There are an estimated 13,000 cases of multidrug-resistant tuberculosis (MDR-TB) emerging in South Africa each year [1]. These estimates are primarily based on a national survey performed in 2001, combined with routinely reported case numbers, and thus many believe this to be an under-estimation of the current situation. In addition, South Africa has a growing epidemic of extensively drug-resistant tuberculosis (XDR-TB) associated with high mortality among HIV infected individuals [2]. The continued emergence of MDR- and XDR-TB poses a significant threat not only to tuberculosis control but also to progress made in the expanded provision of antiretroviral treatment (ART) for HIV.

Drug-resistant tuberculosis (DR-TB) requires much longer and more costly treatment regimens than drug-susceptible tuberculosis, and in most high HIV prevalence settings, there is limited capacity for diagnosis. Thus, in many settings, few patients are diagnosed with DR-TB and even fewer receive adequate treatment. The HIV epidemic has driven dramatic increases in tuberculosis case notifications in southern Africa [3]. While expanding access to ART is expected to ultimately reduce tuberculosis case notifications, it may also contribute to the large pool of individuals with increased vulnerability to TB created by the HIV epidemic [4]. The convergence of these conditions: the high rate of tuberculosis prevalence, a vulnerable population and the existence of undiagnosed and untreated drug resistant tuberculosis create the potential for dramatically increasing epidemics.

To date, there have been limited data available on the prevalence of DR-TB in high HIV prevalence settings. Only 12 countries in the African region have conducted nationwide surveys since 2000, with few disaggregating by HIV status [1]. While a number of countries are planning national representative surveys, such surveys aimed at deriving nationwide estimates of DR-TB burden may mask pockets of extremely high tuberculosis drug resistance, particularly in settings with existing high rates of both HIV and tuberculosis. There is an urgent need to quantify the extent of the drug resistant tuberculosis epidemic in these settings in order to advocate for and develop strategies for control. This study aimed to assess the burden of tuberculosis drug resistance in a peri-urban setting in Khayelitsha Township outside Cape Town, South Africa.

Eastern Europe and the former Soviet Union have been described as global “hot spots” for tuberculosis drug resistance [14]. This has primarily been based on assessments of the proportion of all TB cases suffering from drug resistant disease. However a more accurate reflection of the burden imposed by MDR-TB and the threat of increasing spread can be given through assessing population based incidence rather than proportions [15]. Using this approach, South Africa has an estimated population incidence of MDR-TB similar to that in the Russian Federation; 26/100,000/year and 27/100,000/year respectively [1].

The data presented here show that in Khayelitsha, a densely populated urban township in South Africa, the estimated burden of MDR-TB is extremely high, at 51/100,000/year based on notified TB cases, with incidence likely to be considerably higher taking into account incomplete tuberculosis case detection in the community. A large proportion of MDR-TB cases have pre-existing second-line tuberculosis resistance and indeed XDR-TB in the absence of extensive previous second-line treatment (data not shown). These data suggest a burden of MDR-TB more than twice that previously estimated for South Africa. Given the high population density, poverty, high HIV and TB prevalence in Khayelitsha, these data are unlikely to be representative nationally. However the living conditions in Khayelitsha are reflective of the large proportion of South Africans who are most at risk for tuberculosis. Urban and peri-urban townships like Khayelitsha therefore should be the focus of particular attention for both surveillance and epidemic control.

Currently available diagnostics for tuberculosis drug resistance rely on culture and are therefore slow, cumbersome and commonly only available through centralised laboratories. As a result, DST is only selectively available if at all and even in South Africa is only available for previously treated TB cases. The data from Khayelitsha suggest that a large proportion of MDR-TB cases occur in new TB suspects, who are not routinely tested for drug resistance. These patients are therefore likely to receive ineffective first-line anti-tuberculosis treatment resulting in likely amplification of resistance, poor treatment outcomes including increased mortality, and not least fuelling increasing transmission through remaining infectious and inadequately treated in the community. If DST is only accessible for those failing treatment, a large proportion of cases will be missed due to the high risk of death among HIV positive patients with untreated DR-TB [2]. Early diagnosis and improved case detection, through increasing access to DST, either with culture or newer diagnostics such as the line probe assays, is therefore fundamental to both identifying the scale of this epidemic and to developing strategies for control, in addition to reducing mortality.

The extent of MDR-TB among new, previously untreated TB cases in this survey suggests that at least half of all MDR-TB is due to ongoing primary transmission in Khayelitsha. Transmission may be even higher; up to 80% of cases may be transmitted, as it cannot be assumed that MDR-TB among previously treated cases is always due to resistance amplification. While this is a gross approximation of transmission, clearly transmission remains a substantial cause of incident MDR-TB cases in this setting.

Tuberculosis drug resistance has traditionally been blamed on poor TB control programmes and poor patient compliance with treatment. However, HIV infection has also been suggested to contribute to both an increased risk of acquiring resistance and to the risk of direct infection with DR-TB. Acquired rifamycin resistance has been demonstrated among HIV positive TB patients in well controlled clinical trials and other studies [16]–[18]. Contributing factors in these studies include low CD4 levels, co-administration of ART, extra-pulmonary TB and treatment for co-morbidities. Drug malabsorption has been demonstrated among HIV positive patients receiving tuberculosis drugs [19], [20], but there is limited data among those receiving concomitant ART. Given that in high TB prevalence areas, HIV positive individuals, even those receiving ART, are likely to repeatedly develop active tuberculosis and receive treatment [21], the development of DR-TB, independent of poor treatment adherence and other programme factors can be hypothesised.

HIV infection was not significantly associated with rifampicin resistant TB in multivariate analyses, either overall or among previously treated TB cases in this large community based representative survey. Rather, consistent significant associations were found between recent TB treatment and rifampicin resistance. These data suggest that any observed associations between HIV infection and DR-TB may be mediated through the propensity for HIV infected individuals to be repeatedly treated for TB and that HIV is not an independent risk factor for infection and development of active DR-TB disease. However, without prospective data and molecular genotyping of strains from subsequent TB episodes, it is not possible to differentiate the extent of acquisition of resistance during TB treatment, and the impact of HIV infection and concomitant ART on resistance acquisition, from reinfection with a DR-TB strain. It may be that HIV infected individuals who have been treated for TB previously are more exposed to DR-TB in nosocomial settings. Indeed, nosocomial transmission is suggested to be a significant cause of MDR- and XDR-TB transmission in Msinga district, KwaZulu Natal, South Africa [22], while previous hospitalisation was also an independent predictor for MDR-TB among previously treated TB cases in the South African national prevalence survey [8].

This survey is subject to the usual limitations in survey design and data collection. While restricted to two primary care clinics in Khayelitsha, these two clinics were responsible for diagnosing and treating approximately 50% of TB cases in Khayelitsha in 2008. Nonetheless, if nosocomial transmission is a significant factor driving DR-TB transmission, the risk of DR-TB infection through a larger clinic may be greater than that in the smaller primary care clinics in Khayelitsha. While previous tuberculosis treatment was verified through medical record review when possible, there is likely to be a tendency for patients to not report previous treatment in order to avoid receiving daily streptomycin injections and the longer treatment course. While such a bias could lower our estimate of overall MDR-TB prevalence, the data still suggest a substantial number of MDR-TB cases would be diagnosed if all TB cases were to be tested.

The Khayelitsha tuberculosis treatment programme reports reasonable treatment outcomes for 2008; currently treatment success stands at 82% for new TB cases and 50% for previously treated cases [6]. However this is a relatively recent improvement, with outcomes prior to 2003 significantly lower than this, including substantial rates of treatment interruption and default. Such conditions are likely to have contributed to the initial development of acquired resistance among patients receiving poor tuberculosis treatment [23]. However, the data presented here suggest that while acquired resistance may remain important, the great majority of MDR-TB is now due to direct transmission of already resistant tuberculosis strains. The overall lack of association with HIV infection is therefore unsurprising.

Although HIV infection, along with previous sub-optimal tuberculosis treatment programmes, may have contributed to the initial emergence of tuberculosis drug resistance, the high community HIV prevalence in Khayelitsha does not appear to be a significant factor selectively driving DR-TB transmission in this setting. Rather high HIV prevalence is driving transmission of both drug susceptible and drug resistant tuberculosis. High rates of transmission of drug resistant tuberculosis highlight the need for improved infection control measures, both in health care facilities and at community level. Based on the large burden of DR-TB in this setting and given that it is likely that the epidemic is being driven by transmission, innovative models of care aiming to diagnose and treat as many DR-TB cases as possible and as early as possible will be required to interrupt transmission. Such models will by necessity require rapid DR-TB diagnostics as close to point of care as possible, and for all TB suspects, along with decentralised treatment of patients. It is unlikely that any centralised system will be able to cope with the large numbers of patients requiring treatment or to hold them on treatment for the full time required. Existing tuberculosis treatment services will need to be utilised and strengthened in order to expand access to diagnosis and treatment for drug resistant TB.