Will shorter, safer and more effective TB regimen reach those in need?

Shobha Shukla *

77th National Conference of Tuberculosis and Chest Diseases (NATCON) held in Agra, India

"Patients in India and other countries are falling ill with drug-resistant TB every day. We believe these patients should not have to wait, they need better treatments today – not one or few years down the line. We have the data and strong scientific evidence to show why shorter, safer, more effective regimens to treat drug resistant TB be scaled up programmatically” said Dr Animesh Sinha, Advisor for Tuberculosis at Médecins Sans Frontières (MSF) or Doctors Without Borders.

Yet, as per the Global TB Report 2022, currently only 92 countries are using the shorter MDR-TB regimens. What is more appalling is that of the 1.5 million MDR-TB patients to be treated between 2018-2022 as per targets set at the UN high-level meeting on TB - only 43% could receive any treatment at all till end of 2021. At the same time the burden of drug-resistant TB increased globally with 450,000 new cases of rifampicin-resistant TB in 2021.

Short Regimens to treat drug resistant TB

“Results of the TB PRACTECAL clinical trial (Pragmatic Clinical Trial for more effective, less toxic MDR-TB treatment regimen) show that the all oral 6 month long BPaLM (Bedaquiline, Pretomanid, Linezolid, and Moxifloxacin) regimen was found to be effective in 89% of the patients (regardless of their HIV status) with rifampicin resistant TB of the lungs, as compared to less than 60% efficacy of the almost 24 month long standard of care regimen. Patients on BPaLM also had fewer side effects as compared to those on standard of care”, said Sinha, who was among the experts at the 77th National Conference of Tuberculosis and Chest Diseases (NATCON) held in Agra, India.

Short regimen is cost effective too

Two sub-studies were also done as part of TB PRACTECAL. One sub-study shows that patients who were on shorter regimen had better quality of life than those on standard of care regimen.

The second sub-study shows that shorter regimen is economical for the patient as well as for the service provider. Patients on BPaLM had a much shorter hospital stay and the period of follow up, as well as investigations were drastically reduced, said Sinha. “Patients could get back to their lives - get back to their studies or jobs- much quicker than those who were on standard of care regimen. BPaLM regimen is shorter, effective, safer, less toxic and more economical for patients. There is no reason why it should not be made available at the earliest to everybody who is suffering from drug-resistant TB.”

BPaL regimen

The ZeNix study showed that the all oral 6 month long BPaL (Bedaquiline, Pretomanid, and Linezolid) regimen had 89% treatment efficacy in people with extensively drug-resistant TB (XDR-TB) and treatment intolerant or non responsive MDR-TB of the lungs.

“Those who do not have fluoroquinolone resistance can receive BPaLM regimen and those who are later found to have fluoroquinolone resistance, can be given BPaL regimen for the rest of their treatment”, explains Leena Menghaney of MSF Access Campaign.

Toxicity related to Linezolid, one of the medicines used in these regimens, is of concern. But reducing the dosage and duration of linezolid has made the regimens more patient friendly and less toxic, without affecting their high efficacy.

“We found in TB PRACTECAL that linezolid was better tolerated in the shorter regimen arms compared to the standard of care regimen. When Linezolid is taken in smaller doses for shorter duration it is better tolerated and effective,” said Sinha.

In its latest 2022 updated guidelines for the treatment of MDR-TB, WHO has recommended programmatic use of the shorter, safer and more effective all oral BPaLM and BPaL regimens in place of the existing longer regimens.

The BPaL regimen has got approval at the technical and policy level and India’s National TB Elimination Programme (NTEP) is in the process of introducing it within its programme, said Dr KS Sachdeva, Director of South East Asia Regional office of the International Union Against Tuberculosis and Lung Disease (The Union), and former Deputy Director General of India’s Central TB Division, Ministry of Health and Family Welfare, Government of India.

“An ongoing ICMR study is evaluating the BPaL regimen in many centres across the country, including my hospital. Preliminary results are expected to be shared in 2024 and by 2025 we will have the final results to be able to roll out this regimen”, informed Dr Surya Kant, Head of the Respiratory Medicine Department at King George’s Medical University (KGMU).

Meanwhile, India is already using bedaquiline and delamanid based 9-11 months long, all oral regimens to treat drug-resistant TB. The uptake of this shorter treatment regimen is fairly good and it is well entrenched in the National TB Elimination Programme, said Dr Sachdeva.

However, he cautioned against doing away completely with the longer duration treatment. “MDR-TB is complex to treat and we have close to 10-15 drugs for it. We have to ensure that the patient is sensitive to all the drugs that he/she is given. If there is a varying sensitivity pattern and they are sensitive to a lesser number of drugs, then we have to design a regimen that best suits their clinical profile. So some MDR-TB patients may still need to be put on the longer all oral regimen, even after the short regimen is introduced. We should not do away with the longer regimen. Also, even if there is a very small number of patients who need injectables and are not tolerating the oral replacement therapy, we should not totally junk the injectable drugs and they should be kept in reserve. We do not want any patient to suffer any chronic morbidity or mortality just because there is no option to treat them with other drugs”, opined Dr Sachdeva.

Menghaney laments that while we are on the cusp of breakthrough for adults with short oral regimens, children with TB have been neglected and are at the bottom of hierarchy. While we have child friendly formulations of linezolid based regimens, we do not have generic versions of paediatric formulations containing Delamanid. We have to replicate adult regimens for children faster. We cannot leave them behind.

Menghaney’s concerns are real and corroborated by the poor progress made in achieving the target set at the "UN high-level meeting on TB" of putting 115000 children globally on MDR-TB treatment during 2018-22. Only 15% of this target was met by 2021.

Match optimism with actions on the ground

India remains one of the top 30 high TB burden countries and one of the 10 countries that have a high burden of all three: TB, HIV-associated TB and MDR-TB and rifampicin-resistant TB. The rate at which new infections of TB are declining in India every year is low. But the Indian government has promised to end TB by 2025 - five years ahead of the global target to eliminate it by 2030.

“India has set ambitious targets. Now, we need to match this optimism with our actions on the ground, so that these targets are reachable. Shorter regimens will help not just India but all countries in ending TB and delivering on SDGs also because we will be spending resources wisely as this regimen makes economic sense for the patient and service providers – which means we can treat and serve more patients – or use those resources to improve diagnostic coverage”, says Sinha.