Introduction

In India, tuberculosis (TB) is a serious public health concern with 2.42 million cases were reported in 2022, an increase of 13% from 2021, which indicates the highest number of cases ever reported in a single nation.(1–8) The bacterium that causes TB, Mycobacterium tuberculosis, has undergone genetic mutations over time, leading to drug resistance and the emergence of novel variants that present significant obstacles to the control or management of the TB epidemic.(1,3,4,8–14) Drug-resistant tuberculosis (DR-TB) is primarily classified into two categories: multidrug-resistant TB (MTB) and extensively drug-resistant TB(XDR).(3–5,9,12,14–16) The MDR-TB refers to TB strains that are resistant to at least two of the most powerful first-line drugs, isoniazid and rifampicin.(3,8,12,14) The patient with XDR-TB, on the other hand, is resistant to isoniazid, rifampicin, and at least three of the six main classes of second-line drugs (e.g., aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserines, and para-aminosalicylic acid).(12,15) The India TB Report divides DR-TB into four categories based on the type of drug resistance (Fig. 1).(4,17) In India, the DR-TB cases have risen from 2012 by 17402 to 91841 in 2022 (Fig. 2).(7) However the incidence of DR-TB incidence has significantly increased since 2012, but get slightly decline between the COVID-19 waves that started in 2020 (72787 Cases) and 2021 (70787 cases) (Fig. 2).(7,18–21) Numerous factors, including a history of TB treatment, limited access to diagnostic and treatment facilities, lost follow-up, co-infection with HIV infection, subpar healthcare infrastructure, insufficient funding for TB control programmes, and ineffective policies and strategies, have been associated with the emergence of DR-TB in India.(3,10,12,22,23)

Fig 1: Different types of DR-TB are divided into four categories, as described by the India TB Report 2023.

Fig 2: Year-wise reported incidence of different types of DR-TB in India.

Demography and Drug-Resistant Tuberculosis

The prevalence of DR-TB varies by region, age, and gender, according to a several studies carried out in India among various populations.(1,2,6,8,9,12–14,22–28) Men are 3.5 times more likely than women to be exposed to the risk of developing DR-TB because of their frequent drinking and smoking habits. It has been noted that DR-TB risk factors vary by gender.(6,24,26–29) Additionally, Maharashtra, Gujarat, and Uttar Pradesh accounted for 48% of all cases of DR-TB in the country in 2022.(7) In comparison to other age groups, DR-TB is becoming more common in economically active age groups (18–54 years).(1,6,8,9,14,16,22–29) As a result of the drug regimen used to treat DR-TB being linked to a higher risk of treatment failure, relapse, and mortality, which manifests in higher rates of morbidity and mortality and also reported to have high risk of developing DR-TB, particularly in young children and pregnant women.(1,2,12,15,26,30) One of the main reasons among children of pediatric age for the development of DR-TB is close contact with DR-TB patients. (6,7,13)

Poverty and drug resistance are major interconnected challenges that significantly impact the fight against TB in India. Patients with DR-TB often belong to lower or middle socioeconomic classes and face various socio-economic challenges.(22–27,29) They are more likely to be married, come from joint households (i.e., with more than four individuals), and have limited education, with the majority having only a high school attainments.(22–27,29) These people frequently live in crowded rural areas, use traditional smoke appliances to cook (i.e., Chulha), and work as labourers.(22–27,29) Their socioeconomic status, combined with a lack of knowledge about TB treatment, puts them at a higher risk of developing DR-TB.(23,25–27,29) Furthermore, poverty exacerbates the problem by resulting in poor nutrition, overcrowding, and a lack of education and awareness, all of which weaken the immune system and increase vulnerability to TB infection and the development of DR-TB.(22–26,28,29)

Objective

The main goal of this in-depth review study is to evaluate and comprehend the DR-TB epidemic's precarious situation. The goal of the study is to examine the difficulties encountered across India, such as the demographics of those affected, the methods used for diagnosis and treatment, and the policies and programmes currently in place for the control of DR-TB. The present study also aims to offer insightful information on the epidemiology of DR-TB, efficient clinical management techniques, and public health approaches for addressing the burden of DR-TB in India.

Methodology

Utilizing a wide range of international and national electronic databases, including prestigious sources like BMC journals, the Directory of Open Access Journals (DOAJ), Google Scholar, JSTOR, PubMed, PLOS ONE, ResearchGate, Science Direct, and the Government Database, a thorough systematic diagnosis and literature review were meticulously carried out. The carefully selected search terms "drug-resistant tuberculosis in India," "comorbidities associated with DR-TB," "treatment challenges in DR-TB," and "DR-TB diagnosis challenges" were used to ensure a thorough examination of the literature that was already in existence. Furthermore, pertinent technical reports and government databases were carefully identified and assessed while strictly adhering to predetermined inclusion criteria to uphold the results' integrity and reduce bias (Fig. 3). Also, duplicate scientific papers yielded from different search engines were excluded. The lengthy process ended with the (N=37) downloading of the entire manuscript, which included both the abstracts and the full-length manuscripts. This allowed for the interpretation, revision, and eventual completion of this comprehensive review article.

Fig 3: Steps to select the manuscripts and complete this comprehensive review article.

Consequences of Drug-Resistant Tuberculosis

Early TB detection enables the development of an effective treatment regimen, lowers the risk of future drug resistance, and limits the spread.(5,7,14,18–21,31) However, due to the emergence of DR-TB, there are several problems with treating TB, such as the cost of care, a lack of diagnostic tools and laboratories, a higher risk of transmission, newly identified M. tuberculosis strains, ongoing mutations in this bacteria, social stigma and discrimination, social and economic issues, as well as other related health issues.(2,8–10,12,28,30,32) The use of additional therapies, such as second-line therapies and injections, which are connected to more detrimental side effects than conventional TB treatment, is also one of the emerging causes of DR-TB. (2,30) According to Shah et al. (2), Husain et al. (30), and Kumar et al. (33), India contributed to over one-fourth (26%) of the global burden of DR-TB (in 2022), underscoring the disease's rising prevalence and the difficulties encountered in implementing the updated National Strategic Plan, which aims to eradicate TB by 2025.(2,5,7,30,33) Contrarily, DR-TB therapy lasts longer than 24–48 months compared to drug-sensitive TB, making it more difficult, and expensive for low- or middle-income families to manage.(2,15,17,28,30,32) Due to the highly contagious nature of DR-TB, patients must also be isolated for longer periods of time. Additionally, no close contacts should be present, as this could increase the risk or vulnerability of the situation.(15,17,28) The fact that patients and caregivers experience social stigma and prejudice while undergoing DR-TB therapy is one of the key issues brought up by numerous research investigation, primarily because of societal misunderstandings, mistrust, misconceptions, and myths.(2,12,28) The majority of DR-TB patients experience social problems and feel helpless because of their poor socioeconomic status and the prolonged treatment of DR-TB, which exacerbates their psychiatric comorbidities and makes treatment more difficult.(15–17,28,29) The primary causes of psychiatric comorbidities among DT-TB are disease duration and literacy among the vulnerable and caregivers.(28,32)

Comorbidities associated with Drug-Resistant Tuberculosis

The TB epidemic with associated comorbidities is vulnerable over time and has challenging consequences and situations for diagnosis and treatment, which eventually get mutated into DR-TB.(1,15,16,28,29) Undernutrition, HIV, diabetes, alcohol, and tobacco are major and significant associated comorbidities among TB patients that have a higher odds of emerging or developing DR-TB.(1,15,16,28,29) These comorbidities compromise the immune system, increase the risk of treatment complications, and contribute to the development of drug resistance. In addition to the complexities of managing DR-TB, patients suffering from comorbidities and vice versa complicate overall health outcomes.(1,15,16,28,29)

Undernutrition

Nutrient intake must be appropriate to promote normal development, growth, and overall health.(5,7,18–21) One of the most pressing problems continues to be undernutrition, which affects 663 million people worldwide. (5) A few of the significant contributors to undernutrition include poverty, inadequate infant feeding and care practices, poor maternal nutrition and health, and recurrent illnesses.(5,7) Undernutrition is a significant factor that amplifies the vulnerability of TB patients to DR-TB and contributes to delayed treatment, ultimately result in mortality. (1,14) This is demonstrated by the fact that India ranked 107th out of 121 nations in the Global Hunger Index in 2022. (5) Additionally, nutritional deficiencies can lead to stunted growth, weakened immune systems, cognitive impairments, and an increased risk of TB.(1,14) Working with TB patients during treatment is more challenging and difficult because of undernutrition, which makes it difficult for the body to maintain a strong immune system.(1,7,14) It is difficult for the National Tuberculosis Elimination Programme (NTEP) to manage this dual burden in addition to the side effects of DR-TB treatment because, according to the India TB Report, a total of 7.38 lakh TB patients are malnourished.(1,14) In a similar vein, a large body of research indicates that DR-TB is brought on by a number of factors, such as weight loss, a BMI of less than 18.5 kg/m², a decrease in appetite, and issues with food absorption during protracted and difficult TB treatment. (1,7,14,27)

HIV

Human immunodeficiency virus (HIV) is a major global public health issue with 40 million cases worldwide, where India ranks in third place with 24 lakh cases of people living with HIV.(5,7,16,34) However, HIV is a causative agent of acquired immune deficiency syndrome (AIDS), which affects directly the body's immune system and makes it prevalent to get sick from diseases like TB, which is one of the most dreadful viruses ever because there is no cure for HIV infection.(5,15,16,25,26,29,31,35) The most common way of transmitting HIV is through unprotected sex or through the exchange of body fluids like blood, breast milk, semen, and vaginal fluid.(5,7,16,35) Conversely, HIV infection gets worse when it gets associated with diseases like TB and increases the risk of ramifications that lead to DR-TB.(5,14,15,25,26,29,31,35) Several studies revealed that HIV-TB infection is dominant in males, with an average age group of about 30–40 years and a higher frequency of drug resistance among HIV-TB patients.(5,7,16,18–21,25,26,29,31,35) In 2022, the India National AIDS Control Programme (NACP) and the NTEP monitored 37578 total HIV/TB cases.(7)

Alcohol

Worldwide, drinking alcohol has caused major negative health effects for decades and has become a common behavior and way of life.(5,7,18–21) The National Family Health Survey (NFHS-5, 2019-21) in India found that alcohol usage has had a substantial impact on people of all ages and genders, increasing societal and personal problems, especially in rural areas. In addition, there are 160 million alcohol users in the country who consume billions of liters of alcohol annually, with the percentage of users continuously rising each year.(5,7,34) Contrarily, numerous studies have shown that alcohol use disorders and TB worsen the illnesses and constitute a dual burden, which makes things critical and more complicated over time by causing mutation which increases morbidity and mortality, and ultimately leading to DR-TB.(14,29) Ramifications may occur for people with DR-TB who continue drinking while receiving treatment.(25,26,29) Additionally, due to a lack of social support, divorced or widowed TB patients are more likely to experience depression and anxiety, which can lead to alcohol use. This makes it even harder for them to adhere to treatment and increases their risk of developing DR-TB.(17,26,29,32) The dual burden of alcohol and DR-TB causes a major hindrance in the direction of diagnosis and treatment, and can lead to mutations within M. tuberculosis, eventually resulting in DR-TB. This, in turn, leads to treatment complications and, potentially, mortality.(10,14,17,26,29,32)

Diabetes

Diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose, which lead over time to serious damage to the heart, blood vessels, eyes, kidneys, and nerves.(5,26,29,36) Globally, 422 million people have diabetes, of whom India contributes 77 million adults, and 25 million are at high risk of developing diabetes.(5,7,26) Diabetes compromises the immune system, making individuals more susceptible to TB infection and progression.(7,26,29,36) However, the majority of people do not know or are ignorant of their diabetes status, and those who had concomitant diabetes during prior TB treatment episodes had eight times greater odds of getting DR-TB.(7,26,35,36) Additional delays in treatment, prolonged exposure to anti-TB drugs, and impaired immune responses among diabetes patients lead to ramifications and mortality.(14,15,26,29) Furthermore, managing such a dual burden among individuals exacerbates health outcomes, ultimately leading to increased rates of morbidity and mortality.(16,36)

Tobacco

The coexistence of tobacco use has emerged as a significant public health concern, leading to 8 million deaths worldwide annually, with India accounting for 1.35 million of these deaths.(5) Nicotine, a highly addictive substance present in tobacco, represents a substantial risk factor for infection from any airborne disease.(5,7,29) Furthermore, tobacco use and exposure to toxic second-hand smoke have a higher risk of getting infected with TB, progression from infection to active TB disease, increased risk of recurrence and death from TB globally, and eventually lead to substantial social and economic costs.(26,29) According to the India TB report (2023) in 2022, across India, around 2,10,543 TB patients were identified as tobacco users, with 67157 being linked with tobacco cessation services.(7) However, a number of studies revealed that the common cause of worsening the vulnerability of TB patients and spreading DR-TB was a history of residing in places with second-hand smoke and past tobacco use, whether it was chewing or smoking.(26,27,29) Moreover, the dual burden of such a kind of disease in public health concerns potentially impacting treatment outcomes and increasing the burden on healthcare systems.(5,7,18–21,26,27,29)

Diagnosis and Treatment of Drug-Resistant Tuberculosis

In India, DR-TB is rapidly increasing, and healthcare professionals are facing significant difficulties in diagnosing and treating DR-TB, which has serious ramifications.(2,12,15,23,24,30,37) It is challenging to monitor, manage, and regulate DR-TB treatment in pediatric patients.(4,6,13,15) In the DR-TB cases in children, the dosage of second-line anti-tuberculosis drugs was based on the patient's body weight.(13,15) Additionally, due to the frequent and severe toxicity profile of second-line drugs, female DR-TB patients of reproductive age are at increased risk for harm to both themselves and their fetus.(6,13,15)

The NTEP has intended to expand the DR-TB diagnostic service network, diagnosis tests, monitoring services, and efforts of stakeholders to enhance health outcomes, support quality-assured diagnostic services, and provide a specific role in providing ambulatory care for patients.(3,7,8,11,15,18–21,24,28,33,37) India's “Drug-Resistant TB Diagnostic Service Network" includes the National Tuberculosis Reference Laboratory, Intermediate Reference Laboratories, private laboratories, and private and government treatment centers.(7) Despite this support system, the main difficulties faced by healthcare professionals are a lack of modern laboratory infrastructure, qualified staff, and appropriate facilities for handling and processing specimens particularly in rural areas.(2,37) In addition to the DR-TB diagnosis network, DR-TB is frequently diagnosed using culture-based techniques; however, this process takes at least 12 weeks to complete.(23,24,30) However, due to their cost and limited availability of rapid molecular testing techniques, are difficult to use in rural areas.(15,23,24,30,37) Patients with DR-TB may experience psychiatric comorbidities, such as anxiety and depression, because of financial strain, misconceptions, familial obligations, and emotional distress.(17,28,32) Non-pharmacological interventions, such as psychological and emotional support, psycho-education, and methods like muscle relaxation, mindfulness, and keeping a thought journal, are given by caregivers, numerous agencies, institutions, private and public organizations, and health professionals to treat these psychiatric comorbidities.(17,28,32)

Policy and programmatic responses to Drug-Resistant Tuberculosis

The DR-TB is a growing global health problem, with 27% of infections coming from just one country: India. DR-TB is already a pandemic in India because of this frightening incident. Despite this, the Indian government has implemented a variety of targeted initiatives (Fig 4), treatments, and policies to deal with the rising prevalence of DR-TB in the nation.(3,7,8,15,24,28,33,37) These include encouraging stakeholder engagement, strengthening health systems, putting patient support and social protection in place, implementing infection prevention and control measures, and encouraging research and innovation.(7,28,33,37) The main aim of the Indian government is the RNTCP, which is currently called the NTEP.(15,33,37) To improve the management of DR-TB, the NTEP devised the programmatic management of DR-TB (PMDT), which focuses on early detection, diagnosis, and appropriate treatment of DR-TB cases.(3,7,8,15) Under the NTEP, India established the largest TB laboratory network in the world, enabling rapid diagnostic methods to conduct universal drug susceptibility testing (UDST) under one roof to quickly and affordably diagnose DR-TB.(3,7,24,33) "Liquid Culture Media'' and "Nucleic Acid Amplification Test" (CABNAAT and TrueNat) are these rapid diagnostic tests, particularly for detecting pediatric, HIV-TB, and EPTB. Moreover, the "Line Probe Assay" is a more precise and quick molecular DST assay to diagnose MDR and XDR-TB.(3,4,7,13)

Fig 4: Implemented different schemes and policy to reduce incidence of DR-TB under NTEP in India

The Direct Observed Treatment Short Plus (DOTS) treatment scheme (internationally recommended) calls for giving new DR-TB patients supervision for a period of six months to ensure that drug intake is being monitored.(5,7,15,18–21,33) However, insufficient data and a lack of intensive monitoring make the situation vulnerable in the TB epidemic with DR-TB.(15,33) Furthermore, new anti-TB drugs (e.g. Bedaquiline, Delaminid and Linezolid) with additional monitoring were made available for the treatment of DR-TB and demonstrated a significantly improved patient outcome.(1,8,37) In addition, the Indian government launched a TB-free campaign in order to reduce stigma and discrimination, implement new healthcare facilities (e.g., proper ventilation, use of masks, and isolation of patients), provide appropriate training to healthcare professionals, and raise awareness regarding highly contagious DR-TB. Even though the world is evolving, chronic illnesses like DR-TB still necessitate lengthy treatment regimens that may cause family disruptions and an increase in dropout rates and child labour.(27,29,37) To provide supportive compression and reduce the occurrence of DR-TB in low- and middle-income households in March 2018, the Direct Benefit Transfer Schemes were introduced.(37) In accordance with this, 500 INR is sent in stages to the patient's bank account each month to provide for proper dietary support and, as a reward during treatment, transportation allowances.(27,33,37) Additionally, the Indian government has taken steps to improve access to healthcare, particularly in rural areas, using a public-private partnership strategy. It has included the private sector in joint NTEP initiatives to improve access to care and reduce the TB epidemic with DR-TB.(7,33) Furthermore, a real-time web-based surveillance system known as "Nikshay" "NikshayAushadi," and the Lab Information Management System were established as part of the NSP in order to improve surveillance, implement robust reporting, and effectively monitor treatment.(3,7,33)

Future Challenges of Drug-Resistant Tuberculosis

Future efforts by the Indian government to control the TB epidemic, particularly regarding DR-TB, will face significant challenges due to the high percentage of latent TB cases.(7,18–21,33) The emergence of new DR-TB strains, which can result from mutations in the M. tuberculosis bacteria as a result of comorbidities and environmental factors, will be one of the biggest challenges. (4,5,7–10,14,15,23,24,30,37) Strong strategies will be required to halt the highly contagious nature of these new DR-TB strains.(3,5,12,14–16) To enable the early and precise detection of DR-TB cases with a patient-centered approach, ongoing research and development initiatives, monitoring and social support, investments in cutting-edge diagnostic technologies, laboratory infrastructure, and campaigning will be necessary.(15,28) To improve treatment outcomes for people with DR-TB in India, significant funding will also be required.

Conclusion

The emergence of DR-TB, which continues to be a global public health concern, has made affected populations more vulnerable. The Indian government must implement a multifaceted, multi-sectoral strategy to effectively combat this epidemic. This entails making sure that there is an ongoing supply of efficient medications, putting in place routine monitoring and assessment mechanisms to spot gaps in the healthcare system, and collaborating with various stakeholders like government organizations, pharmaceutical firms, and academic institutions to ensure thorough reporting and prompt treatment of all DR-TB patients. Collaboration with non-governmental organizations and private partners is also necessary to address issues like patient education, stigma, and restricted access to healthcare in remote and underserved areas. Regular campaigns and the planning of free medical camps can aid in bringing attention to the issue and helping those in need. By putting these suggestions into practice, the Indian government can effectively combat DR-TB and lessen its effects on public health.

Acknowledgement

The authors gratefully acknowledge the help and cooperation of the Department of Anthropology, Sikkim University. The present review study was financially supported in the form of the University Grants Commission-Non-NET Fellowship, and Sikkim University is also being acknowledged.

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