Efficacy and safety of bedaquiline containing regimens in patients of drug-resistant tuberculosis: An updated systematic review and meta-analysis

Background Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis and leads to serious complications if left untreated. Some strains of Mycobacterium tuberculosis are multi-drug resistant and require treatment with newer drugs. Bedaquiline based treatment regimens have been used in patients who are diagnosed with drug resistant tuberculosis. The aim of this study is to assess the efficacy and safety profile of bedaquiline-based treatment regimens using a systematic review of existing literature and meta-analysis. Methods In this study, an electronic search was carried out on PubMed, ScienceDirect, and Cochrane library to find relevant literature from March 2021 onwards. Random-effects model was used to assess pooled treatment success rate and 95 % CIs. p-value of <0.05 was suggestive of publication bias. The review is registered with PROSPERO: CRD42023432748. Results A total of 543 articles were retrieved by database searching, out of which 12 new studies met the inclusion criteria. The total number of articles included in the review was 41 including 36 observational studies (having a total of 9,934 patients) and 5 experimental studies (having a total of 468 patients). The pooled treatment success rate was 76.9 % (95 % CI, 72.9–80.4) in the observational studies and 81.7 % (95 % CI, 67.2–90.7) in the experimental studies. Further subgroup analysis was done on the basis of treatment regimens containing bedaquiline only and treatment regimens containing bedaquiline and delamanid. The pooled treatment success rate in the studies consisting of patients who were treated with regimens containing bedaquiline only was 78.4 % (95 % CI, 74.2–82.1) and 73.6 % (95 % CI, 64.6–81.0) in studies consisting of patients who were treated with regimens containing bedaquiline and delamanid. There was no evidence of publication bias. Conclusions In patients of drug resistant tuberculosis having highly resistant strains of Mycobacterium tuberculosis undergoing treatment with bedaquiline-based regimen demonstrate high rates of culture conversion and treatment success. Moreover, the safety profile of bedaquiline-based regimens is well-established in all studies.


Introduction
It is believed that about one-fourth of the world's population has been exposed to tuberculosis bacteria.Globally, tuberculosis (TB) ranks as the thirteenth most prevalent cause of mortality, and it stands as the second most significant infectious agent (after COVID-19) responsible for fatalities, surpassing both HIV and AIDS.In 2021, the global mortality rate due to tuberculosis (TB) reached 1.6 million individuals, while approximately 10.6 million individuals were afflicted with the disease [1].In recent years, the emergence of drug resistance in tuberculosis (TB) has been attributed to various factors, including the inappropriate utilization of TB medications, such as their incorrect and inadequate prescription by healthcare professionals, the availability of substandard drugs, and non-compliance of patients leading to discontinuation of therapy [1].Multidrug-resistant tuberculosis (MDR-TB) is a variant of tuberculosis (TB) that is characterized by bacterial strains exhibiting resistance to isoniazid and rifampicin, which are recognised as the two most efficacious first-line drugs for the treatment of TB [2].MDR-TB which is also resistant to any fluoroquinolone was defined as Pre-Extensively Drug-Resistant Tuberculosis (Pre-XDR-TB) while MDR-TB which is also resistant to any fluoroquinolone and at least one of the injectables second line drugs was defined as Extensively Drug-Resistant Tuberculosis (XDR-TB) [3].
Multidrug-resistant tuberculosis (MDR-TB) poses a significant challenge to public health and represents a health security concern, necessitating intricate and financially burdensome treatment protocols [1].On a global scale, the number of incident cases of multidrug-resistant tuberculosis (MDR-TB) in 2021 was approximately 450,000, reflecting a 3.1 % increase compared to the 437,000 cases reported in 2020 [2].The treatment outcomes for MDR-TB are suboptimal, as evidenced by a success rate of approximately 50 % among patients undergoing treatment [4].XDR-TB poses significant challenges in terms of treatment, necessitating longer and more complex therapeutic regimens compared to MDR-TB.The available treatment options are characterized by limitations in terms of efficacy, high costs, and potential toxicity [5].In 2018, the World Health Organisation (WHO) reported a global treatment success rate of 39 % XDR-TB [6].
Bedaquiline, a recently developed drug, has demonstrated notable efficacy in the management of MDR-TB.The drug in question represents a novel therapeutic agent that operates through a distinct mechanism of action in comparison to the currently available anti-tuberculosis medications.The efficacy of bedaquiline has been demonstrated in reducing the duration of treatment for MDR-TB and enhancing the rate of treatment success [7][8][9].Bedaquiline was included in the World Health Organization's recommended all-oral regimen as a substitute for injectable treatments in patients with MDR-TB [7].
To better analyze the effectiveness and safety of bedaquiline in MDR-TB, we conducted an updated meta-analysis.

Search Strategy
This meta-analysis was conducted and reported in conformity with the Cochrane and PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines [22].We searched for original studies reporting the efficacy of dosing regimens consisting of bedaquiline in patients of MDR-TB/ pre-XDR TB/ XDR TB confirmed after culture or drug-susceptibility testing.An electronic search was conducted on Cochrane CENTRAL, MEDLINE, Scopus, and ClinicalTrials.gov databases from March 2021 till August 2023.Detailed search strings for each database are presented in the Supplementary Table S1.No restriction regarding country, race or publication language were set.Reference list from related main studies and review articles were also checked for additional relevant studies.The review is registered with PROSPERO: CRD42023432748.

Study selection and eligibility Criteria
Articles were selected if they met the following prespecified eligibility criteria: (i) single arm observational or experimental studies (ii) patients who have been diagnosed with MDR-TB per WHO criteria [23]; (iii) patients who have been treated with dosing regimens containing bedaquiline; and (iv) treatment success (i.e, cultural conversion) was reported.The exclusion criteria included (i) non human studies, case series, editorials, abstracts, reviews, comments and letters, expert opinions, studies without original data, duplicate publications, and articles describing tuberculosis patients who were recruited without a confirmed bacteriological diagnosis.
TB caused by Mycobacterium tuberculosis strains and fulfilling the definition of MDR-TB or rifampin-resistant TB and also resistant to any fluoroquinolone was defined as Pre-Extensively Drug-Resistant Tuberculosis Pre-XDR-TB.Tuberculosis caused by M. tuberculosis strains and fulling the definition of MDR-TB or rifampin-resistant TB and also resistant to any fluoroquinolone and at least one additional group A drug was defined as Extensively Drug-Resistant Tuberculosis (XDR-TB) [3].
Treatment outcomes were recorded in accordance with adapted definitions of those given in the WHO guidelines, as follows: treatment success, defined as the combination of the number of patients who completely recovered and that of those who completed their treatment; death, defined as mortality from any cause while on treatment; and treatment failure defined as unsuccessful treatment, as determined by positive cultures at the end of the treatment regimen [24].

Data extraction and Quality Assessment
The articles retrieved from the systematic search of databases were exported to EndNote Reference Library Software, and duplicates were removed.Two independent reviewers (Nashwan.A. and Ali.A.) first screened the remaining articles on the basis of title and abstract, after which the full text was reviewed to assess relevance.Any discrepancies were addressed through discussion until a consensus was reached.The primary outcome of interest was the treatment success rate i.e., the number of patients who completed their treatment and also achieved a cure according to WHO guidelines.The following data were extracted from all eligible studies: first author's name; year of publication; study duration; type of study; country or countries where the study was conducted; the number of patients with MDR-TB; patient age; treatment protocols (treatment regimens and duration of treatment); demographics; adverse effects; drug resistance status; and outcomes.Quality assessment of the included studies was done using two different assessment tools (checklists): one for observational and one for experimental studies adopted from the Joanna Briggs Institute.Critical Appraisal Tools [26].Items such as study population, measure of exposures, confounding factors, extent of outcomes, follow-up data, and statistical analysis were evaluated.

Data Analysis
Comprehensive Meta-Analysis software, version 3.3 (Biostat Inc., Englewood, NJ, USA) was used to perform statistical analyses.The pooled success rate with 95 % CI was assessed using the random-effects model.The random-effects model was used because of the estimated heterogeneity of the true effect sizes.We conducted a separate analysis for observational and experimental studies respectively, Additionally, subgroup analyses stratified by type of study and treatment regimen [bedaquiline-based (BDQ) regimen, bedaquiline and delamanid-based (BDQ + DLM) regimen] were performed to minimize heterogeneity.Heterogeneity across studies was evaluated using Higgins I 2 where a value of 50 % and more was considered.Publication bias was statistically assessed by using Begg's test, as well as funnel plots, a value of p < 0.05 being considered indicative of statistically significant publication bias and funnel plot asymmetry being suggestive of bias [25].

Results
We searched the databases for articles after March 2021.As shown in Fig. 1, the electronic search across three databases yielded a total of articles.After the removal of duplicates, the titles and abstracts of articles were screened.Of those, 193 were selected for a full-text review.After a full-text review, 12 new studies were chosen for updating the previous version of the systematic review and meta-analysis.In total, 41 studies are included in the updated version of this review.The studies [10][11][12][13][14][15][16][17][18][19][20] were divided into two groups: 36 observational studies including a total of 9,934 patients, and 5 experimental studies including a total of 468 patients.The patient's mean age was 36.2 years.The treatment duration ranged from a minimum of 5 months to a maximum of 22 months with most studies having a treatment duration of 6 months.Out of the patients, 3510 were HIV+, and 6,999 patients had prior TB treatment.The earliest study was published in 2014, and the latest study was published in 2023.Table 1 summarizes the baseline characteristics of patients included in individual studies.

Quality of the included Studies
The checklist for observational studies [26] showed that the observational studies included had a low risk of bias (Table 2).On the other hand, the included experimental studies had a high risk of bias for participant assignment, randomization, group concealment, and assessor blinding (Table 3) according to the checklist for experimental studies [26].

Subgroup Analysis
The subgroup analysis of included studies in the review is shown in Table 5 based on treatment regimen and type of study.33 of the 41 included studies with a total of 9,241 patients used bedaquilinecontaining regimens and the pooled treatment success rate was 78.4 % (Fig. 4).8 of the 41 studies with a total of 764 patients used treatment regimens including bedaquiline and delamanid.The pooled treatment success rate for their patients was 73.6 % (Fig. 5).

Discussion
To the best of our knowledge this meta-analysis is the largest and updated study conducted to date, involving a patient population of 10,402 individuals.The aim was to assess the safety, efficacy, and tolerability of treatment regimens containing bedaquiline in patients diagnosed with MDR-TB and XDR-TB who were undergoing treatment.This up-to-date meta-analysis provides evidence indicating that the use of regimens containing bedaquiline in 36 observational studies resulted in a treatment success rate of 76.9 %, the treatment failure rate was 4.7 % and death rate was 8.9 %.Pooled results of 5 experimental studies indicated that the success rate was 81.7 %, treatment failure rate and death rate was 3.6 %.The most common AEs are QTc prolongation, liver disorders, hematological disorders, gastrointestinal symptoms, arthralgia, dermatological disorders, and peripheral neuropathy.These findings suggest that bedaquiline-containing regimens are safe and effective for the treatment of MDR-TB and XDR-TB, with higher treatment success rates and lower mortality rates observed in experimental studies.However, large powered trials are warranted to confirm these findings.
The study found that treatment regimens containing bedaquiline had high treatment success rates and lower mortality rates.This can be attributed to the unique mechanism of action of this drug that inhibits the mycobacterial energy metabolism by specifically targeting ATP synthesis.It is effective against all forms of Mycobacterium tuberculosis, including active, dormant, replicating, non-replicating, intracellular, and extracellular bacteria.Amongst all anti-TB drugs approved, bedaquiline is the only drug, which targets the energy metabolism of mycobacteria [27].Additionally, bedaquiline has a high volume of distribution, extensive tissue distribution, and high plasma protein binding (>99.9 %) and terminal half-life of ~5.5 months [27].The dynamic pharmacokinetics and unique mechanism of action make it a viable treatment option.Bedaquiline can be used in combination with other anti-TB drugs.This helps to improve the efficacy of the treatment regimen and reduce the risk of resistance [28].However, further research is warranted to study drug interactions with bedaquiline.The majority of the patients, specifically 9,321 out of a total of 10,402, underwent a treatment regimen lasting approximately six months.Among these patients, 6,690 individuals, accounting for approximately 72 % of the total, experienced successful outcomes from the treatment.The efficacy of BDQ-containing regimens for the treatment of BDQ has been substantiated by the significant rate of success observed over a 6-month treatment duration.Furthermore, the TB-PRACTECAL (Pragmatic Clinical Trial for a More Effective, Concise, and Less Toxic Multidrug-Resistant Tuberculosis Treatment Regimen[s]) [29] and STREAM-2 (The Evaluation of a Standard Treatment Regimen of Anti-Tuberculosis Drugs for Patients with Multidrug-Resistant Tuberculosis) [30] trials have provided evidence of the effectiveness of treatment regimens containing BDQ, with durations of 6-9 months.Collectively, these findings indicate that when combined with efficacious adjunctive medications, a duration of 6 months of BDQ may be satisfactory for a considerable number of patients [20].
The findings of our study indicate that bedaquiline-containing regimens exhibit efficacy and safety as a viable treatment choice for individuals afflicted with drug-resistant tuberculosis.The results of our study align with other individual trials and observational studies that have documented positive outcomes associated with the use of bedaquiline [10,[30][31][32][33].Our results are also consistent with the previous meta-analysis by Hatami et al. [21] in which the results of 29 studies recruiting almost 4000 patients were pooled and the average treatment success rate for observational and experimental studies was around %. Another systematic review and meta-analysis conducted in found that bedaquiline exhibits the ability to attain a higher rate of culture conversion and a reduced risk of mortality in patients with drug-

Questions:
1. Were the two groups similar and recruited from the same population?2. Were the exposures measured similarly to assign people to both exposed and unexposed groups?3. Was the exposure measured in a valid and reliable way? 4. Were confounding factors identified? 5. Were strategies to deal with confounding factors stated?6. Were the groups/participants free of the outcome at the start of the study?7. Were the outcomes measured in a valid and reliable way? 8. Was the follow-up time reported and long enough for outcomes to occur? 9. Was follow-up complete, and, if not, were the reasons for loss to follow-up described and explored?10.Were strategies to address incomplete follow-up utilized?11.Was appropriate statistical analysis used?
O. Ur Rehman et al.
Patients have demonstrated encouraging responses to bedaquiline, however, bedaquiline, like any medicine, can cause unwanted side effects that must be watched for and dealt with.Nausea, headache, arthralgia, and a loss of appetite were the most often reported adverse reactions to bedaquiline.Most of these were not serious enough to warrant stopping treatment with the medication [8].One concerning thing is that bedaquiline can cause a condition called QT prolongation, which causes a delay in the heart's electrical activity and can cause irregular heart rhythms.When coupled with other medications that have the same effect or with other heart problems, QT prolongation can significantly raise the risk of sudden cardiac death.Therefore, patients

Table 3
Quality assessment of the experimental studies included in the meta-analysis.

Questions:
1. Was true randomization used for assignment of participants to treatment groups? 2. Was allocation to treatment groups concealed?3. Were treatment groups similar at baseline? 4. Were participants blind to treatment assignment? 5. Were those delivering treatment blind to treatment assignment? 6. Were outcome assessors blind to treatment assignment? 7. Were treatment groups treated identically other than the intervention of interest?8. Was follow-up complete, and, if not, were differences between groups in terms of their follow-up adequately described and analyzed?9. Were participants analyzed in the groups to which they were randomized?10.Were outcomes measured in the same way for treatment groups?11.Were outcomes measured in a reliable way? 12. Was appropriate statistical analysis used? 13.Was the trial design appropriate and were any deviations from the standard randomized controlled trial design accounted for in the conduct and analysis of the trial?with or at risk for QT prolongation should use bedaquiline with caution, and regular ECG monitoring is advised [34].Additionally, bedaquiline can also cause hepatotoxicity manifested by increased liver enzymes, jaundice, or hepatitis.This can occur either independently of drug interactions or in conjunction with other hepatotoxic anti-tuberculosis medicat ions.Patients with or at risk for liver illness should use bedaquiline with caution, and routine liver function testing is advised [35].However, bedaquiline's efficacy and safety in the treatment of multidrug-resistant tuberculosis (MDR-TB) were evaluated in an observational retrospective cohort research.The findings demonstrated that bedaquiline is a well-tolerated and safe medication with promising preliminary efficacy [36].Since bedaquiline is a relatively new medication, studies assessing its long-term safety and efficacy are still in their infancy.Therefore, it is crucial to utilize bedaquiline in   accordance with the standards and recommendations issued by the World Health Organization and other organizations.Bedaquiline is most effective when used in conjunction with other medications, under close medical supervision, and tailored to the specific needs of each patient [37].Bedaquiline's cost-effectiveness and effect on drug-resistance patterns, as well as the appropriate dose, duration, and regimen, require more study.Bedaquiline-containing regimens are effective in treating MDR-TB and XDR-TB, with higher treatment success rates.However, the treatment failure rates and death rates, although low, should not be ignored.One of the reasons could be inadequate adherence to treatment.Patients must take bedaquiline for the full course of treatment, which is 24 months [27].If they do not take their medication as prescribed, the risk of treatment failure and death increases.Additionally, with the increased exposure of these medications to patients in all prescribed multidrug-resistant and rifampicin-resistant tuberculosis treatment regimens, resistance might increase in the population [38].Moreover, bedaquiline can cause serious side effects, such as liver damage and QT prolongation [39].These side effects can lead to treatment discontinuation, which increases the risk of treatment failure and death.
However, our study possesses certain limitations.Both experimental and observational studies were incorporated in this analysis, potentially resulting in heterogeneity.While the incorporation of observational studies in this meta-analysis adds vulnerability to residual bias, a seperate analysis was conducted for these study groups to assess their individual impact and implications.The main limitations include variations in the time period of drug usage and adjunctive dosing regimen of patients, as well as discrepancies in patient characteristics observed across different studies.Moreover, we exclusively considered published articles while excluding unpublished ones from our screening process.It is also important to note that the scope of this study was restricted to articles written exclusively in the English language, so excluding any publications in other languages from the review process.
In conclusion, this up-to-date meta-analysis of observational and experimental studies provides evidence that bedaquiline-containing regimens are safe and effective for the treatment of MDR-TB and XDR-TB.The treatment success rate was 76.9 % in observational studies and 81.7 % in experimental studies.The mortality rate was 8.9 % in observational studies and 3.6 % in experimental studies.The most common adverse events were QTc prolongation, liver disorders, hematological disorders, gastrointestinal symptoms, arthralgia, dermatological disorders, and peripheral neuropathy.However, large powered trials are warranted to confirm these findings.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Fig. 1 .
Fig. 1.PRISMA Flow Diagram showing search strategy adopted for conducting this review.

Fig. 2 .
Fig. 2. Treatment success rate of the pooled observational studies.

Fig. 3 .
Fig. 3. Treatment success rate of the pooled experimental studies.

Table 1
Studies Included in the Meta Analysis.

Table 2
Quality assessment of the observational studies included in the meta-analysis.

Table 4
Adverse Events (AEs) in the studies included in the meta-analysis.

Table 5
Summary of Subgroup Analysis.