Drug-resistant Tuberculosis – A Looming Crisis

Sir, Tuberculosis (TB) is a preventable and curable infectious disease caused by the bacteria Mycobacterium tuberculosis. It affects the lungs but can also spread to other parts of the body. TB is transmitted through the air when an infected person coughs, sneezes or speaks. The Global TB Report 2022 from the World Health Organisation (WHO) estimates that 10.6 million people globally contracted TB in 2021, and 1.6 million people died from it.[1] In many low- and middle-income nations, TB is a serious public health issue because it is frequently linked to deprivation, malnutrition and crowded living conditions. People with HIV are 18 times more likely to develop TB than those without HIV, making them particularly vulnerable to the disease.[2] According to the WHO’s Global TB Report 2022, Asia accounted for 59% of all new TB cases and 63% of all TB deaths in 2021. In Asia, this translates to around 6.4 million cases of TB and 1 million related deaths in 2021.[1] Amongst all communicable diseases that impact the productive age group in the WHO Southeast Asia Region (SEAR) countries, TB is the biggest source of disability-adjusted life years lost amongst residents of the region.[3] There won’t be global TB elimination without TB elimination in SEAR, and drug resistance is a significant obstacle to the elimination of TB.[4] Drug-resistant TB is brought on by either the spread of Mycobacterium tuberculosis strains that are already resistant or by the inadequate treatment of susceptible strains. Treatment of drug-resistant TB is more expensive, is time-consuming and has poor outcome than drug-susceptible TB treatment.[5] If a TB infection is caused by a colony of bacteria that are resistant to both isoniazid and rifampicin, first-line anti-TB drugs, the infection is said to be a case of multidrug-resistant TB (MDR TB). Today, about 4.1% of TB cases in the world are from MDR TB bacteria. This equated to about 450,000 MDR TB infections in 2021, out of which 191,000 led to the death of the patient. India is especially vulnerable in this regard. According to the WHO, 26% of MDR TB cases in 2021 were reported in India, the highest in any country in the world.[1] The treatment success rate for MDR/isoniazid and rifampicin-resistant TB was reported as 59% globally in 2020, compared with 86% for new and relapse drug-susceptible TB. According to the WHO, only 1.5 million of the estimated burden of MDR or rifampicin-resistant TB patients were enrolled in treatment in 2020. This highlights a capacity gap for diagnosing and treating DR-TB, which results in the continued spread of drug-resistant strains.[6] During the 20 years from 1944 to 1964, not only were 11 medications found that could kill M. tuberculosis, but also the first randomised clinical trials in the annals of medicine were carried out. These studies demonstrated that to successfully treat TB, two key guidelines must be followed: (i) combining medications will prevent M. tuberculosis from acquiring drug resistance and (ii) prolonged treatment will not only cure the patient but also stop illness relapses.[7] Given that there was full susceptibility to these treatments, the aforementioned clinical trials demonstrated that it was important to combine at least 2–3 medications to prevent the emergence of resistance. This axiom, which was acknowledged as true several decades ago, cannot be accepted today because (i) it is likely that a sizable proportion of patients have developed resistance to one or more of the medications employed and (ii) some of these medications may not be very effective against M. tuberculosis. Therefore, operationally and for ease of management, the association of 3–4 drugs, depending on their activity, has been approved for the treatment of all TB cases.[8] Rifampicin is a rifamycin derivative that initially became available in 1972 to treat TB. It is one of the most powerful anti-TB medications, and along with isoniazid, it forms the foundation of the multidrug approach to treating TB. Rifampicin is active against growing and non-growing (slow metabolising) bacilli.[9] The mode of action of rifampicin in M. tuberculosis is by binding to the β-subunit of the RNA polymerase, inhibiting the elongation of messenger RNA. The majority of rifampicin-resistant clinical isolates of M. tuberculosis harbours mutations in the rpoB gene that codes for the β-subunit of the RNA polymerase. As a result, conformational changes occur that decrease the affinity for the drug and result in the development of resistance.[10] Isoniazid was first made available as an anti-TB drug in 1952, and it continues to serve as the foundation for the treatment of TB along with rifampicin. Isoniazid, in contrast to rifampicin, only acts against actively replicating bacteria that are metabolically active. Isoniazid, also known as isonicotinic acid hydrazide, is a prodrug that must be activated by the catalase/peroxidase enzyme katG, which is encoded by the katG gene.[11] Isoniazid acts by inhibiting the synthesis of mycolic acids through the NADH-dependent enoyl-acyl carrier protein-reductase, encoded by inhA.[12] Gene mutations in the katG and inhA or its promoter region are linked to the two main molecular mechanisms of isoniazid resistance.[13] As per a recent study, high-level isoniazid resistance as well as cross-resistance to ethionamide were induced by a mutation in the inhA regulatory area together with a mutation in the inhA coding region.[14] A far more severe form of TB called ‘extensively drug-resistant TB’ (XDR TB), first identified in 2006, also exists. This disease is resistant to various drugs in addition to isoniazid and rifampicin, including linezolid, bedaquiline and at least one fluoroquinolone. 0.29% of all TB cases in the world are of XDR TB. This may seem like a small number, but this percentage will only increase as drug resistance becomes more widespread amongst TB bacteria. Funding initiatives to combat TB would appear to be a wise investment given that an estimated 1.6 million people die each year from this preventable infectious illness, but funding information for TB paints a different picture. Comparatively, $20 billion was spent on HIV, while an estimated $10.9 billion was spent on TB in 2017.[15] The study conducted by Silva et al.[16] serves as a stark warning of the severe financial risks associated with continuing to ignore TB. The authors project that 31.8% million people will die from TB-related causes between 2020 and 2050, resulting in $17.5% trillion in economic losses. This estimate is based on a study of yearly mortality risk increases for 120 countries. In order to prevent 23.8% million deaths and save $13.1 trillion in expenses, TB mortality must be decreased by 90% by 2030 (as stated in Sustainable Development Goals). By 2020, the WHO end TB initiative aims to end the catastrophic costs that TB patients and their families endure. According to data, the majority of households incur costs equating to more than half their annual income over the course of TB illness.[17] However, little has been done to date to cut patient-level expenses, and the 2020 objective has not been met, with an estimated 49% of TB patients still having to face catastrophic costs. As most countries do not yet have systems in place to track progress towards this goal, even this high number is probably an underestimate. Additional costs, both social and psychological, can occur due to discrimination against those infected with TB and members of their households. Family and friends may reject TB patients, they may receive less social support during treatment or they may lose their jobs. The costs of discrimination are both psychological and economic. Discrimination, whether experienced or expected, has been found to be associated with increased anxiety and depression and lower life satisfaction, as well as with higher unemployment and lower income. In some developing countries, discrimination against TB sufferers has taken particularly damaging forms, such as divorce or lowered prospects of marriage. Discrimination against those suffering from TB also has epidemiological consequences. Social support for the patient has been found to be critical to adherence to treatment, without adherence to treatment, the likelihood of a cure is lower, relapse and death are more likely and further transmission of the disease occurs. Current medications for TB may be largely effective for the present, prudence and good sense dictate that we prepare for the time when current TB medications begin to fail on a large enough scale, something that will inevitably happen as these drugs are used over and over. Without timely steps being taken, this threat could severely impact public health and well-being. At present, we take for granted the profound benefits that come with living in the antibiotic era and remain blissfully unaware of the dangers of antibiotic resistance and of the magnitude of the problems that it can cause, especially in the case of a disease such as TB. A few measures seem self-evident. Rigorous campaigns need to be launched to combat the injudicious use of TB drugs, making sure that they are used only when necessary and preventing their injudicious consumption. It must be emphasised that we must continue to sustain the human scientific endeavour, which requires governments, universities and pharmaceutical companies to allocate resources towards drug research. The development of novel antibiotics must outpace the expansion of drug resistance for us to stand a chance at defeating not just TB but also all bacterial infections. No matter how effective and promising drugs such as bedaquiline and delamanid may seem, they too will not last forever. A steady stream of new options must be kept flowing as new variants of bacteria keep emerging. In sum, the emergence of drug-resistant forms of TB is a pressing issue which warrants urgent attention. At the end of the day, the responsibility of preventing the further evolution and propagation of this disease falls on the present generation. We must ensure, through collective effort, that the decreasing trends in TB infections observed over the past few decades are maintained, and that the emergence of drug-resistant forms of TB is controlled. As a species, we have managed to control and overcome diseases which were, at one time or another, considered insuperable. A collective effort of all nations and peoples can put an end to the TB epidemic as well. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.