In Desperate Need

Madhukar Pai

Antimicrobial resistance (AMR) is rapidly emerging as a major global health challenge. Drug-resistant tuberculosis (DR-TB) is a perfect example of the threat posed by AMR. The most common form drug-resistant TB is multi-drug resistant TB (MDR-TB), which means that TB bacteria are resistant to two of the best first-line antibiotics - isoniazid and rifampicin. Globally in 2015, WHO estimated that an estimated about half a million people developed MDR-TB, with India, China and Russia accounting for nearly half of these cases. Even children are impacted by DR-TB, with recent estimates suggesting that MDR-TB in children may be far more prevalent than previously understood.

Extensively drug-resistant (XDR-TB) strains are resistant to at least four of the core anti-TB drugs, and XDR-TB has been reported by over 100 countries. About 10% of people with MDR-TB have XDR-TB. Some studies have also reported totally drug-resistant strains of TB, resistant to all antibiotics tested. This is a TB ‘superbug’ that is virtually untreatable and takes us back to the sanatorium era, where we had very little to offer patients with TB, except for bed rest and sun light.

Drug-resistant TB is a nightmare for patients, families, and doctors. Patients have to endure a prolonged (up to 2 years) and toxic treatment with multiple drugs (more than 14000 pills, as tall as a 30-storey building, if you stacked the pills end to end!), including painful, daily injections for 6 months. Deepti Chavan was diagnosed with TB at the age of 16, after weeks of experiencing symptoms. In all, she endured six years of toxic drug therapy, including 400 painful injections, and had much of her affected lung removed to recover from a severe form of drug-resistant TB.

Check out these pictures: the picture on the left shows a miserable looking me, with all the pills and injections I would have to endure, if I had DR-TB.

Frequently, treatment for DR-TB includes the use of injectable drugs (eg, capreomycin, kanamycin). However, these drugs result in hearing loss in up to 50% of patients. To understand the profound impact of hearing loss on individuals, please watch this TEDx talk by Nandita Venkatesan, a TB survivor from India. Stories of people like Deepti and Nandita show the devastating impact of DR-TB and the desperate need for less toxic and safer therapies.

Enduring long therapies, however, does not ensure good outcomes. One in two patients with drug-resistant TB die because of it. Treatment of DR-TB is also very expensive because of the high cost of second-line TB drugs. So, if there is one area of TB care that is in desperate need of innovation, it is treatment of DR-TB. 

Thanks to the work of TB Alliance, Bill & Melinda Gates Foundation, and several partners, there is some hopeful news emerging. In a trial called NIX-TB, TB Alliance and partners are evaluating a dramatically shorter, 6-month, oral drug combination for XDR-TB (see the happier looking me in the pictures above, on the right side!).  

Nix-TB is an ongoing open label study in South Africa of bedaquiline (by Janssen Pharmaceuticals), pretomanid (by TB Alliance) and linezolid given orally for 6 months. Preliminary trial results, presented at the CROI conference in Feb 2017, show very promising results. 34 have completed the 6 months of therapy with the Nix drug regimen and 20 have been followed to the primary endpoint at 6 months after treatment. All surviving patients were culture negative by 4 months, with 74% negative at 8 weeks.

These results are very promising and exciting and make me optimistic for the future. For too long, we have allowed DR-TB patients to suffer with horrible, painful, long therapies. It is time for the TB field to innovate rapidly and come up with better solutions! Nix-TB study is a welcome first step toward establishing a truly “universal” treatment, a regimen to which there is no pre-existing resistance and could therefore treat any type of TB. According to TB Alliance, if the regimen tested in Nix-TB is successful and safe in XDR-TB, the study will expand to include people with MDR-TB. TB Alliance is also working on another drug regimen with great promise - BPaMZ (Bedaquiline + Pretomanid + Moxifloxacin + Pyrazinamide). Regimens like Nix and BPAMZ could significantly improve TB control efforts globally. 

As new TB drugs, as well as shorter and better regimens are emerging, high TB burden countries have to gear up for rapidly scaling up such innovations. Unfortunately, there is a big gap between innovation and access in TB. This must change! So, countries must make plans and anticipate the introduction of new regimens, pave the way for their rapid regulatory approval, and offer early access to their patients who need need therapies. After all, as we argued in a paper recently, TB innovations mean little, if they cannot save lives. 

Disclosure: I serve on the Access Advisory Committee of TB Alliance. I have no financial interests with any drug or pharmaceutical company.

Originally published in Nature Microbiology.