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According to the Global Tuberculosis Report released by the World Health Organization (WHO) in 2018, as of 2017, there were about 10 million new-onset TB patients worldwide, of which about 484,000 were new-onset rifampicin-resistant tuberculosis (RR-TB). Of these, 78% are multidrug-resistant tuberculosis (MDR-TB) and 6.2% are MDR-TB patients with extensive drug-resistant tuberculosis (XDR-TB). China is one of the countries with a high incidence of MDR-TB and RR-TB, with about 57,000 new cases of MDR-TB per year, but its cure rate is only 54%; about 37,000 new cases of RR-TB per year, but its cure rate is less than 62%. In this context, the treatment of MDR/RR-TB is the focus and difficulty of tuberculosis control in mainland China and even globally.
Bequiline is the first new anti-TB drug approved on the market since 1971. Bedaquinoline is a Class A drug in the Guidelines for the Comprehensive Treatment of Drug-Resistant Tuberculosis issued by the WHO in 2020, the Chemotherapy Guidelines for Drug-Resistant Tuberculosis issued by the Chinese Tuberculosis Association in 2019, and the Expert Consensus on the Treatment of Multidrug-Resistant and Rifampicin Tuberculosis (2019 Edition) issued by the Tuberculosis Branch of the Chinese Medical Association. Bedaquinoline was approved by the Mainland Food and Drug Administration to enter the Chinese market in January 2020. In order to use bedaquinoline, the only new drug in the domestic market, the author summarizes the clinical application and research progress of bedaquinoline.
First, the molecular structure and mechanism of action of Bedaquinoline
The chemical name of bedaquinoline is (1r,2s)-1-(6-bromo-2-methoxy-3-quinoline)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol with the formula C32H31Bn2O2 C4H4O4 with a relative molecular mass of 671580.
Bedaquinoline is a representative diarylquinoline drug that exerts an anti-MTB effect by inhibiting the synthesis of adenosine triphosphate (ATP) in Mycobacterium tuberculosis (MTB). Bedaquinoline can bind to ATP synthase oligomer C, affect the activity of ATP synthase proton pump, block the synthesis of ATP, thereby blocking the ATP energy supply of Tuberculosis bacillus, playing an antibacterial and bactericidal role. Due to the different mechanisms of action of bedaquinoline, there is no cross-resistance to traditional anti-TUBERCULO drugs and has strong antibacterial activity against sensitive, resistant and dormant strains.
Second, the current situation of bedaquinoline in the treatment of MDR/RR-TB
In 2012, bedaquinoline was approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDR/RR-TB. Subsequently, the U.S. Centers for Disease Control and Prevention (CDC) and the WHO issued guidelines that bedaquinoline could be used as part of the combination of MDR-TB in the absence of other effective treatments. Clinical data from multiple countries support this guideline. In addition, in 2018, the WHO reclassified anti-TUBERCULO drugs, and bedaquinoline was listed as the drug of choice for long-term treatment of MDR/RR-TB. In 2018, the Tuberculosis Branch of the Chinese Medical Association organized experts to reach an expert consensus on the clinical application of the new anti-tuberculosis drug Bedaquinoline.
III. Indications of Bedaquinoline and its clinical application
Currently, the indications for bedaquinoline are based on two Phase IIb clinical trials targeting patients with MDR/RR-TB.
1. MDR-TB: conventional drugs fail to constitute an effective chemotherapy regimen, such as in vitro resistance to pyrazinamide in the A, B, and C groups, or adverse drug events, poor tolerance, or contraindications.
2. RR-TB: when conventional drugs cannot form an effective chemotherapy regimen, such as in vitro resistance or adverse drug events, poor topirazinamide in second-line anti-tuberculosis drugs in groups A, B and C or contraindicated.
3. XDR-TB: When beidaquinoline is added to form an effective chemotherapy regimen, it can be applied.
1. Evaluation of the application of bedaquinoline in the long-term treatment of MDR-TB and/or RR-TB
In a 2018 meta-analysis published in the journal Lancet, the authors sifted through observational and experimental articles on MDR-TB using bedaquinoline in the treatment of MDR-TB from databases such as Medline, Embase, and Cochrane Library. In total, 12,030 patients were selected from 50 studies in 25 countries. The results showed that bedaquinoline reduced the risk of initial treatment failure and recurrence by a dominance ratio of 0.10 (95% CI: 0.05 to 0.14) and a dominance ratio of -0.14 (95% CI: -0.19 to -0.10) after mortality risk mediation. The results of the study show that long-term treatment regimens containing bedaquinoline can further improve the success rate of treatment and reduce the mortality rate, thus laying the foundation for its dominant position in the treatment of MDR/RR-TB.
2. Evaluation of the application of bedaquinoline in the short-term treatment of MDR-TB and/or RR-TB
There are currently several short-term treatment options in the world that contain bedaquinoline. Based on data from the South African Tuberculosis Project, the World Health Organization assessed a total oral short-term chemotherapy regimen containing bedaquinoline. The South African protocol is 4 to 6 BDQ-LFX/MFX-ETO-EMB-PZA-INHH-CFZ/5 LFX/MFX-CFZ-PZA-EMB (BDQ: Bedaquinoline; Lfx: Levofloxacin; Mfx: Moxifloxacin; Etoo: Ethiopian; EMB: Ethanol; PZA: PZA: Pyrazine; Isoniazid: High-Dose Isoniazid; Cfz: Chlorpromazine). The results showed that bedaquinoline could significantly improve the treatment success rate of patients with MDR-TB and significantly reduce the rate of loss of follow-up. The above regimen is indicated for patients who have not previously been exposed to second-line agents and have been shown to be sensitive to fluoroquinolones. Treatment outcomes are similar regardless of whether the patient is hive or not. However, due to the lack of data, the effectiveness, safety and tolerability of the above protocols need to be evaluated in a timely manner under experimental conditions. And the time is short, this scheme has not yet been widely used.
3. Summary
The WHO's Integrated Guidelines for Drug-Resistant TB, issued in 2020, recommend three standardized treatment regimens of bedaquinoline for the treatment of MDR/RR-TB (1) for MDR/RR-TB for the treatment of MDR/RR-TB for the full oral short-course treatment; (2) for the treatment of MDR/RR-TB for individualized, long-course treatment; and (3) for the treatment of XDR-TB. For patients diagnosed with MDR/RR-TB, patients with fluoroquinolone resistance, no disseminated TUBERCULOsis, and no severe extrapulmonary tuberculosis) are recommended for 9 to 12 months if they meet certain criteria (i.e., no more than one month before the use of second-line anti-TB drugs included in this program), and standard short-course injections containing bedaquinolones are recommended. Most of the current ongoing MDR/RR-TB clinical trials are oral regimens of bedaquinoline for a duration of 6-9 months, and short-term treatment regimens are the future treatment trend for MDR/RR-TB.
Fourth, the use and dosage of bedaquinoline
As part of the combination of MDR-TB, the active ingredient diarylquinoline can be used to treat mycobacteria. MDR-TB may last up to 24 weeks, during which time multiple medications are required (at least four other medications are used)
Weeks 1 to 2: 400 mg orally once daily for 2 weeks. Weeks 3 to 24: 200 mg orally three times a week for 22 weeks.
V. Adverse reactions and safety of bedaquinoline
1. Adverse reactions
> 10%: nausea (38%), joint pain (32.9%), headache (27.8%).
1-10%: elevated aminotransferase (8.9%), increased blood amylase (2.5%).
2. Security
Studies have shown that bedaquinoline fumarate tablets are at risk of elevated transaminases and prolonged QT intervals, but their incidence is low. A large cohort study showed that the incidence of QT interval prolongation was 13% in cases of elevated transaminases. 33%, but the QTc < 500 ms by repeated ECG was determined, and treatment was not interrupted. There was also no statistically significant difference in the overall incidence of adverse reactions between the two groups. It can be seen that although the application of bedaquinoline fumarate tablets has certain risks such as QTc prolongation and elevated transaminases, it does not significantly increase the risk of adverse reactions in treatment. An interim analytical cohort study from the United States also pointed out that although bedaquinoline fumarate tablets have a widespread QT interval prolongation, the overall patient tolerance is good and the safety is good.
Sixth, bedaquinoline post-market price and medical insurance policy
The original drug of Bedaquinoline listed in China was developed by Janssen-Cilag International N.V. (Janssen-Cilag International N.V.) in the United States, and its trade name is Sirturo, and the pharmaceutical specification is 100mg/tablet and 188 tablets/bottle (box).
In 2018, with the support of the new anti-tuberculosis drug introduction and protection project, eligible patients in mainland China received a betdaquinoline donation. This initiative not only benefits patients, but also provides more experience for doctors to further apply the drug. From April 2020, the 27 drugs under the national agreement are tentatively designated as outpatient specific drugs and included in the scope of outpatient reimbursement for medical insurance, including bedaquinoline. At present, the reimbursement area is limited, and other channels can be selected.
7. Summary and Outlook
In recent years, various chemotherapy regimens containing bedaquinoline have been used for MDR/RR-TB and XDR-TB, with high success rates and good safety. The clinical application of bedaquinoline is becoming more and more extensive, and the mainland also has some experience in the use of this drug. Through the clinical research project of TMC207-C209 and the promotion of the "Anti-TUBERCULO New Drug Introduction and Protection Project", mainland China has achieved a win-win situation for patients and clinicians. However, the optimal combination of bedaquinoline with other drugs, the combination with new drugs, the use of short-term regimens, the monitoring and prevention of drug resistance, the use of special populations and extrapulmonary tuberculosis, and the efficacy and safety of drugs used for more than 6 months need further research and exploration.
bibliography
Liao Weiming, Yuan Xiaoliang. Research progress in the treatment of multidrug-resistant tuberculosis with bedaquinoline regimen[J]. Chinese Journal of Antituberculosis, Vol. 43, No. 6, 2021, pp. 619-624, ISTIC CA, 2021:Natural Science Foundation of Jiangxi Province.
Shaw Heping. Guidelines for chemotherapy for drug-resistant tuberculosis (2019 Simplified Edition)[J]. China Journal of Antituberculosis, 2019(10).
Tuberculosis Branch of Chinese Medical Association. Expert Consensus on the Treatment of Multidrug-Resistant and Rifampicin-Resistant Tuberculosis in China (2019 Edition)[J]. Chinese Journal of Tuberculosis and Respiratory Disease, 2019, 42(10):733-749.
[4] Ghajavand H , Kargarpour Kamakoli M , Khanipour S , et al. High Prevalence of Bedaquiline Resistance in Treatment-Naive Tuberculosis Patients and Verapamil Effectiveness[J]. Antimicrobial Agents and Chemotherapy, 2019.
[5] Huitric E , Verhasselt P , Andries K , et al. In Vitro Antimycobacterial Spectrum of a Diarylquinoline ATP Synthase Inhibitor[J]. Antimicrobial Agents and Chemotherapy, 2007, 51(11):4202-4204.
[6] Organization W H . Use of Bedaquiline in the Treatment of Multidrug-resistant Tuberculosis[J]. 2013.
[7] Rawal S , Sood R , Mahajan N , et al. Current status and future prospects for tuberculosis. [J]. international journal of pharmaceutical sciences & research, 2010.