Factors Associated With Drug-resistant Tuberculosis in the Deprived Population in the State of Paraná – Brazil


 BackgroundTuberculosis remains a serious public health issue worldwide, affecting people in vulnerable situations. The study aimed to analyze factors associated with drug resistant tuberculosis among patients who were in prison in the state of Paraná. MethodAn ecological study was carried out on Drug-Resistant tuberculosis cases registered through the Information System of Paraná, Brazil (from 2008 to 2018). Descriptive statistics of quantitative parameters was applied, being calculated with absolute frequencies. Additionally, binary logistic regression was performed, where the Odds Ratio was calculated with its respective confidence interval. The Akaike Information Criterion and the likelihood ratio tests, Wald test, Anova and Mc Fadden tests were performed to choose and validate the model. The IBM SPSS and Statistics version 25 and RStudio software version 4.0.4 were used for data analysis. Result653 cases were registered as tuberculosis cases in prison, and among these, 98 cases were Drug-Resistant TB. The schooling level among the study population was 8 to 11 years of education (OR: 0.41, 95%CI: 0.16 – 0.93), negative culture (OR: 0, 29; 95%CI: 0.09– 0.74) and smoking (0.02, 95%CI: 0.01 – 0.74) all these were factors associated with drug-Resistant TB. With the study population having the clinical pulmonary form (OR: 9.87, 95%CI: 1.55 – 23.81) and having a positive microscopy in the fourth month of follow-up (OR: 6, 46, 95%CI: 1.04 – 53.79), it was more likely to develop resistance. ConclusionThe study showed that the variables; education, culture exam, smoking, pulmonary clinical form, and follow-up microscopy were associated with drug resistance in the treatment of tuberculosis.


Introduction
Tuberculosis (TB) remains a serious public health issue worldwide due to its magnitude, transcendence, and strong social relationship, affecting people in vulnerable situations. According to data from the World Health Organization (WHO) TB is among the 10 leading causes of death worldwide and is the leading cause of death from a single infectious agent, surpassing the human immunode ciency virus (HIV)/Syndrome of Acquired Immunode ciency (Aids) 1 .
In Brazil, in 2017, nearly 70,000 new cases of TB were reported, which represented an incidence rate of 33.5 cases per 100,000 inhabitants. In the period from 2008 to 2017, an average annual drop of 1.6 was observed, however it is noteworthy that in 2017, 19 (70.4%) Brazilian capitals had an incidence rate higher than that recorded in the country 2 .
Drug-resistant tuberculosis (TBDR) is characterized by resistance to any of the drugs considered for the treatment of TB, when con rmed through the sensitivity test or rapid molecular test for tuberculosis (TRM-TB), which constitutes a serious threat to public health, making it even more di cult to control the disease and eliminate the disease 3 .
The TBDR is more frequent among groups in situations of social vulnerability, including the con ned population, which is 28 times more likely to develop the disease when compared to the general population 4 .In recent years the proportion of active TB cases in this population has increased signi cantly, even surpassing the cases of TB-HIV co-infection 5 .
The emergence of TBDR cases is mainly related to the irregular use of medications and treatment defaults. According to the national guidelines, TB treatment for those who have not been treated previously consists of rifampicin, ethambutol and isoniazid for at least six months, and resistance to one of the rst-line drugs requires replacement by second-line drugs and increased treatment time, which may predispose to abandonment 3 .
The treatment duration for TBDR has ranged between 18 to 24 months, which is three or four times longer compared to the treatment for sensitive cases, which often results in a worse outcome, such as failures or treatment interruption 6-8 . The TBDR is more present in socially vulnerable groups, including the Homeless Population and the People Deprived of Liberty (PDL), a study shows that developing TB in these populations is 28 times more likely compared to the general population 4 .
In Brazil, the problem of TB is not only in the detection of cases, but also in ensuring that these detected cases complete their treatment, with treatment success being around 71%, when the recommended rate is at least 85% 9 , which suggests that many people with TB are dropping out of treatment before completing it and therefore becoming vulnerable to developing TBDR.
In this context, it is worth highlighting the National Policy for Comprehensive Health Care for Persons Deprived of Liberty in the Prison System (PNAISP), established by inter-ministerial ordinance No. 1, of January 2, 2014, with the objective of expanding the health actions of the Uni ed System for PDL. Among the multiple guidelines of the PNAISP, a speci c line of action for the control of TB was incorporated.
However, most studies in which TBDR is the study objective are carried out in the general population, with little emphasis on PDL, which reveals an important knowledge gap. The TBDR epidemic in PDL is considered hidden in many scenarios, which points to an important and necessary topic to be investigated for the advancement of knowledge in this área 10 .
Thus, the systematic monitoring of TBDR within prisons is essential to eliminate the possibilities of community transmission, in addition, knowing which factors are associated with this clinical condition is strategic in the sense of designing larger intervention policies and projects. Thus, the study aims to show which factors are related to TBDR among populations deprived of liberty in southern Brazil.

Method
Study setting This is an ecological study carried out in the state of Paraná, which is one of the 27 federative units in Brazil, located in the southern region of Brazil. The state has a population of approximately 10 million inhabitants distributed in 399 municipalities, representing 4.5% of the Brazilian population 11 .
Regarding social indicators, the state of Paraná has the fth highest Human Development Index (0.74) in the country, the fourth lowest illiteracy rate (0.52%) and the fourth lowest infant mortality rate (13.8 deaths/1,000 live births) among Brazilian federative units 12 .
The Paraná prison system is composed of 55 prison units distributed in nine regions of the State 13 . In the state of Paraná, the PDL comprises a total of 29,831 people while, according to the last survey available by the National Penitentiary Department carried out in 2019, the total number of PDL in Brazil is 748,009 13 .
In the State of Paraná, the PDL, in the year 2019, comprised a total of 29,831, which represents 3.98% of the national PDL, mostly male (94.66%), in a closed regime (62.20%) and with at least 1 child (65.0%). Regarding the available places, 20,740 (95.03%) for men and 1,084 for women (4.97%) 13 .

Reference population
The study population consisted of sensitive TB cases and those bacteriologically con rmed for TBDR noti ed in the Noti cation Diseases Information System It is noteworthy that to compose the study population TB patients / cases were ltered "institutionalized" for reporting forms by the year 2015 and from 2015 as "prisoners". The inclusion criteria were TB cases in PDL, whose drug resistance con rmation was performed by means of sputum culture with positive sensitivity test and identi cation of resistant bacillus in Rapid Molecular Test, following the criteria established by the National Tuberculosis Control Program.
The exclusion criteria were cases in which the noti cation had blank data 14 .

Statistical analysis
Initially, consistency analysis of the database records was performed and descriptive analysis of the cases was applied to characterize the pro le of the population studied, for which descriptive statistics and quantitative parameters were used, and absolute and relative frequencies were calculated using the IBM software SPSS Statistics version 25.
To identify the factors associated with TBDR in PDL, binary logistic regression was used based on the variables present in the SINAN noti cation form, where variables that could explain the variable of interest were chosen, the dependent variable being the occurrence of TBDR. and the selected independent variables were: sex, age, race/color, education, type of entry (new case, recurrence, re-entry after abandonment, don't know, post-death), clinical form, associated diseases (HIV, AIDS, alcoholism, diabetes, mental illness, use of illicit drugs, tobacco), clinical examinations performed (chest x-ray, culture, histopathology, bacilloscopy, sensitivity test or TRM-TB) and performance of directly observed treatment.
All selected independent variables were dichotomized (0 and 1) as well as the dependent variable (drug resistance) which was also dichotomized (0: sensitive TB; 1: TBDR). Then, the selected variables were tested for multicollinearity from the variance in ation factor, excluding those with an index greater than 10 15 . After the initial selection process of the independent variables, the Logistic Regression was conducted using the RStudio software version 4.0.4. The best model was chosen from the lowest values of the Akaike Information Criterion (AIC) 16 .
After exhausting all the possibilities of the analysis and arriving at the nal model (smaller AIC), the likelihood ratio tests, Wald test, Anova and Mc Fadden were performed to validate the model. It is also noteworthy that for the nal model with the best parameter of comparison, the calculation of the Odds Ratio (OR) and their respective 95%CI was performed for the statistically signi cant variables (p<0.05).

Ethical aspects
The study was authorized by the Paraná State Health Department -SESA and approved by the Ribeirão Preto College of Nursing with the Certi cate of Presentation for Ethical Appreciation (CAAE) nº 31631520.2.0000.5393. As it involved the use of secondary data, the study did not require the Informed Consent Term.

Results
A total of 653 cases of TB were reported in adults deprived of their liberty during the study period, with a minimum age of 18 years and a maximum of 82 years of age, with a mean of 27 years and a median of 29 years of age. Of these reported cases, a total of 98 TBDR cases were observed, with a minimum age of 18 years and a maximum of 61 years of age.
The Table 1 shows the sociodemographic and clinical pro le of TB cases in people deprived of liberty reported between 2008 and 2018 in the state of Paraná, Brazil. The highest percentage affected males (n=639; 97.9%), in people of white race/color (n=438; 67.1%), with incomplete 5th to 8th grade (n=256; 39.2 %) and of the total of 14 women, none was pregnant at the time of diagnosis. Regarding the clinical pro le of TB, most cases were characterized by being new (n=563; 86.22%); mostly in the pulmonary form (n=611; 93.57%) and had the outcome of cure (n=434; 66.46%).

Discussion
The present study aimed to highlight the factors associated with TBDR in PDL in the state of Paraná, and it was identi ed, after conducting logistic regression, When the educational level has been evaluated, it was evidenced that the higher the level of education, the lower the chance for the development of TBDR.
Since, the educational level directly implies self-care with health, and low education can make the individual more prone to risky behaviors and reduce their perception and self-care in relation to their clinical status, in addition to being associated with possible treatment failure, thus allowing the possibility of drug resistance, abandonment and death from TB 17 .
The educational level directly implies self-care with health, since low education can make the individual more prone to risky behaviors and thus reduce their perception of their clinical status, in addition to being associated with possible treatment failures, increasing possibility of drug resistance 17 .
In this perspective, a low level of education (less than eight years of schooling) has been associated with a higher risk of dropping out during TBDR treatment, and in turn this is associated with a set of precarious socioeconomic conditions 18 .
The population of the Brazilian prison system is considered, for the most part, young and with low access to education, since just over 10% of the PDL attend educational activities, whether for schooling, professional training, income generation, culture or sport 19 .
The literature highlights how factors that increase the risk of contracting TB are the unhealthy habits and lifestyle of this population, such as using illegal drugs, alcohol, tobacco, malnutrition and even other pathologies, which corroborates the ndings of this study, since not using tobacco was characterized as a lower chance of developing TBDR 20 .
From this perspective, according to epidemiological data, the relationship between using illicit drugs and having TB is increasing, evidencing a public health problem. A research carried out in a university hospital in São Paulo showed that patients who drink alcohol, smokers and those who use illicit drugs fail to undergo TB treatment more often than those who did not have any of these risk factors 21 , increasing the likelihood of progressing to drug resistance for TB. The clinical pulmonary form was the most prevalent, which may hypothesize that it is the form that mostly causes drug resistance. However, if considered that in the cases included in this study, it was observed that 98.98% among the reported cases had this clinical form, it is expected that most cases of drug resistance present this form of TB.
As for the sputum culture, when a person is positive, it allows to state that this person supports the TB transmission chain, that is, he can infect about 10 to 15 people during a period of one year, which increases the concern when we are talking about those deprived of liberty living in overcrowded places, besides this person can directly transmit the resistant form of TB 3 .
It is known that sputum smear microscopy is a simple, safe method, used all over the world and has a low cost 22 . Given the above, it is expected that those who have a negative sputum culture have less chance of developing TBDR, whereas having a positive bacilloscopy in the 4th month of treatment represents a threat, as it indicates that the drugs used did not have the expected effect and thus, did not interrupt the chain of transmission and increases the chance of developing TBDR.
Furthermore, with regard to the PDL, it is worth noting that the Brazilian prison system was regulated in 1984 and since then it has brought debates about fundamental rights. In this perspective, the increase in the number of people deprived of liberty is a reality in Brazil, since in December 2017, the country had the third largest prison population in the world, with a predominance of black people with low education, with 88% not having completed high school 19 .
It is noteworthy that the structural conditions in prisons are crucial for the health-disease process of PDL. The environment is hostile and unhealthy, which enables the occurrence and spread of different diseases, including TB, as well as enhancing the possibility of the development of TBDR 23 .
This reality is also present in other countries, since TB in PDL is a global problem, especially in developing countries. Unhealthy conditions, inadequate treatment for TB, poor ventilation, overcrowding, lack of sun with consequent vitamin D de ciency, among other aspects, negatively contribute to the spread and permanence of the disease in this population 10,24 .
The inadequate treatment of TB, carried out inside the prisons, exposes the other people who live with the PDL, be they the workers as well as the visitors themselves, increasing the transmission chain. Thus, in addition to enhancing the transmission of the disease, it increases the possibility of transmitting TB already in its resistant form, which ends up hindering the treatment and consequently the control of the disease, making it impossible to reach the third objective for sustainable development in its sub-item 3.3 of the 2030 agenda proposed by the United Nations, which is to end epidemics, including TB 10, 25 .
Since 2000, Brazil has had on average, an annual growth rate of its prison population of 7.14%, Paraná concentrates 6.88% of the country's prison population (Brasil, 2017). The occupancy rate, which is calculated by the ratio between the total numbers of people deprived of liberty and the number of spaces in the prison system. In June 2017 in Brazil, a rate of 171.62% was recorded and the crime of theft and drug tra cking represent the majority of reasons for deprivation of liberty 19 .
With the growth of this population, the implementation of the National Tuberculosis Program in prisons becomes increasingly important, since the actions proposed by the Ministry of Health are partially applied 26 .
TB is a disease that has treatment and cure, however, the patient must commit to the treatment until the end, as well as, that the State guarantees the effective treatment through directly observed treatment 3,7-8,10,20 . Thus, one of the reasons for the high mortality rate from TB would be the lack of patient adherence to treatment, which also increases the incidence and appearance of multidrug-resistant bacilli 24,27 .
The delay in the diagnosis of the disease is generally related to the naturalization of the lack of assistance to PDL, the interpretation of the prison as a place of "death" and "suffering" and the deprivation of the right to health for the PDL due to its position before society, which highlights the inequity of access to health care for this population group 28-29 . Thus, this context points to another major challenge in disease control, which is the need for changes in the conceptions of the right to health within prison units 20 .
The invisibility of this population by the state, the low concern with re socializing, as they are a neglected population, mostly with low income and education, living in poverty, living in precarious conditions in overcrowded prisons, suffering prejudice and being absent of effective public policies is the reason that this and other diseases prevail within prison systems, being a national public health problem that ends up infringing the Federal Constitution itself 23,30 .
Considering that the study showed positive microscopy in the fourth month of treatment as a factor associated with TBDR and the habit of not smoking and the presence of negative culture as protective factors, it is essential to develop public policies aimed at this population. It is suggested to invest in improving health conditions in the prison system, promoting healthy lifestyle/behavior and monitoring symptomatic respiratory diseases. For strategic monitoring in the admission of the deprived of liberty, active case nding for diseases, in addition to TB, should be intensi ed, treating this disease as a priority, bringing the State's responsibility and the importance of using strategies so that the PDL can be a priority. Building life projects, providing the reduction of social inequality is also important.
It is noteworthy that the study has limitations related to data collected from the SINAN of the State of Paraná, since the data may suffer from underreporting, mainly due to the diagnostic di culty involved in TBDR, caused, for example,, due to the lack of indication of patients for sensitivity tests, as well as the di culty in collecting blank information in the database and the impossibility of knowing and evaluating the history of previous treatment for TB.

Conclusion
From the results, factors associated with TBDR were evidenced, which are public health problems and that contribute to the permanence of this disease. There is a need for advances to improve the public health care network, from the perspective of tuberculosis surveillance, so that there is continuous improvement of health surveillance in the country, such as the systematic use of bacilloscopy throughout treatment, an important predictor to predict the occurrences of TBDR.
For this, the importance of building feasible policies with the reality of penitentiaries is highlighted, considering all aspects that permeate it, without forgetting the inequity of access to health due to the naturalization of the lack of care, as well as the indifference and the position generated facing society.

Declarations
Ethics approval and consent to participate: