|CHECK AND CHECKMATE - THE NEW MOLECULAR CHESS
|Year : 2017 | Volume
| Issue : 2 | Page : 108-110
Bedaquiline and delamanid: Sharing the indian experience
Jai B Mullerpattan, Zarir F Udwadia
Department of Respiratory Medicine, PD Hinduja National Hospital and Medical Research Center, Mumbai, Maharashtra, India
|Date of Web Publication||30-Nov-2017|
Zarir F Udwadia
Department of Respiratory Medicine, PD Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai - 400 016, Maharashtra
Source of Support: None, Conflict of Interest: None
Currently, India is home to the highest number of multi-drug resistant tuberculosis (MDR-TB) patients in the world. Until now, MDR-TB was being treated with repurposed drugs which are toxic and are required to be given for up to 2 years. Two new oral anti-TB drugs, bedaquiline and delamanid have received approval in 2012 and 2014 respectively. While presenting the pharmacology, evidence of efficacy, WHO recommendations, current status of access as well as future directions regarding these two novel anti-TB agents, this paper delves into the India narrative recounting the short clinical experience thus far.
Keywords: Bedaquiline, delamanid, multi-drug resistant tuberculosis
|How to cite this article:|
Mullerpattan JB, Udwadia ZF. Bedaquiline and delamanid: Sharing the indian experience. Astrocyte 2017;4:108-10
| Introduction|| |
There are an estimated 580,000 patients with multi-drug resistant tuberculosis (MDR TB) globally with about 130,000 of these in India alone. Almost 1.7 million people died due to TB globally with about a third of them in India. Treatment for MDR TB involves prolonged treatment for 2 years with repurposed drugs that are both costly and toxic. Bedaquiline is the first new anti TB drug approved almost 40 years after rifampicin. This was soon followed by Delamanid. Studies have shown increased culture conversion while using these drugs in combination with an optimised background regimen. However, access to these drugs is proving to be a challenge in many parts of the world including India. Results from ongoing studies regarding combination of these drugs, all oral-shortened regimens for MDR-TB as well as validity of use of these drugs in special populations such as children are keenly awaited.
| Bedaquiline|| |
Bedaquiline, a diarylquinoline, is a mycobacterial ATP synthase inhibitor. It is the first new anti TB agent in almost 40 years after rifampicin. Initial phase 2 study  showed that addition of bedaquiline to standardized regimen led to decrease in the time to sputum conversion as well as increased proportion of patients who had sputum culture conversion (48% vs. 9%). The phase 2b study  showed that addition of bedaquiine to a background regimen showed a reduction in time to culture conversion from 125 to 83 days. Cure rates were 58% in the bedaquiline group compared to 32% in the placebo group.
Bedaquiline received accelerated USFDA approval on 31st December 2012. It has been approved for administration for 24 weeks. The recommended dose is 400 mg daily for 2 weeks followed by 200 mg thrice a week for 22 weeks. The half-life of bedaquiline is 5.5 months.
Bedaquiline is generally well tolerated. It may cause prolongation of QTcF intervals and this needs regular monitoring. QtcF intervals should be below 450 ms before starting bedaquiline and should not exceed 500 ms during treatment.
Pyrazinamide may potentiate action of bedaquiline. Clofazimine has cross resistance with bedaquiline.
WHO guidance recommends bedaquiline be used in cases of MDR TB where an effective regimen with 4 drugs cannot be designed or when there is additional fluoroquinolone resistance. However, bedaquiline should not be added to a failing regimen. It should be used cautiously in patients infected with HIV. QTcF intervals should be closely monitored. Caution should be exercised while using other drugs that may increase QTc intervals such as moxifloxacin and clofazimine. At present, bedaquiline is approved in patients aged 18 years with pulmonary TB.
Access to bedaquiline
Over 800 patients received bedaquiline through the compassionate use program. In India a total of 100 patients have received bedaquiline via the compassionate use program. Of these, 40 patients were at a single centre at Hinduja Hospital Mumbai, which showed a culture conversion of 65% when bedaquiline was used in a cohort of PreXDR and XDR TB patients who had failed earlier individualized treatment. The time lag from application to receiving bedaquiline was almost 45-60 days. Bureaucratic bottle-necks have meant around 65 courses of bedaquiline might expire without getting to patients.
Apart from compassionate use, bedaquiline has also been made available through National TB program.
Over 10,000 patients have received bedaquiline through various national programs. In India, about 567 patients have received bedaquiline via the conditional access program. The conditional access program was started in 6 centers in 5 cities across India. The government plans to scale up access to bedaquiline across 143 centers with about 3000 courses of bedaquiline.
| Delamanid|| |
Delamanid, a nitro-dihydro-imidazooxazole derivative, is a new anti TB medication that inhibits mycolic acid synthesis  and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis (MTB).
Assessment of the 14-day early bactericidal activity of delamanid against MTB in patients in South Africa showed that delamanid administered at doses of 200 and 300 mg daily resulted in a decrease in the sputum MTB burden that was similar to that of the potent antituberculosis drug rifampin in previous studies of early bactericidal activity.
In a multicentric randomized controlled trial  among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P = 0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P = 0.04).
Delamanid was approved for use in Europe and Japan in 2014. The recommended doses are 50 mg twice a day for 24 weeks for weight 20 kg to 34 kg; and 100 mg twice a day for 24 weeks for weight over 35 kg. For weight less than 20 kg expert opinion should be sought. The main side effects are headache, nausea and dizziness. QTcF intervals may be prolonged by delamanid.
WHO recommends that delamanid may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB (conditional recommendation; very low confidence in estimates of effect). While the WHO recommends that delamanid be used in patients more than 18 years old, based on recent pharmacokinetic/pharmacodynamic data, experts have recommended that delamanid can be used in patients more than 6 years of age provided they weigh more than 20 kg.
It should be used with caution in patients with HIV, liver disease, and is contraindicated with QTcF >500 ms.
The WHO principles of an adequate background regimen should be followed. There should be regular monitoring and pharmacovigilance. Informed consent of the patient should be taken.
Access to delamanid
Delamanid is marketed by Otsuka. As of September 2017, 688 patients were put on delamanid under programmatic conditions. 3238 courses of delamanid were also ordered from Global drug fund. Only 51 patients have used delamanid in India, that too on a compassionate use basis.
Otsuka has not yet launched Delamanid in India despite getting a patent in 2011. Activists have been asking the Indian government to force Otsuka to bring the drug to India. Otsuka has now licensed Mylan to market the drug in India and South Africa. A conditional access program plans to enroll 400 patients on delamanid in the next 6 months.
Combined bedaquiline and delamanid use
The WHO does not recommend combined use of bedaquiline and delamanid due to lack of data regarding the same. A recent report of 5 patients with XDR TB with combined use of the two drugs showed 1 cure, 3 culture conversions and 1 death. The drugs were well tolerated with no life-threatening arrhythmias.
Prolonged use of bedaquiline
While the WHO recommends use of bedaquiline for 6 months, reports of prolonged bedaquiline use have shown favorable outcomes with no significant increase in toxicity. 45 patients with MDR TB had received bedaquiline for median of 361 days. While 11% had QTcF >500 ms, there were no life-threatening arrhythmias.
| Future Studies|| |
Bedaquiline is being studied as part of Stream 2 trial  to replace kanamycin in the short course WHO regimen to create an all oral regimen. At the same time, the Phoenix trial  is looking at the efficacy of delamanid vs isoniazid in preventing active disease among MDR TB contacts. The results of these two studies may well revolutionize the management of drug resistant tuberculosis.
Randomized controlled trials looking at combinations of delamanid and bedaquiline in order to achieve shortened oral regimens for drug resistant tuberculosis are urgently required.
| Conclusions|| |
Bedaquiline and Delamanid are the gen-next antitubercular drugs which have shown great promise in clinical trial as well as field conditions. However, access to these drugs is still a challenge. Considering the large burden of MDR-TB in India, greater access to both these drugs is urgently required. Further studies regarding combinations of these drugs and the use of these drugs in special populations such as children is keenly awaited.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
World Health Organization. Global Tuberculosis Report 2017. Geneva: World Health Organization; 2017.
Andries K, Verhasselt P, Guillemont J, Göhlmann HW, Neefs JM, Winkler H, et al.
Adiarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis
. Science 2005;307:223-7.
Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, et al.
The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N
Engl J Med 2009;360:2397-405.
Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al.
Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N
Engl J Med 2014;371:723-32.
Hartkoorn RC, Uplekar S, Cole ST. Cross-resistance between clofazimine and bedaquiline through upregulation of mmpL5 in Mycobacterium tuberculosis
. Antimicrob Agents Chemother 2014;58:2979-81.
World Health Organization. The use of bedaquiline to treat MDR-TB: Interim policy guidance. Geneva: World Health Organization; 2013.
Udwadia ZF, Ganatra S, Mullerpattan JB. Compassionate use of bedaquiline in highly drug-resistant tuberculosis patients in Mumbai, India. Eur Respir J 2017;49. pii: 1601699.
Barry PJ, O'Connor TM. Novel agents in the management of Mycobacterium tuberculosis
disease. Curr Med Chem 2007;14:2000-8.
Diacon AH, Dawson R, Hanekom M, Narunsky K, Venter A, Hittel N, et al.
Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. Int J Tuberc Lung Dis 2011;15:949-54.
Gler MT, Skripconoca V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al
. Delaminid for multi-drug resistant pulmonary tuberculosis. N
Engl J Med 2012;366:2151-60.
Available from: http://www.sentinel-project.org/wp-content/uploads/2016/06/Sentinel_NewDrugs_Webinar.pdf. [Last accessed on 2017 Nov 02].
World Health Organization. The use of delaminid in the treatment of multi-drug resistant tuberculosis: Interim policy guidance. Geneva: World Health Organization; 2014.
Guglielmetti L, Jaspard M, Le Dû D, Lachâtre M, Marigot-Outtandy D, Bernard C, et al.
Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur Respir J 2017;49. pii: 1601799.
Maryandyshev A, Pontali E, Tiberi S, Akkerman O, Ganatra S, Sadutshang TD, et al.
Bedaquiline and delamanid combination treatment of 5 patients with pulmonary extensively drug-resistant tuberculosis. Emerg Infect Dis 2017;23:1718-21.
Available from: https://www.newtbdrugs.org/pipeline/trials/stream-trial-stage-2. [Last accessed on 2017 Nov 02].
Available from: http://www.tbonline.info/posts/2017/1/13/resist-tb-webinar-phoenix-trial/. [Last accessed on 2017 Nov 02].