European Journal of Cardiovascular Medicine

Drug-resistant Tuberculosis is a major threat to controlling the TB burden. Globally in 2022, the number of people newly diagnosed with TB was 7.5 million, and in the same year, 1.30 million deaths were reported. In 2022 globally an estimated 4,10 000 people developed multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB)^.[1] India is ranked number one among the eight countries that accounted for 66% of new TB cases in the year 2022, 40 percent of the Indian population is infected with TB bacilli.^[2]  India bears 27% of the global burden of multi-drug resistant TB (MDR-TB), with an estimated 124,000 people developing the disease in the country in 2019. HIV prevalence among incident TB cases is 2.7% (2.7-2.7%) and Multi Drug Resistant (MDR)/Rifampicin Resistant (RR)-TB is 9.1 (5.3-14).^[3] The findings of National drug resistance surveillance reports from 2014 to 2016 revealed that 28% of TB patients were resistant to any drugs such as 22% among new and 36.82% among previously treated, and the proportion of total MDR TB in India was at 6.19% (5.5-6.9) i.e. 2.84% (2.28-3.5) among new cases and 11.62% (10.21-13.15) among previously treated pulmonary TB cases^[4] Major reasons is that these patients are difficult to treat because they continue to develop resistance to chemotherapy, poor compliance, treatment failure, Comorbid conditions like diabetes and HIV are mainly accounted for the progress of drug resistance in TB. Other important predictors are previous treatment history, addiction to alcohol and smoking, and adverse reactions to TB medication. Although social determinant factors also play an important barrier to ending TB^[5]. WHO reports that key epidemiology social determinants are such as poor socioeconomic background, underprivileged working conditions, and other social determinant factors include inadequate housing, overcrowding, poor physical environment, and health care needs^[6]. Epidemiological information on risk factors of MDR-TB is important for the prevention and control of drug resistance. However, there is a lack of information in the study area and at large in our country. With this background, we aimed to identify the independent risk factors including social determinants of MDR-TB among Tuberculosis patients for planning targeted programmatic interventions to reduce the burden of multidrug-resistant tuberculosis. 

Age and sex matched case-control study was conducted among the Cases, whose age more than 18 years or older and who were diagnosed and confirmed cases of MDR-TB under (RNTCP) accredited CDST or CBNAAT lab, resistant to at least INH and RMP (two first-line anti-TB drugs) from Kancheepuram district. Using these selection criteria, we classified cases into three groups based on diagnosis and treatment.

1. New cases of TB who had received first line Anti TB drug under the DOTS provided by RNTCP. These cases were Rifampicin sensitive by CBNAAT. The drugs taken were, Isoniazid, Rifampicin, Pyrazinamide, ethambutol and streptomycin during the initial phase and Isoniazid, Rifamipicin and ethambutol in the continuation phase, every month sputum microscopy has been checked for these cases, at the end of the fifth month positive smear microscopy were found, with the help of drug susceptibility test, they were found to be resistant to Isoniazid and Rifamipicin
2. New cases of TB who received first line drugs and whose treatment was considered a failure after a positive smear following an eight month re-treatment regimen (2HRZES+1HRZE+HRE) which they developed resistant to at least Isoniazid and Rifampicin during their drug sensitivity test
3. Cases with history of previous TB infection or relapse or defaulter whose treatment was considered a failure after a positive smear following an eight month treatment regimen and they developed resistance to at least Isoniazid and Rifampicin initial drug susceptibility test

By convenient sampling method 40 cases were recognized based on the diagnosis and treatment and Controls were 120, with culture-confirmed drug sensitive TB patients, who were sensitive to first-line drugs such as (INH, RMP, Pyrazinamide, ethambutol, and streptomycin) cases and controls were included in the ratio of 1:3. Study was conducted during the period of January 2023 to may 2023. Patients who were willing to give a written consent and those who were able to participate in the interview were included and patients who were severely ill patients and unable to participate in the interview and patients who have not given the written consent were excluded from the study. The questionnaire has five components. Demographic profile, previous treatment history, Clinical History,housing conditions and Co-morbid conditions like Hypertension, Diabetes, HIV-CO infection, and COPD.

Face and content validation of the questionnaire was done by individual experts from the Pulmonology and Community Medicine department and internal consistency and reliability were seen by using Cronbach’s Alpha (0.78). The Institutional Ethics Committee approved the study, and we obtained written informed consent from all the participants. We conducted an in person interview of cases and controls accompanied by health workers who were given training about the questionnaire before the initiation of study.

Statistical Analysis: Collected data was entered in MS Excel and analyzed using SPSS Software version 26. To obtain frequency and percentage for cases and controls, we used descriptive statistics analysis. Univariate analysis was performed to identify the crude association between dependent and independent variables. The dependent variable was the existence of MDR-TB, and the independent variables were socio-demographic, behavioral, co-morbid conditions, and housing conditions. Statistical significance was determined using p-value <0.005 as a cutoff point and the Mantel-Haenszel Odds ratio was used to measure pooled odds ratio and to find out the strength of association. Those variables that showed significant association at p-value < 0.05 in univariate analysis were measured for multinomial logistic regression analysis to find out the independent predictors of MDR-TB among the study subjects. Study was approved by the Institutional Ethical Committee (IEC)

A total of 160 study participants, 40 were cases and 120 were controls participated in the study. Among the cases 55 % were aged > 32 years, in controls 35.8% were aged > 32 years. Among the study participants, males constituted 85% of the cases and 59.1% of controls. Almost 67.5% of the cases attended up to high school, whereas in controls 30% attended up to high school. In this present study, 20 % of cases were unemployed, and in controls 22.5% were unemployed. Almost 85% of cases and 56.6 % of controls had a monthly income of rupees less than 10,000. Among the study participants, 80% of the cases reported overcrowding whereas in controls, 34.2% had reported. Almost 82.5% of cases reported inadequate ventilation whereas 25.8% of controls were reported.

Figure: 1 Diagrammatic representation of co-morbid conditions among cases and controls

Table 1: Univariate analysis of socio-demographic characteristics of the participants

On Uni-variate analysis of socio-demographic variables, there was no significant difference observed between cases and controls such as age, gender, education, and occupation. A significant difference was observed in the total income of the family, overcrowding, and inadequate ventilation as shown in (Table 1).

Table: 2 Univariate Analysis of Behavioral risk factors of the participants

p value* < 0.05 is statistically significant using Mantel Hanzal odds ratio

However, smoking, passive smoking, and persistent stress & sadness proved to be a significant behavioral risk factor in the univariate analysis as shown in (Table 2)

Table 3: Univariate analysis of Co-Morbid conditions of the study participants

p value* < 0.05 is statistically significant using Mantel Hanzal odds ratio

Univariate analysis of co-morbid conditions like HIV-CO infection, previous TB, and Default TB were found to be significant as shown in (Table 3).

Table 4: Multiple Logistic regression analysis of predictors of MDR-TB

On multinomial logistic analysis, five variables were identified as independent predictors for MDR-TB, such as overcrowding, previous TB treatment, Low-income status, passive smoking, and inadequate ventilation as shown in (Table:4)

This study conducted to find social determinants as a risk for MDR-TB and it has provided appropriate information about risk factors associated with MDR-TB to support and reduce the TB burden. The factors identified are income, overcrowding, previous TB treatment, default treatment, inadequate ventilation, and passive smoking which were strong predictors of MDR-TB. We observed MDR-TB most prevalent in the age group > 32 years, the findings observed in this study were found to be similar to various studies conducted by Mukati et al and Munje et al at Nagpur and the contrary, the study conducted by Prakash et al found among the age group[7,8,9]. In our study we found that males constituted 85% of the cases and in controls 15%. A study done in Uganda by Okethwangu D et al observed men were affected more than women per 100,000 with a p-value < 0.01 due to poor adherence to first-line anti-TB treatment ^[10].

Cases who were with low income <10,000 in cases 85% and in controls 56.6%, overcrowding reported by 80% of the cases and in controls 34.2%, smoking history of cases are 80% and in controls 36.6%, Alcohol abuse among cases were 40% and in controls18.3%, persistent sadness because of the disease among cases reported were 77.5% and in controls 13.4%. Cases who reported a history of passive smoking is 57.5%and in controls 31.6%, persistent stress reported among cases was 70% and in controls, 46.7%, and Inadequate ventilation among the cases reported was 82.5 % and in controls 25.8%, which tells us that low income with small living space and inadequate ventilation are more likely chances of developing MDR-TB. Because infectious disease and poverty have a high probability of acquiring the infections often spread hand in hand^[14] which shows that low socio-economic factors are important determinants for acquiring infections, a comparative study conducted by Xin-Xu Li et al observed that the risk factors of primary drug-sensitive TB and primary MDR-TB are more likely to happen in the low socio-economic group^[11].

Among the study participants, the observed Co-morbid conditions such as Diabetes were 40% in cases and controls 26.7%. Hypertension among the cases was 17% and in controls 3.4% and COPD among cases 40% and in controls 20%. On Univariate analysis between the socio-demographic factors and MDR-TB, we identified income of the family, overcrowding, and inadequate ventilation are significantly associated. Income of the family income <10,000 with an OR=4.333 (95% CI;1.692-11.093) P=0.000 means that cases with lower income have four times higher risk of developing MDR-TB similar finding observed by Djibut et^[12].

Other socio-demographic factors such as overcrowding that is > 5 members in the small living space are significantly associated with MDR-TB with an (OR=7.707 (95%CI; 3.255- 18.245). A similar study was done by Xin-Xu et al on MDR-TB per capita living space < 40 m2 (OR = 4.65; (95% CI = 1.06–20.38)^[11] Sachin et al observed MDR-TB to be associated with staying densely in a small living space, those observations suggest the vulnerability of women for MDR-TB^.[13] Inadequate ventilation is associated significantly with MDR-TB with an (OR=13.53 (95%CI;5.435-33.701) This similar finding was observed by Venkatesh et al, that 72.7%. of inadequate ventilation which is higher in proportion.^[14]

Among the behavioral risk factors passive smoking and persistent sadness are significantly associated with MDR-TB. passive smoking with an (OR=2.919 (95%CI;1.399-6.091)) after an adjustment(AOR=9.649(95%CI;7.891-31.87), similar study done by Leung et al OR=1.67(95%CI 0.72-3.86) which is not statistically significant. The reason was found to be loss of ciliary motility and immune depression along with social factors^.[15] For persistent sadness (OR=22.388(95% CI; 9.0135-55.612) and it is statistically significant, a similar study conducted by Mojes et al OR=3.88 (95% CI: 1.63-9.24).^[16]

Among co-morbid conditions, previous TB treatment, default treatment, and HIV co-infection are associated with MDR-TB. Previous TB treatment (OR=9.8722(95% CI; 4.374-22.277) and AOR 14.82 (95% CI; 9.699-36.117). A similar study was conducted in South Africa, in which a history of TB treatment failure/completion observed is the main predictor of MDR-TB than newly diagnosed patients, It is also one of the main barriers to TB control.^[10] Studies done in Georgia resistance is due to the repeated and inappropriate way of taking the medication that made the bacteria mutate and develop resistance against the drugs.^[17] Among the cases of TB default treatment (OR=6.184(95% CI:3.685-14.290) and on AOR=2.496(95% CI:0.134-47.669) it is not a statistically significant, similar study done in Uzbekistan OR=3.84(95% CI:1.41-11.11) which is statistically significant. Among the HIV-Co Infection and MDR-TB (OR=3.0833 95% CI:1.1003-8.6400) and AOR=8.855 (95%CI:0.2421-77.831)) it is not significantly associated.^[18] A systematic analysis and meta-analysis have reported that HIV-positive cases have a 24% higher risk of MDR-TB compared to HIV-negative ones.^[19]Another study done by Suchindran et al observed no significant association between MDR-TB and HIV co-infection^.[20]

Strengths and limitations: We assessed a wide range of social determinant factors which could be a good addition to the evidence on the risk factors of MDR-TB, which is to help the policymakers and public health authorities to take immediate action.

 Limitations, firstly, the findings are subject to recall bias, which could have potentially reduced the strength of the associations observed. However, most of the information was gathered from patient exposures that occurred before the onset of the disease. Additionally, the small sample size limits the generalizability of the results to the broader population.

The government of India is committed to eliminating TB from the country by 2025 which is five years ahead of the global target of 2030 under the sustainable development goals. National Strategic Plan for tuberculosis elimination 2017-2025 in India to quickly reduce TB incidence and mortality. Our study observed some risk factors associated with MDR-TB, based on our various social determinant factors, which had been identified as barriers to complete cure of MDR-TB and also it is challenging for the health care workers and policymakers. So our findings will help in identifying the risk factors related to social determinants, which also emphasize the importance of health education, cough, hygiene, and nutrition management among the community and also celebrating World TB Day in the community to raise awareness about TB and strengthen the health care system at all levels for active case finding and management.

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