed, whereas it was still observed in the HRZE group after 24 weeks of treatment. Furthermore, a minimal 20.5 weeks was predicted to be required to reach a 95% cure rate using the BDL regimens.[ 46 ] These findings may explain why most studies carried out monitoring of sputum conversion in DR-TB patients in the 6th month. Negative sputum in the 6th month is expected to remain negative until the end of treatment, indicating successful treatment. Beyond its bactericidal activity, delamanid alter the function of host immune cell. The balance between pro-and anti-inflammatory responses is vital in limiting the infection among DR-TB patients. Delamanid down-regulated the level of CXCL-10, a pro-inflammatory cytokine, and produced additional benefits for DR-TB patients to reduce inflammation via regulation of JAK2/STAT1 signaling.[ 47 ]
Although previous studies have reported a favorable outcome in regimens containing bedaquiline and delamanid , concomitant use of them was associated with unfavorable outcome as reported by Vambe et al. ,[ 48 ] compared with bedaquiline or delamanid as a single drug. It may more likely due to additive adverse effects of bedaquiline and delamanid . Furthermore, the number of patients receiving bedaquiline and delamanid was small. Therefore, prompt for collection of more data on the combined use of these regimens was required.
Our systematic review provides updated information regarding the efficacy or effectiveness of regimens containing bedaquiline and delamanid to manage DR-TB patients. Until now, delamanid has been categorized in class C due to limited previous data and the risk of potential side effects. However, a regimen containing bedaquiline and delamanid is relatively safe since no mortality related to QTc prolongation.[ 49 ] Based on existing data regarding the benefits of delamanid , this drug may move up to class A or B.
CONCLUSION
The use of regimens containing bedaquiline and delamanid for longer individual treatment in DR-TB patients offers a favorable outcome in increasing sputum culture conversion and cure rate.
Limitation of study
This review has several limitations. At the beginning, the optimized background therapy co-administered with bedaquiline and delamanid are relatively heterogeneous, which is likely to lead to an overinterpretation of the effectiveness of the bedaquiline and delamanid . In addition, of 12 observational studies, 8 were retrospective cohorts with various sample sizes. In accordance with the nature of retrospective studies, monitoring patient adherence is difficult. Furthermore, only two studies analyzed the factors that influence favorable or unfavorable outcomes.
Ethical statement
Since the present study was a systematic review, ethical approval was not applicable.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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