Overview of drug resistant Mycobacterium tuberculosis strain types in Africa
Molecular epidemiological data
The molecular mechanisms of drug resistance as well as the evolution of drug resistant strains in Africa have been studied using a variety of genotyping tools [13, 14, 15, 16]. This has provided some insight into the transmission dynamics of drug resistant TB. Most studies under review here have used spacer oligonucleotide typing (spoligotyping) to describe the molecular epidemiology of drug resistant TB in Africa although there are a number of studies which have used highly discriminatory methods which include whole genome sequencing (WGS), insertion sequence 6110-restriction fragment length polymorphism (IS6110-RFLP) and mycobacterial interspersed repeat units-variable number of tandem repeats (MIRU-VNTR) [13, 14, 15, 16].
Population structure of drug resistant TB genotypes in Africa
Sporadic molecular mycobacteriological studies have been conducted within Africa (Figures 2 and 3), with South Africa having the vast majority of data on the continent. Diverse genotypes have been associated with drug resistant TB (Figure 2, Figure 3, Table 3), with particular genotypes being more predominant [10, 11, 17, 18, 19, 20, 21]. For instance, the Beijing genotype is widespread across parts of Africa [22, 23, 24]. The population structure of drug resistant TB is however not homogeneous (Figures 2 and 3), with certain strains being more predominant in specific population groups [12, 24, 25, 26, 27, 28]. For example, the Haarlem and CAS genotypes are predominantly associated with drug resistance including MDR-TB in parts of North and East Africa while in Southern and West Africa the Beijing and LAM genotypes are highly associated with drug resistance (Figures 2 and 3) [26, 29, 30, 31, 32, 33, 34]. Further, country-wise comparisons show a correlation between genotypes associated with drug susceptible TB and drug resistant TB, implying that drug resistant TB is to a large extent acquired by individuals within their respective African countries [10, 12, 19, 32, 35].
Associations between specific drug resistant TB strains and HIV co-infection have been noted, with high mortality rates being observed in the context of TB/HIV co-infection [22, 35, 36, 37]. Genotypes such as Beijing, Haarlem and LAM have been associated with high levels of drug resistance and high mortality rates in both HIV seropositive and seronegative individuals [30, 38, 39, 40]. A clear distinction has been observed in the population structure of genotypes associated with mono-resistance, MDR- and XDR-TB (Table 3). In parts of South Africa the F15/LAM4/KZN and Beijing genotypes have been associated with XDR-TB while LAM11_ZWE is associated with MDR-TB in parts of Zimbabwe [33, 41, 42].
A high degree of clustering of drug resistant TB isolates has been observed in parts of Africa [43, 44, 45, 46]; this is of great concern as it implies that there is recent and ongoing transmission of drug resistant TB strains within the region. Furthermore, a correlation between drug resistant strains in the adult population and in children has been demonstrated [47], suggestive of adult to child transmission. There is however very limited molecular typing data on drug resistant TB amongst children and household contacts of drug resistant TB patients in the rest of Africa to confirm this.
Modern lineages (East Asian, EAI and Euro American) have been associated with drug resistance in Central and West Africa (Figures 2 and 3) [48, 49], regions predominantly associated with Mycobacterium africanum (MAF) [48, 49, 50, 51]. Lineage 5 (West-Africa 1) and 6 (West-Africa 2) however continue to predominate in West Africa and are largely associated with drug susceptible TB [52, 53, 54, 55]. The introduction of these drug resistant “modern strains” threatens management of drug resistant TB in the region [56, 57, 58, 59, 60].
Application of molecular methods to describe transmission dynamics of drug resistant tuberculosis in Africa
Acquired MDR- and XDR-TB
There is evidence that acquisition of MDR-and XDR-TB also plays an important role in the burden of drug resistant TB in endemic regions of Africa [64, 65, 79, 80, 81]. Inadequate treatment has been shown to be a significant driving force in the development of drug resistant TB, driven by factors such as poor adherence to treatment, diagnosis delay and low quality anti-TB drugs [82, 83]. The severity of drug resistance in South Africa has been demonstrated to be much higher than other parts of Africa, this could be related to South Africa being the first country to administer second-line treatment on the continent in 2001 [84], and could be also be related to better reporting in South Africa.
The WHO recommends the use of a standardized TB treatment regimen which has been adopted by most countries in the region [2]. In the absence of laboratory monitoring and surveillance, mainly due to poor infrastructure and lack of resources, the risk of acquiring resistance is heightened in high TB burden settings [62, 82, 85]. Further, standardized TB treatment has been shown to be unsuccessful in preventing the spread of drug resistant TB [83, 86]. Therefore, there is a need to implement routine DST and surveillance, supported by molecular epidemiology, for active case finding and to guide effective TB treatment in high risk population groups. On the contrary, a standardised shorter MDR-TB regimen has been demonstrated to be highly effective, with a treatment success rate of 89%, in Cameroon, a high MDR-TB setting [87].
Outbreaks
Drug resistant strains of M .tuberculosis have been linked with 6 distinct outbreaks in parts of Africa [21, 22, 36, 62, 82, 88]. Outbreaks are characterised by sporadic spread of a particular strain of drug resistant TB unlike ongoing transmission which is characterised by constant spread of strains over a longer period of time. A prominent outbreak in Tugela Ferry KZN (mostly amongst HIV positive individuals) involving the F15/LAM4/KZN lineage, brought global focus onto XDR-TB and revealed that XDR-TB strains are transmissible [36]. The main factors associated with the outbreak were an inadequate TB control program coupled with a high HIV prevalence in the affected population [36]. This stresses the need for improved TB infection prevention and control (IPC) measures, together with rapid diagnostics in the successful control of TB in general and XDR-TB in particular.
Outbreaks in vulnerable population groups of institutionalized and HIV positive individuals have also been documented [36, 82]. High clustering rates of drug resistant isolates were observed in a mining community which had a high rate of HIV sero-positive individuals [82]. The outbreak was as a result of an inefficient TB control program and diagnosis delay with the biannual chest radiography screening only diagnosing 30% of TB cases in this group of miners [82]. Recommendations have since been made to improve detection and to promote parallel treatment of TB and HIV in high risk groups [82].
Community outbreaks of MDR-TB in HIV sero-negative, non-institutionalized individuals have also been reported [22, 62]. Molecular investigations have revealed diversity in genotypes associated with outbreaks of drug resistant TB. Genotypes initially identified to be responsible for drug resistant TB outbreaks have been demonstrated to re-emerge in communities as was the case in Tunisia [88]. A subsequent MDR-TB Haarlem strain outbreak was reported amongst the post-outbreak patients’ population group in which the same strain was identified as the progenitor [88]. The findings of these drug resistant TB outbreak studies emphasise that MDR-TB and indeed other drug resistant TB outbreaks are not limited to specific population groups such as the immunocompromised and the institutionalized [22, 88].
There is some evidence that particular bacterial genotypes are associated with outbreaks. The Beijing genotype for instance, which is endemic in parts of South Africa, was linked to an outbreak of MDR-TB at a school in the Western Cape Province [21]. Molecular characterization confirmed that all isolates belonged to cluster R220 [21]. The genotype was further associated with a streptomycin-resistant outbreak in Benin [62]. The occurrence of an outbreak caused by the Beijing genotype in West Africa further highlights the regional emergence of “modern strains” which appear highly virulent and pose a potential threat to TB control efforts in the region.
While host and strain genetics may play a role in driving outbreaks, inappropriate treatment, non-compliance to treatment and delays in diagnosis are amongst risk factors that have been linked to outbreaks within the continent [22, 36, 82].
Nosocomial transmission
The extremely limited data on nosocomial transmission of drug resistant TB in Africa is alarming and places emphasis on the need for molecular epidemiological studies in these high risk settings. Hospital-acquired drug resistant TB has been reported in Africa [11, 82, 89, 90]. An outbreak of the XDR-TB F15/LAM4/KZN strain was described in a district hospital in Tugela Ferry, KZN, South Africa [89]. Epidemiological links for 82% of the patients were made and clustering was observed in 92% of strains [89]. The major risk factors that have been associated with hospital-acquired drug resistant TB are lack of proper IPC measures such as overcrowded wards, poor ventilation and delayed diagnosis [11, 89]. This coupled with the high HIV prevalence experienced in most TB endemic regions makes nosocomial transmission a significant driving force in the transmission of drug resistant TB strains.
Rather than a single point-source outbreak, social network analysis has revealed that patients linked to nosocomial transmissions have a high degree of community interconnectedness [82, 89, 91]. This implies that transmission is occurring both in the community and in the health care facilities. Prolonged exposure to patients with drug resistant TB and frequent, concurrent hospital admissions were common in most XDR-TB patients providing strong evidence that nosocomial transmission had occurred [89, 91].
Transmission of TB and drug resistant TB in particular is not only limited to patients receiving care and treatment in health care facilities but has been described in healthcare workers (HCWs) [92]. HCWs are at an increased risk of acquiring drug resistant TB at the work place, especially in the absence of effective IPC measures [93]. It has been demonstrated that diabetes mellitus and HIV infection are common co-morbidities in HCWs that were infected with MDR-TB in a teaching hospital in South Africa [92]. Other factors that have been associated with occupational acquisition of drug resistant TB and TB in general include: increased contact with patients who typically present to the health care facility when they are highly infectious, complacency and low awareness of self-risk typically seen in longer-serving HCWs [92, 93].
Recommendations made towards improved control measures are to prevent transmission through early diagnosis of resistant TB, minimize congregation areas in hospitals by redesigning wards and out-patient areas and use of personal protective equipment [90, 91, 92, 93].
Migration
Migration has been demonstrated to play a critical role in the spread of drug resistant TB strains globally, with the majority of cases being reported in high-income countries originating from economic migrants from high TB burden countries [94]. There is abundant literature from high-income countries owing to excellent TB surveillance and monitoring [94]. In Africa however, there is very limited information on the impact of migration on transmission of drug resistant TB; this is mainly due to poor surveillance and monitoring. Further, migrant populations typically have poor access to health care and social structures.
Lineages and strains that had previously not been described in particular population groups have been hypothesised to have been introduced to various regions by immigrants [43, 86, 94]. However, the absence of baseline data makes it rather difficult to prove this hypothesis as there is very limited data on drug resistant genotypes that are in circulation within Africa. On the other hand, migration is rife in Africa, mainly due to political instability, civil wars and poverty, and it poses a major concern in the fight against TB and drug resistant TB in particular [95, 96].
Drug resistant strains with streptomycin resistance were detected in a refugee camp in Kenya [43]. Upon comparison to strains in the general populace, the refugee strains were unique to the camp [43]. The nomadic nature of refugees means that they are highly capable of spreading drug resistant strains [95]. There is a higher possibility of refugees failing to complete treatment due to their drifting nature and instability. Further, there is a possibility that the transmission of drug resistant strains is facilitated by a poor TB control program in the country of origin and/or in the refugee camp [43, 87, 95, 97].
Migration is not only an important factor in transmission of drug resistant TB across country borders and across continents, it has also been demonstrated to be an important means of transmission within countries as a result of movement to new cities and provinces in search of better employment opportunities and better health care facilities [43, 98]. For instance, the F15/LAM4/KZN strain has been shown to be widespread both in districts of KZN and in surrounding areas [98, 99]. Further, transmission of drug resistant TB strains has been demonstrated between provinces and districts in South Africa [100, 101]. This stresses a need for rigorous screening of migrants coming from high TB endemic regions and also calls for development and implementation of TB IPC polices in congregate settings in high TB burden regions. However, the above mentioned recommendations are currently not feasible in most African countries due to the porosity of the borders; therefore it is recommended that employers be more vigilant with screening of migrant workers.