No new antibiotic has been developed to fight tuberculosis for several decades. The emergence of more lethal drug-resistant strains of Mycobacterium tuberculosis is now forcing a change in the status quo. The urgency to address MDR TB prompted a fast-track approval of some of these treatments well before the availability of their safety and efficacy data from phase 3 programmes.
The first drug to treat TB in more than forty years, bedaquiline was approved in 2012 by the US FDA as a part of the accelerated approval for use in MDR and XDR TB.
In the following year,. the WHO gave a conditional recommendation to use bedaquiline (BDQ) in MDR TB patients where other standard regimens cannot be designed.
The drug belongs to a new class of drugs called the diarylquinolines which blocks the proton pump for ATP synthase of mycobacteria.
Data from clinical studies have shown an increased risk of death with BDQ treatment. Johnson & Johnson, the maker of the medicine, also warns of QT prolongation with the use of the drug.
Phase 3 studies are ongoing to assess the safety and efficacy of BDQ.
BDQ was introduced at six sites in 5 Indian states under Conditional Access Programme (CAP) in March 2016. In the absence of phase 3 data, the Drug Controller General of India (DCGI) approved the use of BDQ under RNTCP through conditional access.
900 patients have been initiated on a BDQ-containing regimen at 21 sites as of the end of 2017. The programme will expand the usage of BDQ to all states as per their preparedness, according to TB India Report 2018.
Delamanid belongs to a new class of TB drugs called nitroimidazoles. In 2014, the WHO issued interim policy guidance on the use of delamanid (DLM) in MDR-TB regimen in adult patients with pulmonary TB. The drug received approval in Europe, Japan and South Korea in the same year. The WHO extended the use of DLM to children aged 6-17 years in 2016, following a review of data from a 6-month safety, efficacy and pharmacokinetic trial of paediatric patients. These data were also considered to be of very low certainty based on GRADE evidence assessment.
In mid-October 2017, Otsuka Pharmaceutical announced the final results of Trial 213 to the public during the annual UNION World Conference on Lung Health in Mexico.
The phase 3, multicentre, randomized, double-blind, placebo-controlled clinical trial compared two regimens for the treatment of MDR-TB in adult pulmonary TB patients.
The trial data found that the longer MDR-TB regimen, used as the optimised background regimen, had an overall treatment success rate of 81%, much higher than the global value of 54% reported to WHO.
Studies to evaluate the efficacy of DLM in children with MDR TB (Otsuka 233) and paediatric MDR TB HIV patients (Otsuka 232) are underway.
National TB programmes and other stakeholders are advised to only add DLM to a longer MDR-TB regimen when it cannot be composed according to WHO recommendations. When an effective and well-tolerated longer MDR-TB regimen can be otherwise composed, the addition of delamanid can be avoided.
In August 2017, DCGI issued permission to import formulations of DLM (50 mg) tablets to treat pulmonary MDR-TB in adult patients. Accordingly, the guidelines were prepared for use of 400 courses of DLM in 7 states.
Rifapentine, a rifamycin antibiotic, inhibits RNA polymerase in MTB. The drug was approved by the US FDA in combination with isoniazid (INH) for the treatment of latent TB infection (LTBI) in patients two years of age and older at high risk of progression to TB disease in 2014, following a priority review.
Weekly regimen of rifapentine with isoniazid for three months has been found effective in the prevention of active tuberculosis
India’s health ministry may allow the import of rifapentine for the treatment of LTBI, waiving off the local clinical trials requirement, otherwise mandatory for all new drugs to be introduced in India, reports said.
Pretomanid is an experimental bicyclic nitroimidazole-like molecule currently undergoing phase 3 trials. The compound was shown efficacious at doses of 100–200 mg daily in studies conducted on adult patients with pulmonary TB. Also, no evidence of mutagenicity has been detected in genotoxicity studies and no significant cytochrome P450 interactions. This compound has been developed by TB Alliance.
Trials explore new strategies to tackle TB
Clinical trials of several novel drug regimens are currently underway as part of efforts to tackle drug resistance and stop TB infection in its tracks
STREAM (Standardised Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR TB) is an ongoing study supported by USAID. It is a multi-centre international randomized control trial to evaluate shortened regimens for patients with MDR TB.
STREAM Stage 1 is phase 3 study which compares the standard WHO MDR-TB regimen with a 9-month, modified Bangladesh Regimen. The study has been completed and results are pending.
STREAM Stage 2 aims to compare 6 and 9-month bedaquiline-containing regimen against the WHO and Bangladesh regimen in a phase 3 study.
NeXT (New Treatment Regimen for Patients with Multi-drug Resistant Tuberculosis), an open-label RCT of a 6-9-month, injection-free regimen containing bedaquiline, linezolid, levofloxacin, ethionamide/high dose isoniazid and pyrazinamide, is currently in phase 3.
NiX-TB, a phase 3 study of bedaquiline, pretomanid and linezolid in patients with XDR-TB and MDR-TB for 6 months, with an option of 9 months, has been completed.
TB-PRACTECAL (Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s)) is a multi-centre, open label, multi-arm, randomized, controlled, phase 2-3 trial evaluating short treatment regimens containing bedaquiline and pretomanid in combination with existing and re-purposed anti-TB drugs for the treatment of biologically confirmed pulmonary MDR-TB.
IMPAACT 2005 is a phase1/2 study to evaluate the pharmacokinetics, safety and tolerability of DLM in combination with optimised multidrug background regimen (OBR) for MDR-TB in HIV-infected and HIV-uninfected children with MDR-TB. It is currently enrolling non-US participants in Botswana, India, South Africa and Tanzania.
endTB is a phase 3, randomized, controlled, open-label, non-inferiority, multi-country trial evaluating the efficacy and safety of new combination regimens for MDR-TB treatment.
DELIBERATE is evaluating the drug-drug interactions and combined QT effects of bedaquiline and delamanid in a phase 2 programme.
DRAMATIC is a proposed investigational regimen combining two new drugs, BDQ and DLM, with three anti-TB agents of known potency, linezolid (LZD), levofloxacin (LFX), and clofazimine (CF), to provide a shorter, better-tolerated and more effective MDR-TB treatment regimen for persons with fluoroquinolone-susceptible MDR-TB.