Factors Contributing to the High Prevalence of Multidrug- Resistant/Rifampicin-Resistant Tuberculosis: A Study From Russia

Background: Rapidly growing prevalence of multidrug-resistant/Rifampicin-resistant tuberculosis (MDR/RR-TB; resistance to Isoniazid and Rifampicin/Isolated resistance to Rifampicin) is putting in jeopardy the WHO End TB strategy. This study aimed to identify factors contributing to the high prevalence of MDR/RR-TB in Khabarovsk krai region of Russia. Methods: A cross-sectional retrospective study was conducted. Clinical, demographic and drug susceptibility testing data on 1440 patients were analyzed. Factors associated with MDR/RR-TB were identied through logistic regression analysis, along with in-depth interviews with eight patients, ve healthcare managers and ve doctors. Findings: 618 patients (42.9%) were identied with MDR/RR-TB. Patients with a history of imprisonment were 16.53 times (95% CI 5.37 to 50.88,) more likely to have MDR/RR-TB, whereas re-treatment patients were 2.82 times (95% CI 2.16 to 3.66) more likely to have MDR/RR-TB. Other inuencing factors included presence of disability (AOR is 2.32, 95% CI 1.38 to 3.89) and cavitary disease (AOR is 1.76, 95% CI 1.37 to 2.25). Poor knowledge, progressive tiredness of prolonged TB treatment and inability to hospitalize infectious patients without their consent were perceived by the interviewees as major inuencing factors. Conclusions: Incarceration and treatment history, regardless of outcome, were identied as major factors inuencing MDR/RR-TB prevalence. It is essential for TB care system to eliminate legal loopholes, which deprive doctors of means to enforce quarantine procedures and epidemiological surveillance on infected patients, former and current inmates. In addition, increasing people’s awareness of TB, early detection and appropriate treatment of patients with TB are needed for successfully combating MDR/RR-TB.


Introduction
The continuous increase of multidrug-resistant/Rifampicin-resistant tuberculosis (MDR/RR-TB; resistance to Isoniazid and Rifampicin/Isolated resistance to Rifampicin) throughout the globe is a major public health issue. Treatment of MDR/RR-TB is more toxic to the patient, less effective (the 2019 reported global treatment success rate is only 56%) and carries much higher economic burden on the patients and the healthcare system, thus jeopardizing TB control efforts in developed and developing counties alike [1][2][3].
Russia carries one of the greatest burdens of MDR/RR-TB in the world. In 2019, MDR/RR-TB accounted for 35% of all new TB cases and 71% of all previously treated TB cases, with an MDR/RR-TB incidence of 27 per 100,000. Even so, the number of detected TB cases in Russia is continuously falling; the prevalence of MDR/RR-TB cases in Russia is the second highest in the world despite occupying only 23rd rank of total TB incidence [4][5].
Alarmed by the serious general epidemic TB situation and high MDR/RR-TB prevalence in particular, the government of the Russian Federation alongside the Russian Society of Physiologists have developed speci c policies and guidelines corresponding with WHO TB strategy and guidelines in order to eradicate the existing issues [8]. Thus, joint TB control programs with international partners have been initiated, research funds have been extended, centralized electronic database of patients created, and new diagnostic techniques and policies implemented. However, progress is far from satisfactory, as despite the overall decrease in total TB incidence, the prevalence of MDR/RR-TB is continuing to rise [4,[6][7].
It is crucial to identify the underlying reasons for such high MDR/RR-TB prevalence so that more feasible and cost-effective approaches can be developed to control this trend. International reviews as well as some country-level studies have identi ed that risk factors for MDR/RR-TB vary depending on country, region, or locality. Among the most prevalent are poverty, overcrowding, HIV co-infection, diabetes, alcoholism, smoking, cavitary disease and even young age. Thus, in clinical practice, it is essential to assess general risk factors as well as ones speci c to the region of residence of the patients [8][9][10][11][12][13].
This study was undertaken in Khabarovsk Krai, in the Far East of Russia, where the proportion of MDR-TB among newly diagnosed cases (38%) was estimated to be the third highest in the country, signi cantly higher than the national average of 29.3% in 2018 [14]. Unfortunately, there is a notable gap in research into MDR/RR-TB rates between high and low prevalence regions of Russia. Despite some studies carried out in low-prevalence regions, factors in uencing MDR/RR-TB in high-prevalence regions have rarely been investigated [15][16][17].

Data collection:
The study was conducted in the central "Tuberculosis Hospital" of Khabarovsk Krai. This institution collects and processes information about all patients with tuberculosis in Khabarovsk Krai and functions as a reference laboratory at the regional level. The Federal Register of TB patients (FRTP) was used in this study as a source of data, which is a subsystem of the digital Uni ed State Healthcare Information System (USHIS). Anonymous data on every patient that was diagnosed with TB in Khabarovsk Krai from January 2018 to December 2019 was collected. The surveillance covered all healthcare institutions in the region and strictly followed the guidelines developed by the WHO and the International Union against Tuberculosis and Lung Disease [19].

Diagnostic and including criteria:
An acid-fast bacilli sputum smear, culture (with both liquid and solid media) and real time PCR alongside with Drug Susceptibility Testing (DST) are routinely implemented as initial diagnostic tests in all patients with suspected TB in Khabarovsk Krai. In this study, a patient whose sample was positive for mycobacterium tuberculosis (MTB) in at least one of the 4 initial diagnostic tests was de ned as having active pulmonary TB. Patients whose samples were negative for the MTB in all 4 initial diagnostic tests were de ned as having non-active pulmonary TB and were thus excluded from the study.
Various DST techniques were employed to detect MDR/RR-TB in patients. DST alongside the sputum culture tested MTB resistance to most rst and second-line anti-TB drugs.
A liquid and solid media sputum culture tested MTB resistance to the following agents: Isoniazid, Rifampicin, Ethambutol, Streptomycin, Linezolid, Capreomycin, Amikacin, O oxacin, Levo oxacin, Kanamycin, Ethionamide, Para-aminosalicylic acid and Cycloserine. DST in direct PCR was performed with Allele-speci c polymerase chain reaction aimed to identify rpoB, katG, inhA, embB and gyrA gene mutations associated with resistance to Isoniazid, Rifampicin, Ethambutol and uoroquinolones [20]. All DST strictly followed the procedures and methods set out by WHO and the International Union against Tuberculosis and Lung Disease [19].
Patients with other types of drug resistance were excluded from the study. A new patient was de ned as a patient with TB who had never been treated for TB previously, or who had received anti-TB drugs treatment for less than 1 month. A re-treatment patient was de ned as a patient who had received anti-TB drug treatment for more than 1 month [6].
In-depth interview: The interviewees were purposely selected based on their roles and experience in TB control. A total of 8 re-treatment and newly diagnosed patients completed the interviews, including one with a history of incarceration. In addition, 10 healthcare workers involved with their treatment likewise completed interviews, including 5 physicians and 5 health administrative o cials. Patients with TB were asked to answer when, where, and why they had received TB services, as well as how they were treated and what problems did they face. The administrative o cials were asked to answer questions in relation to the arrangement of treatment regimens and compliance of providers and patients. The physicians were asked to answer questions about their experiences and problems in treating patients with TB. The interviews were digitally recorded, transcribed and thematically coded. The nal sample size was determined by a saturation of information when no new categories emerged.

Quantitative data analysis:
Quantitative variables of demographical, clinical characteristics of the patients with MDR/RR-TB were compared with those without MDR/RR-TB. Three regression models were constructed for all cases combined -only new cases and only re-treatment cases, respectively. Independent variables tested in the regression analysis included gender, age, social status, living conditions, substance abuse, history of imprisonment, disabilities, HIV status, history of treatment with Rifampicin and Isoniazid, TB localization, cavitary disease, place of residence, and circumstances of TB discovery. For the re-treatment patients, in addition, were included variables of previous therapy outcome and length of previous treatment with Rifampicin and Isoniazid).
Three separate binary logistic regression models were created. Chi square tests were used for testing statistical signi cance of the models as a whole. Fitness of the models to the data were tested with Hosmer & Lemeshow test. Regression coe cient, Odds ration with 95% con dence interval (95% CI) for each variable category was calculated and Wald statistics method used to determine their statistical signi cance [21]. An analysis was performed using SPSS software V24.0.01.

Qualitative data analysis:
The interview data was analyzed thematically, with the coding framework developed inductively from the data. The initial coding used open coding and theoretical coding. The initial codes were then re ned to produce a smaller set of themes. The coding framework was subject to continuing iterative revision during the course of analysis. An analysis was performed using Nvivo software V11.0.   Findings of quantitative data analysis were partially supported by interviews with patients, health managers, and physicians.
All aspects of TB care in Russia are free of charge. The whole system was designed to provide universal, quality and specialized care that is centralized in TB-designated facilities (TBDF), as depicted on the Figure 1. The one exception from the system is penitentiary facilities that operate separately. As was reported by interviewees, poor nutrition and living conditions, overcrowding, treatment regimens neglect by prisons' medical stuff and prisoners, make these institutions the breeding ground for drug resistance.
After releasing from detention, prisoners mostly disappear from epidemiological surveillance and, even if they show up for further treatment, they often fail to adhere to the regimen and follow-up procedures and there is no legal tools for healthcare providers to enforce surveillance on them.
There was a consensus among interviewees, that the main obstacle toward achieving full patient's compliance, is the length of therapy. Patients become progressively tired as the treatment advances, especially those ones with drug resistance, whose regimens usually last for 24 months or even more.
That, combined with insu cient awareness about consequences of intermitted treatment, leads patients to drop out from the treatment, usually as soon as symptoms disappear.
Healthcare providers stated that both outcome and history of previous treatment contribute to the resistance development contrary to our results that mere fact of previous treatment history is increasing risk of resistance presence regardless of its outcome. Same goes for social status and living conditions, which, according to our statistical data, do not in uence resistance development, but from a clinical standpoint, socially disadvantaged patients (particularly homeless ones) display a greater tendency to acquire MDR/RR TB. Other substantial problem, that was not supported by data but reported by interviewees, is a greater frequency of alcohol and substances abuse. MDR/RR -TB prevalence in those groups is signi cantly higher than average.
Signi cance of disability as a risk factor was a surprise for interviewees; physicians stated that some patients purposely do not comply with treatment in order to worsen their condition and acquire disability status for receiving social security bene ts.
City dwellers have better access to healthcare in general and have a far greater capacity to complete annual chest X-rays in particular. Therefore, cities tend to see a far greater number of people diagnosed with TB than in rural areas. Likewise, the increased population density in cities provides more chances to contract MDR / RR -TB. This can explain an emerging trend observed by physicians -namely, the increase in the prevalence of MDR / RR-TB among newly diagnosed patients.

Discussion
Besides the TB mycobacterium's major biological features leading to the prevalence of MDR/RR-TB, such as mutation potential [22], strains [23] and draft genome sequences [24], TB related service patterns, demographics and clinical factors also have a signi cant impact on the development of MDR/RR-TB.
Not surprisingly, incarceration history was identi ed as the strongest risk factor associated with MDR/RR-TB in all studied groups. In this data, a high prevalence of TB and its drug resistant forms can be seen in prisons all around the world, developed and developing countries alike [25][26][27].
Given this, we propose that Russian penitentiary system makes a signi cant contribution toward increasing prevalence of drug resistant tuberculosis. In 2021, according to Birkbeck University of London, Russia occupies 5th place in the world in term of total prison population. This creates a substantial pool of hosts, carrying drug resistant TB in the population [28]. Among all healthcare facilities in Russia, only penitentiary facilities isolated from the general TB care system (Fig. 1). Such demarcation deprives inmates of proper care and follow up. Either a considerable reduction in the total prison population or inclusion of penitentiary facilities in the TB care system may address the problem.
In addition, this ongoing predicament is explained by a contradiction of Russian laws in the eld of healthcare. No medical procedures can be instituted without a patient's consent, including hospitalization, so some patients just leave TBDF at will. In order to ensure epidemiological surveillance, healthcare providers have to le a claim for forced hospitalization to the court. Paradoxically, there is no legal mechanisms to execute positive court decision without patient written consent, even infectious TB patients can leave TBDF even with court decision of forced hospitalization. In 2011 it was that 3500 out of 6000 lawsuits were satis ed in favor of forced hospitalization, and it took an average of 3 months to obtain court decision and up to 30% of patients left TBDF after forced hospitalization [29]. In order to ensure proper TB surveillance, drastic measures should be taken to eliminate such a loophole in the legal framework.
For reducing the pool of former inmates with MDR/RR-TB, better treatment conditions and epidemiological surveillance in penitentiary facilities must be established. Such intervention of providing TB care for inmates in civil clinics has been implemented in the Tomsk oblast region of Russia from 2000 to 2002. The results showed signi cant increase in compliance, reduction in adverse effect, decrease of TB mortality rate, and increased treatment e ciency among incarcerated patients. Success of this study supports necessity of centralized TB care for all TB patients, but thus far, attempts were made in that direction have proven insu cient [30].
2009 study from Belarus similarly identi ed positive association between disability and MDR/RR-TB prevalence [31]. In Russia, just like in Belarus, disability is a social security policy for people with permanent inability to work. Such studies may support disability status as a risk factor or revile its connection to social security policies. Therefore, there is a need for further investigation of that phenomenon in countries with and without such policies. It should be mentioned as limitation, that we had no data on whether disability was TB-related or determined by another disease, thus the full statistical meaning of this variable remains uncertain.
Our results concerning association between MDR/RR-TB with younger age, cavitary disease, and positive HIV status correspond with previous studies [27,32,33].
Our study has several limitations. We failed to explain the signi cance of o cial employment status as a risk factor among re-treatment patients and insigni cance of social status and living conditions, as these results contradict with previous studies [11,[34][35][36]. Also, our data indicates that outcome of previous treatment does not in uence risk of MDR/RR-TB development which contradicts with previous studies and healthcare providers' interviews [32].
In the end, we want to say that further attempts to better patients' education and public awareness about TB, with continuing coordinated and centralized care for patients with TB, in tandem with greater compliance by patients with TB treatment guidelines, are the keys to success in the battle against MDR/RR-TB.

Declarations
Ethics approval and consent to participate: The informed consents were accepted and signed by all participants and legal guardians of the underage participants of the study. All methods used in the study were performed in accordance with the relevant guidelines and regulations. The Ethics Committees of Harbin Medical University and Far Eastern State Medical University approved the study.