Multidrug resistant tuberculosis in Ethiopian settings and its association with previous history of anti-tuberculosis treatment: a systematic review and meta-analysis

Despite the recent progress of global control efforts, tuberculosis (TB) remains a major public health threat, worldwide [1]. According to the World Health Organization (WHO) 2015 report, TB is the main cause of morbidity among millions of people each year and ranks alongside HIV as a leading cause of death worldwide. There were an estimated 9.6 million new TB cases, and there were also 1.5 million TB deaths, nearly 60% and 26.7% of deaths were reported among men and HIV positive people, respectively. Moreover, the report has also revealed that 5% of TB cases were estimated to have had multidrug-resistant TB (MDR-TB); 3.3% and 20% of MDR-TB cases were among new and previously treated TB cases, respectively [2].

TB continues to be one of the major public health problems in developing countries and is particularly compounded by high burdens of MDR-TB. Approximately, 75% of TB infections occur in Africa, South-East Asia, and Western Pacific regions where HIV is fueling the epidemic [3]. HIV is contributing to large increases in the incidence of TB, notably in Sub-Saharan Africa [4]. In Sub–Saharan Africa, pooled estimate of any drug resistant-TB prevalence among the new cases was 12.6%, and among previously treated patients was 27.2% [5].

The overall burden of MDR-TB is exceptionally high in resource limited countries, where health resources, finances, and the skilled personnel required for diagnosis and management are limited, making containment and the prevention of further spread more difficult [6]. In Ethiopia, the low socioeconomic status of the population, high prevalence of infectious diseases, poor treatment outcomes, longer treatment time (about two years), higher treatment costs, and many more complications make MDR-TB a more complex disease than TB [7, 8]. Based on a WHO report, Ethiopia is ranked as 15th among 27 countries with high burden drug resistant TB with an estimated 5200 cases occurring each year [9, 10].

In Ethiopia, TB has been recognized as one of the main public health threats since half century ago. The national TB control program has adopted a standardized TB prevention and control program so called directly observed treatment, short course (DOTS). At national level, there is one TB program manager who oversees a team of 11 TB program officers who are responsible for each region and work closely with the regional health bureau to maximize appropriate implementation of national TB control and prevention strategies. Ethiopia remains one of the high TB and MDR-TB burden countries where TB remains a significant cause of morbidity and mortality [11, 12].

Although MDR-TB is a growing concern in resource limited countries like Ethiopia, it is largely under-reported, compromising control efforts. Information concerning the true extent of the problem of MDR-TB in the African Region is limited. Since, there are significant gaps in surveillance, and lack of standards for methodology, data sharing and coordination. The overall epidemiology of drug resistant TB is not well understood in Ethiopia [13‐16]. Hence, understanding the burden of the most prevailing infections like MDR-TB is urgently required to guide public health interventions that are both specific and effective. Therefore, the aim of this meta-analysis was firstly, to determine the pooled prevalence of MDR-TB among newly diagnosed and previously treated cases in Ethiopian settings and, secondly, to examine the relationship between previous TB treatment and MDR-MTB infection by conducting a systematic review and meta-analysis.

Multidrug resistant tuberculosis is an increasing global problem, with most cases are arising due to combinations of prescription errors and poor patient adherence. The epidemiology of MDR-TB varies significantly from country to country and region to region. As with all TB, 99% of MDR-TB occurs in high-burden resource-poor countries [14, 39]. Although, Ethiopia is one of the high TB/HIV and multidrug resistant TB (MDR TB) burden countries [13, 40], there is a still a large gap in knowledge about drug resistant TB in the country [14, 15]. So far only two nationwide surveillance studies were conducted to explore the overall epidemiology of MDR-TB in the country. However, in order to determine the current situation of MDR-TB in Ethiopia, up to date and evidence based studies are critically needed. Thus, we conducted this meta-analysis to estimate the burden of MDR-TB in newly diagnosed and previously treated patients in Ethiopian settings. Moreover, this study aimed to explore the significance of previous history of anti-TB treatment on MDR-MTB associated infections, and model its course over time.

Based on this meta-analysis, the pooled prevalence of MDR-TB among newly diagnosed and previously treated TB cases was 2% (95% CI 1% - 2%) and 15% (95% CI 12% - 17%), respectively. It is comparable with a previous meta analysis report that was documented in Sub-Saharan Africa countries, where HIV co-infection is rampant [5]. The report indicated that pooled estimate of MDR-TB prevalence among the new cases was 1.5% (95% CI 1.0–2.3), and among previously treated patients this was 10.3% (95% CI 5.8–17.4%). Likewise, anti-tuberculosis survey in Benin showed that the prevalence of MDR-TB among new and previously treated causes were 1.6% and 11.1%, respectively [41]. Similarly, national wide surveys have been also conducted in Mozambique and Rwanda, the prevalence of MDR-TB among new and previously treated cases were respectively 3.5% and 11.2%, and 3.9% and 9.4% [42, 43]. Drug resistant TB is unsurprisingly significantly associated with the HIV epidemic [44, 45]. There were an estimated 1.1 million HIV positive new TB cases globally in 2011. Around 79% of patients live in Sub-Saharan Africa [46]. It is understood that HIV infection causes suppression of immunological responses which subsequently leads to overwhelming infection by opportunistic and drug resistant strains [47]. According a 2008 WHO report, MDR-TB has been shown to be almost twice as common in TB patients living with HIV compared to TB patients without HIV [8]. Likewise, several studies demonstrated the association of drug-resistant TB with HIV infection [25, 48‐51].

However, the pooled prevalence of MDR-TB among newly diagnosed and previously treated TB cases in the present study; was comparatively higher than that reports noted in economically developed countries [52‐54]. With the availability of high standard diagnostic tests and effective treatment high income countries are moving towards MDR-TB elimination [15, 55]. Moreover, the range of available resources and specific TB control measures makes effective treatment of MDR-TB possible [15, 55]. Despite the introduction of direct observation of treatment (DOT) poor adherence remains a major obstacle to fight drug resistance TB in countries with poor socio economic circumstances like Ethiopia. The reasons for non-adherence are complex and involve more than the patients’ personal characteristics and attitudes. Studies have reported low literacy levels, household members’ fear of catching the disease, discriminatory behavior by health care providers, delays in care seeking behavior and self-denial due to stigma experienced by TB patients as some of the challenges facing adherence to TB treatment [15, 56, 57].

According to subgroup analysis, we observed that the pooled estimate of MDR-TB was significantly higher among studies with sample sizes of less than 100 participants, compared to studies where 100 or more participants were recruited. It is known that variation in sample size has a great effect on estimation. And possibly, the included studies have been carried out in different geographical locations that could have also impact on the observed prevalence. The calculated estimate of MDR-TB was also significantly higher in studies other than the two national surveys. Among the selected studies, 14 have been conducted either in hospital setups or other health institutions, and possibly results high estimate. Moreover, the prevalence of MDR-TB was higher among studies that have used both culture and molecular based detection methods compared to studies used culture alone. The significant variation could be presumably the fact that molecular based assays are the most powerful and highly sensitive techniques compared to conventional methods.

A second finding that highlights the association of previous history of anti-TB treatment with MDR-TB infection was high. As indicated in the study, the observed prevalence of MDR-TB was significantly higher than that among newly diagnosed TB cases (15% versus 2%, P < 0.001). Most importantly, TB patients who had history of anti-TB treatment exposure were 8.1 times more likely to develop MDR-TB infection compared with newly diagnosed TB cases. Previously treated patients often constitute a very heterogeneous group including those who experience relapse after receiving successful treatment, those who return after default, and those who start receiving a re-treatment regimen after having experienced previous treatment failure [58]. There are large evidences that noted that history of anti-TB exposure is one of the main contributing factors in acquisition of MDR-TB [9, 27, 59]. Multidrug resistance among previously treated TB patients usually results from exposure to a single drug that suppresses the growth of bacilli susceptible to that drug but permits the multiplication of pre-existing drug-resistant mutants [60]. It is the most common type of resistance to the first-line drugs and can emerge against any anti-tuberculosis agent during chemotherapy. The occurrence of MDR- TB is also attributable to lack of standard based drug prescription, probably leads to treatment failure and intensifies the population drug resistant strains [61].

Furthermore, we evaluated the time trend of MDR-TB prevalence from 2006 to 2014, which is shown to be stable, does not reflect possible changes in the implementation national TB control programs. A recent global report revealed that the Millennium Development Goal 6 targets on reducing the TB incidence rate has already been accomplished in Ethiopia [40]. Nationally, the TB incidence rate has fallen to 224 per 100,000 of the population in 2013 compared 369 in 1990 [40]. However, the issue of drug resistance in the country remains in question. The low level of reported drug resistance in Ethiopia may not be an accurate reflection of reality, and the limited evaluation may be responsible for this skewed portrayal. In 2010, less than 5% of new and previously treated TB patients were tested for MDR-TB because of limited availability of the test in most developing countries. Specifically, in Ethiopia the ratio of laboratories capable of performing MTB culture and capable of running line probe assay for detection of MDR-TB was 0.1 per 5 million populations. Besides, lack of research based national drug resistance survey data is a barrier to understanding the magnitude of prevalence and incidence of MDR [6, 14, 15].

It should be noted again that a limitation of English literature was posed in our meta-analysis. Also, our analysis was limited by the quality of the included studies and by the fact that many of the DR-TB surveys identified during our searches were excluded because they had not stratified patients according to their treatment history. The existing literature could not be used to depict the exact geographic distribution of MDR-TB prevalence in newly diagnosed and previously treated TB patients, since we did not review data on some regions of the country (such as, Tigray, Afar, Somali, & Gambela). Also, there were some methodological differences between studies.

Our analysis showed that the burden of MDR-TB remains a huge concern in Ethiopian settings. Particularly, the prevalence of MDR-TB was higher among previously treated TB patients. As detailed earlier, previously treated TB patients were 8.1 times more likely to develop a MDR-TB infection compared with newly diagnosed TB patients. Moreover, in the past 10 years, the time trend of MDR-TB prevalence was stable. Therefore, this finding underscores the importance of reducing the burden of MDR-MTB infection in Ethiopian settings. Effective implementation of DOTS program, strict compliance with infection control policies, and enhancing case detection rate through strengthening the TB laboratory capacity including introduction of rapid molecular diagnostic methods and implementation of active case finding through MDR-TB contact screening, seem to be the necessary next steps in this effort.