Tuberculosis is a leading cause of death worldwide. According to the World Health Organization (WHO) over 1.7 million people with tuberculosis died in 2008 [1]. Advanced age, male gender, delays in diagnosis and treatment, drug resistance, and co-morbid conditions including HIV co-infection, diabetes, renal disease and COPD, have been associated with increased risk of death in patients with active tuberculosis [2–8]. A substantial proportion of deaths occur during tuberculosis treatment despite patients being on an appropriate regimen. Since drug-susceptible tuberculosis is a disease in which cure is achievable in a vast majority of patients (>95%) [9], it is plausible that the reported rate of mortality of 25.8 tuberculosis deaths/100,000 person years may be decreased if modifiable risk factors for mortality are identified and targeted early [10]. In this retrospective study, our principle objective was to evaluate outcomes of tuberculosis treatment in a low-incidence setting, where patients were managed at a tuberculosis control program without significant resource limitations. The period during which our study was conducted provides an opportunity to evaluate outcomes not only in HIV-uninfected patients but also a cohort of HIV-infected patients who were HAART treatment naïve, a population that is challenging to find in the United States but represents more than 90% of the estimated 1.4 million HIV-infected tuberculosis cases worldwide [1]. We previously reported our findings on risk factors for relapse of tuberculosis [11]. The current analysis examines the clinical, radiographic and microbiologic characteristics associated with increased risk of death during treatment for drug-susceptible pulmonary tuberculosis with the aim of alerting clinicians and tuberculosis control programs of characteristics that identify groups at increased risk for mortality.

An episode of interruption in therapy from any cause was identified in 205 of 565 study participants. Of the 205, 186 cases had an interruption in therapy that met the study definition for inadequate therapy. Overall, 27% of patients experienced an episode of inadequate therapy during the intensive phase of treatment, and 23% in the continuation phase. Experiencing an episode of inadequate therapy, in particular during the intensive phase, was significantly more common in the patients who died as compared with those who survived (p = 0.001). Analyzed separately by the two causes defined for inadequate therapy, non-adherence versus adverse reactions, the association remained significant for non-adherence during the intensive phase (HR = 3.20, 95% CI 1.64-6.24, p = 0.001), but not for adverse reactions. While the relative hazard was high for the association between adverse reactions during the intensive phase and mortality, the relationship did not reach statistical significance (HR = 1.74, 95% CI 0.73-4.13, p = 0.21). Overall, the median duration of treatment interruption for patients who died was not different from those who survived (37.5 days versus 36 days, respectively, data not shown). Examining the median duration of days a patient received inadequate treatment in more detail, by phases of treatment (Table 1), we found that both intensive and continuation phase interruptions were longer in those who died (median of 23 and 37 days, respectively) as compared with those who survived (median of 18 and 29 days, respectively). Whereas the association between median duration and mortality was in a biologically plausible direction when looked at by phases of treatment, the differences were not statistically significant (all p > 0.1).

Survival curves generated using the Kaplan-Meier method stratified by HIV status and adequacy of intensive phase therapy with follow-up time truncated at 18 months (overall p = 0.001) are shown in Figure 1. The greatest difference in rates of survival were between patients with both HIV co-infection and an episode of inadequate therapy (89.7% survival at 6 months, 81.2% at 12 months), compared with patients with neither HIV co-infection nor inadequate therapy (98.4% survival at 6 months, 97.1% at 12 months) (p < 0.001). Survival rates between those with HIV co-infection and no evidence of inadequate therapy (95.4% survival at 6 months, 94.2% at 12 months) and those without HIV infection who had an episode of inadequate therapy (92.6% survival at 6 and 12 months) were the same (p = 0.41).

In this study, four characteristics were independently associated with increased risk of mortality during treatment for drug susceptible tuberculosis. These characteristics were older age at diagnosis, HIV co-infection, sputum smear positivity for acid fast bacilli at baseline and experiencing an interruption in tuberculosis therapy during the intensive phase of treatment. Whereas prior studies have reported older age, comorbid conditions including HIV and advanced tuberculosis as non-modifiable determinants of death in tuberculosis [4, 13–15], our study identifies treatment interruptions as a risk factor that is potentially modifiable through programmatic action. The association is also important to recognize as it suggests that interruptions in therapy have implications that go beyond recognized increases in risk for microbiologic failure, relapse of disease or even development of drug resistance.

We sought to clarify other aspects related to interruptions, including the timing, duration and cause of interruptions. The timing of inadequate therapy for tuberculosis proved to be important. Interruptions during the intensive phase were associated with mortality, whereas interruptions during the continuation phase were not. This finding suggests that interruptions occurring early, when drugs have bactericidal activity against replicating organisms, have greater implications for risk of death than interruptions during the continuation phase when therapy is focused on clearing persistent bacilli to prevent relapse [16]. In regard to duration of interruptions, the median duration was longer in those that died as compared with those that survived, however, the difference was not statistically significant in either intensive or continuation phases. Next, we explored the two causes of interruptions in treatment, adverse reactions and non-adherence, and found that non-adherence appeared to be driving the association. These stratified analyses may have lacked power to definitively exclude adverse reactions as a risk factor for death, however, we believe that differences between the two causes of interruption make this distinction plausible. In reviewing the treatment interruptions, we found that interruptions from non-adherence often resulted in complete cessation of all medications, in contrast to interruptions from adverse reactions which were handled by temporary cessation of medications followed by swift rechallenge until a tolerable regimen was identified. We also reviewed autopsy reports, death certificates and the medical charts for all 37 patients who died during treatment and found no evidence to suggest that adverse drug reactions played a direct role in any of the deaths. Finally, it is important to note that whereas we found non-adherence to be associated with increased risk for death, the reverse relationship seen between DOT use and death was due to confounding by association given that our program has a strict policy to initiate DOT in all patients at high risk for poor outcomes, including death.

Our study has several limitations. Given its retrospective nature, we were unable to distinguish between the reason for and effect of treatment interruption as it related to the association with death. While we reviewed all available charts, computer records, death certificates, and autopsy information to determine cause of death, a minority of cases had post mortem analyses (7/37). Consequently, factors associated with death were not necessarily causal. Second, our findings are not relevant for HAART treated/exposed populations, as the majority of the HIV-infected individuals in this study were HAART naive. Of the 37 deaths, only one HIV-infected individual was on HAART, precluding our ability to evaluate the role of HAART in preventing death. This is an important limitation given the well recognized benefits of HAART on survival. However, we believe our findings are still relevant as the majority of HIV-related tuberculosis in the world continues to be managed without early initiation of HAART. Finally, we cannot extrapolate these findings to foreign-born individuals who self-reported Asian race as they were excluded from the parent study. A recent evaluation of deaths among 7,999 culture positive pulmonary tuberculosis cases in Shanghai, China, identified advanced age, sputum smear positivity, comorbid conditions and gender as factors associated with death [15]. However, additional studies are needed to determine whether these factors also pertain to foreign-born Asians residing in the US.

In summary, in addition to the nonmodifiable characteristics of advanced age at diagnosis, HIV co-infection and sputum smear positivity at baseline, experiencing an interruption in treatment during the intensive phase of treatment was associated with an increased risk of death. Our analyses suggest that non-adherence, more so than adverse drug reactions, may be driving this association. Continued investment in programs such as DOT that can promote adherence early during treatment for tuberculosis may both improve tuberculosis outcomes as well as decrease mortality.