Multidrug-resistant tuberculosis (MDR-TB) has become a major public health problem and obstacle to global TB control [1, 2]. MDR-TB is associated with higher case fatality rates, especially among HIV-infected patients [3, 4], and is much more difficult and costly to treat than drug-susceptible TB [5]. The worldwide burden of MDR-TB has been growing, and in 2008, there were 440,000 estimated new cases of MDR-TB, or 3.6% of all incident TB cases, compared to 273,000 estimated new cases (3.2% of incident TB cases) in 2000 [5–7]. However, these estimates may not accurately represent the true global burden of MDR-TB as they are based on surveillance reports from only 114 countries, of which only 10 are sub-Saharan countries with recent or complete national data [5].

Despite the lack of comprehensive surveillance data from Africa, MDR-TB has been recognized as an emerging public health concern. In South Africa, clusters of MDR-TB cases have been documented in institutional and community settings and among HIV-infected patients [3, 8–12]. Epidemiologic investigations of these and other outbreaks have demonstrated that previous treatment for TB and transmission in institutional and community settings are important risk factors in MDR-TB development [10–15].

Since 2007, the National TB Control Program (NTCP) in Namibia has documented an increase in drug-resistant TB (DR-TB) [5, 16]. However, there are few population-level data available to evaluate the prevalence of MDR-TB in Namibia. Namibia has one of the highest TB incidence rates in the world, estimated at 665 new cases per 100,000 persons in 2008 [17]. Among incident TB cases, 59% are estimated to be co-infected with HIV [17]. In 2008, 201 cases of MDR-TB were reported to the NTCP, and the estimated prevalence of MDR-TB was 3.8% among new smear-positive TB cases and 16.5% among previously treated TB cases [17]. However, drug-susceptibility testing (DST) is not routinely performed, making the reported prevalence of MDR-TB in Namibia an underestimate of the true burden.

Data about the relative contributions of specific risk factors to the development of MDR-TB in Namibia are also limited. In late 2008, an investigation of only 34 DR-TB patients by the NTCP and the U.S. Centers for Disease Control and Prevention (CDC) found clinical evidence suggesting acquired TB drug resistance related to incomplete TB treatment in the community and primary transmission of DR-TB in the hospital settings (NTCP, unpublished data). In this report, we describe a more extensive epidemiologic investigation of MDR-TB in Namibia, including possible risk factors associated with MDR-TB.

Detecting the emergence and controlling the spread of MDR-TB begins with its timely diagnosis. However, only 3% of re-treatment controls had a documented DST, despite NTCP′s recommendation that all re-treatment patients receive DST. While recognizing limited resources for DST and the high percentage of TB retreatment, Namibia needs to improve diagnosis of DR TB. This will necessitate impressing upon health care personnel the need to comply with NTCP DST guidelines.

Compared to controls, we found MDR-TB cases were 28 times more likely to have been treated for a previous TB episode, and that among those previously treated, the most recent outcome was failure, default, or unknown for roughly 70% of both cases and control. The association between previous TB treatment and MDR-TB has been noted in investigations in other countries [13–15, 24, 25], while more recent studies have observed that it is previous treatment failure that is significantly associated with MDR-TB [3, 25] Our findings underscore the need to improve basic TB control practices to ensure that all TB patients adhere to and complete TB treatment. TB has been recognized as a significant public health problem in Namibia since its independence in 1990 and the NTCP has continually revised its TB control guidelines, in order incorporate updated WHO recommendations and address DR-TB [16, 18, 19, 26]. However, considerable difficulties exist in providing adequate DOT in a vast but sparsely populated country with high TB prevalence and shortages of trained health care workers [17]. As in other sub-Sahara African countries, the NTCP has introduced community DOT treatment, so that patients in remote areas can easily access DOT [27–29]. These and other interventions need to be strengthened to improve basic DOT coverage and prevent continued emergence of drug-resistant strains in Namibia.

Evidence of transmission of MDR-TB within households and in the community in the current study is not surprising and has also been documented in neighboring South Africa [11, 12]. In our investigation, nearly two-thirds of patients being treated for TB were unaware of how TB is spread, making it unlikely that these patients or their families were aware of measures that could prevent the spread of TB. These findings suggest a need for increased TB education for cases and their household members. In the current study, MDR-TB cases were almost twice as likely to have been previously hospitalized, and nosocomial spread of MDR-TB and institutional outbreaks of XDR-TB have been well-documented in sub-Saharan Africa and elsewhere [10, 13, 30]. Although Namibia developed new infection control guidelines in 2008 and WHO recently revised its policy on TB infection [20, 31], TB infection control measures have not been widely implemented in most Namibian facilities. It is essential for countries such as Namibia to implement effective infection control practices, especially in institutional settings.

Like many countries in sub-Saharan Africa, Namibia has experienced an increase in TB incidence, from 322 per 100,000 persons in 1990 to a peak of 817 per 100,000 persons in 2004, largely related to the growing HIV epidemic. There is conflicting evidence as to whether HIV is an independent risk factor for DR-TB [24, 25, 32, 33]. In our investigation, we found that HIV infection was negatively associated with MDR-TB, i.e. HIV infection was ″protective″ against MDR-TB. As suggested by other studies, this may have been due to HIV- infected persons dying at a higher rate than HIV- uninfected person, such that HIV-infected persons were less likely to live to the point of either developing MDR-TB, or to die before being diagnosed with MDR-TB. The higher death rate among HIV- infected persons is possibly caused by the combination of 1) poor treatment outcomes, due to malabsoprtion of anti-TB drugs or lower rates of adherence, and 2) a greater likelihood of being exposed to MDR-TB patients during medical visits or hospitalizations [3, 34–39]. With CD4 count information documented for less than half of HIV-infected cases and controls, improved linkages to HIV care and treatment services and earlier initiation of ART are critical. WHO recently revised its treatment recommendations for HIV-infected TB patients to initiate ART earlier, regardless of CD4 count, and this may be especially important for HIV-infected patients with MDR-TB [40].

Although our investigation showed associations between various characteristics and MDR-TB, assessing these as risk factors is constrained by the limitations of our investigation. First, because of Namibia's resource limitation and the urgent nature of our investigation, DST was performed almost exclusively (96%) on retreatment patients, making retreatment necessary for obtaining an MDR-TB diagnosis. Thus, it was not possible to fully assess the extent of primary MDR-TB transmission and the lack of previous treatment outcome data did not allow us to assess this effect. Second, few controls had a documented DST result, potentially leading to misclassification bias. Generally, this type of misclassification would bias the associations towards the null, suggesting that the associations reported in this investigation are true associations. However, as the major associations were also associated with having a DST, the effect of this misclassification might have a more complex effect. We performed two sub-analyses that restricted the control groups to either CAT I, of which 28/142 (20%) were previous treated for TB or CAT II, of which 87/94 (93%) were previously treated. These analyses suggest that CAT II controls may have been more likely to be misclassified as compared to CAT I controls, for which 5 of the 6 crude associations remained significant. Third, because NTCP guidelines recommend inpatient treatment for patients with DR-TB but not drug-susceptible TB, patients selected from inpatient facilities were more likely to be MDR-TB cases. Documentation was more extensive for inpatients, which could have resulted in an information bias for MDR-TB cases. Although hospitalization status confounds the magnitude of the crude associations, it does not change their significance or direction. Lastly, we were unable to fully assess the temporality of contact with patients with TB or MDR-TB and our study cannot definitively establish nosocomial or household transmission. Additional investigations in Namibia are needed to adequately describe the amount of primary and acquired MDR-TB.

In summary, we found that previous TB treatment, previous hospitalization, and household contact with an MDR-TB case were associated with MDR-TB in Namibia. Our findings reinforce the importance of maintaining strong overall TB control measures, to ensure adherence to diagnostic protocols, that all TB patients complete an appropriate treatment regimen through DOT programs, and that appropriate household and institutional infection control measures are observed. This has become even more critical, in light of the high prevalence of HIV-infection in Namibia, which may decrease adherence and/or the effectiveness of TB treatment and increase the risk of exposure to MDR-TB due to HIV-related hospitalizations. Finally, enhancing patient education is critical in helping patients and their families understand the importance of treatment adherence and implementing measures to prevent the spread of TB within the household and the community.

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of U.S. Centers for Disease Control and Prevention.