Prevalence of multidrug resistant tuberculosis among TB patients in Malaysia.

Background: Currently multidrug-resistant tuberculosis (MDR-TB) poses a signicant public health concern in Malaysia. Objective: This study is aimed to evaluate the prevalence of MDR-TB in Malaysian tuberculosis patients. Method. A retrospective analysis was performed, and data was obtained from the Malaysian National TB Information System (TBIS) between 2009 and 2019. A record of 989 MDR-TB cases were identied and associated risk characteristics such as marital status, gender, ethnicity, employment status, alcohol consumption, diabetic status and smoking status were determined. The statistical analysis was performed using the SPSS software version 20. Results: Overall, the occurrence of MDR-TB among patients with TB infections in Malaysia was 0.34% based on data collected from TBIS. The ndings revealed major variations in the incidence of MDR-TB between male and female patients (0.44%, 0.20%, p < 0.001), single and married patients (1.63% vs 0.24%, p < 0.001), ethnicity (p < 0.001), working and non-working patients (0.48% vs 0.32%, p < 0.001), alcoholic and non-alcoholic patients (0.44% vs 0.32%, p < 0.001), diabetic patients and non-diabetic patients (0.39% vs 0.27%, p < 0.001), followed by smoking and non-smoking patients (0.13% vs 0.27%, p < 0.001). Conclusion: This study provides a substantial assessment of MDR-TB prevalence and associated risk factors that could be useful for the implementation of new strategies in Malaysia's national TB policy.


Introduction
In 2019 about 600 000 MDR-TB cases reported worldwide with an estimated 250 million annual deaths [1]. Global TB report has stated that incidents of MDR-TB continue to rise, potentially threatening to undermine advances in TB control [2]. A variation of socio-economic and health risk account for the high incidence of MDR-TB worldwide. Multidrug-resistant TB is basically an infectious disease caused by inadequate drug-sensitive treatment of tuberculosis [3]. In 2018 almost 480,000 new MDR-TB incidents with 100,000 rifampicin-resistant (RR) incidents were reported worldwide [4]. An approximate 500,000 new isoniazid-resistant (IR) cases have been reported in 2018, of which 78% were MDR-TB cases [5]. Despite this increase, however, the majority of patients diagnosed in 2017 and 2018 were only one in three (32%) of about 500,000 patients who developed (MDR-TB) [6].
MDR-TB is distinguished by high medication costs, longer time of therapy, poor effectiveness compared to vulnerable medicinal products [7]. The MDR-TB epidemic is exacerbated by inadequate health education for TB patients, an increasing number of respiratory infections and some other possible health factors related to this disease [8]. The frequency of MDR-TB cases is projected to increase in 2021 due to lack of knowledge among TB patients and poor awareness of its contributing factors [9]. In developing a comprehensive strategy for health care interventions, a broader understanding of the potential risk factors linked to MDR-TB infection is extremely essential.
However, most of MDR-TB studies has been investigated, mainly in United States and Europe [10]. Indeed, it is quite interesting and important to clarify the prevalence of MDR-TB, which has not been well studied in Malaysia. The purpose of this study is to determine the prevalence of MDR-TB and highlight the relevant health risk factors accountable for the developing MDR-TB infection in Malaysia.

Study design
The occurrence of MDR-TB infection in patients with TB were identi ed between year 2009 to year 2019. All registered TB patients who have been infected with MDR-TB are retrieved from National TB Information System (TBIS), Malaysia. Sociodemographic characteristic such age, gender, ethnicity, marital status and employment, followed by clinical characteristics were recorded into a Microsoft excel data sheet.
The Malaysia TB Information System is a TB patient tracking system in the country that was introduced in 2003 [11]. MDR-TB data were collected and reported regularly by these TB clinics or treatment centers throughout the country using a uniform method [11]. Throughout this process, all MDR-TB cases which reported to Health Department O ce, serves as a data center for the collection, surveillance, monitoring and recording of all MDR-TB events in the state [11]. This data will be used to monitor cases involving MDR-TB not only in treatment facilities but also at national level [11]. This helps in evaluating data produced at national and global level through annual reports to the World Health Organization (WHO) [11]. The TBIS 10A1 (Initial Information on TB Treatment) were used to collect data in this study. The TBIS 10A1 form provides data for individuals with MDR-TB and is intended for enrolment of individuals with TB as well as input information's into the national TBIS database [12]. This shall include accurate details on individual with MDR-TB, including details of socio-demographic, clinical data and initiation of TB therapy [13].

Statistical and Data Analysis
Data obtained from TBIS is used to approximate the prevalence of MDR-TB as well to identify the possible risk factors among TB patients. The data collected from TBIS has been cleaned and converted into an excel spreadsheet. The statistical software (SPSS version 20) was used to analyze data. A 95% con dence interval was used to describe the frequency of MDR-TB.
Prevalence is a term used to describe the overall number of incidents in which the disease is transmitted by the population at risk. In comparison, cases that were not MDR-TB were selected randomly as control measures. The total proportion of population at risk of TB is MDR-TB and non-MDR-TB. In order to calculate the prevalence, the following formula equitation (1) was used.  (2). To calculate the signi cance level, p-value, of the Pearson Chi-square test, CHISQ.TEST is used [14].

Risk factors / Years
For 2011, the cumulative incidence of MDR-TB over total TB was highest compared to other years. In 2012 and 2018 majority of MDR-TB incidence dropped drastically. The frequency of MDR-TB among Malaysian TB patients is still relatively low, which is approximately 0.34% between 2009 and 2019. In addition, independent risk factors, such as socio-demographic characteristics, are also linked to MDR-TB occurrence in Malaysia. Table 4 shows the association of independent factors which contribute to the incidence of MDR-TB in Malaysia. The frequencies of MDR-TB cases in male patients is 732 and in female patients is 241. For TB patients the frequency for male patients is 166,720 accompanied by female patients is 120,372. Within the MDR-TB group, the number of males is equal to females. Pearson's chi-square showed that there is a substantial difference in the occurrence of MDR-TB between male and female individuals (0.44% and 0.20% respectively, with p < 0.001) as depicted in Fig. 2.
The estimated MDR-TB cases are 357 in single patients and 626 in married patients. For patients with TB, the frequency for single patients is 21,483, followed by married patients is 256,609. The proportion of singles in the MDR-TB group is equal to that of married couples in the MDR-TB group. Pearson's chi-square showed that there is a substantial difference in occurrence of MDR-TB between single and married patients (1.63% and 0.24%, p < 0.001) outlined in Fig. 3.

Discussion
In Malaysia, the MDR-TB frequency is low and can be attributed to patients' positive response to rst-line antibiotics such as isoniazid and rifampicin. According Chien et al. [15] TB patients with isoniazid-resistant can be cured at a risk of relapse of less than 5%. Men are at greater risk of being infected with MDR-TB compared to the women identi ed in this study. One potential explanation, according to Caminero et al. [16], that men primarily smoke, drink alcohol and use drugs compared to women. According to Skrahina [17], younger and single individuals tend to be more vulnerable to MDR-TB due to their high participation in social behaviors which includes alcohol intake and smoking compared to older and married individuals. Evidence from this study indicates that MDR-TB infections between different ethnicities may rely on their behavioral activities. Malaya and Indian ethnic groups have a higher incidence of MDR-TB relative to other ethnic groups in Malaysia, and this may be attributed to social behavioral factors such as smoking habits, substance use of drugs and alcohol consumption. Jobless TB infected individuals are more vulnerable to transmission of MDR-TB than those working due to their poverty line, which prevents them from follow up with routine health checks with clinicians in TB centers and purchasing medicines. Study revealed a 3.54-fold higher likelihood of MDR-TB transmission between alcoholics compared to non-alcoholics, indicating the possibility of disease recurrence [18]. The substantial proportion of MDR-TB multidrug-resistant tuberculosis among diabetic patients appears to be growing steadily compared to non-diabetic patients [19]. Smoking is associated with the cessation of (TB/ MDR-TB) treatment and it has been found that this association is independent of alcohol or illicit drug usage [20].

Conclusion
To date, (MDR-TB) cases in Malaysia is relatively low (< 0.34%) compared to global noti cation. Although all Malaysians are free to diagnose and treat, some MDR-TB patients still have a heavy nancial burden on them. Multi-drug resistance TB develops either due to infection with a resistant strain, or as a result of inadequate treatment and poor patient compliance. Proper patient care and commitment to the completion of anti-TB therapy are recommended. The results of the study revealed that all contributing risk factors including age, gender, ethnicity, marital status, smoking, job, diabetic and alcohol intake are associated signi cantly with MDR-TB prevalence and relatively low (< 2.0%) in Malaysia. Reliable MDR-TB prevalence estimates will theoretically help to improve prevention measures, guide successful intervention and follow-up interventions in vulnerable populations, and assist in overall clinical decision-making. In public health perspective, priority actions to develop national guideline for surveillance and monitoring of MDR-TB and engagement with non-pro t organization, civil society and communities for treatment support should be strengthened.

Declarations
Con ict of Interest.