Independent predictors of tuberculosis mortality in a high HIV prevalence setting: a retrospective cohort study

Over the past two decades, HIV co-infection has emerged as the greatest risk factor for developing active TB and causing TB-related deaths [1]. Reducing TB-related deaths is a priority in high burden countries. One of several strategies to reduce TB mortality is to identify those at increased risk of death. This strategy is especially important in developing countries where incident TB is frequent, and access to resources is constrained.

In regions of high TB incidence and high HIV prevalence, risk factors for TB case fatality include: older age (mostly >35 years) [2‐5]; HIV positivity [2, 4, 6‐9]; features of advanced HIV [8, 10‐12]; smear-negative disease [3, 7, 9, 10, 13]; and malnutrition [4, 8, 14]. Studies in South Africa have determined predictors of TB mortality [6, 7, 15, 16]. However, these studies were of small or moderate sample size [6, 7, 15, 16], performed in gold mines with concomitant silicosis [6] or preceded the expansion of HIV services, trimethoprim-sulfamethoxazole chemoprophylaxis and antiretroviral treatment [6, 7, 15, 16].

Identifying predictors for mortality in South Africa in the ART era using TB surveillance data could inform resource allocation and strategies to reduce TB-related mortality. Here, we report our analyses of a complete electronic TB register of over 16,000 TB cases, where we determined predictors of death during TB treatment in a high HIV prevalence setting.

In a surveillance population of over 16,000 adults with active TB, we found several easily identifiable and independent predictors of death during TB treatment. In those not infected with HIV, the risk of death increased with advancing age but decreased with smear-positive disease. In those infected with HIV, the risk of death increased with advancing age and female gender but decreased with a higher CD4 count and ART. These findings inform resource allocation strategies to reduce TB mortality in high HIV/TB settings.

Among HIV-infected adults receiving TB treatment, we found that women were at an increased hazard of death compared to men. This finding is interesting as HIV-infected men without TB typically have worse outcomes on ART, compared to women [27]. This discrepancy suggests that gender-TB or gender-ART interactions exist. Unmeasured confounding such as background mortality gender differences in this community could also explain this difference. Among HIV-uninfected persons with active TB, one study from Bolivia similarly found increased mortality among women, while other studies from Brazil, Italy, China, and Viet Nam found increased mortality among men [28‐33].

Only 30 % of HIV-infected TB cases in our study received ART during TB treatment. This finding is likely because ART was only indicated for those with a CD4 count of less than 200 cells/μL, according to national guidelines at the time [18]. We found that ART reduced the risk of dying in our analysis. This finding occurred despite possible time-dependent confounding [34], wherein the observed benefit of ART would be smaller than anticipated because ART was started in sicker patients at various time-points during TB treatment. Our study adds impetus to current WHO guidelines that ART be initiated among all HIV-infected adults with active TB, regardless of CD4 count [35]. In those infected with HIV, interventions such as starting ART at higher CD4 counts may need to be prioritized in those of advanced age, or of the female gender. In those not infected with HIV, interventions will need to be prioritized in those with advancing age and those with smear-negative disease. Smear positive disease was protective of death among HIV-uninfected TB cases. Patients with smear negative disease may have had a diagnosis other than TB. Our previous study investigated reasons for clinical deterioration in patients on TB treatment. We found that 4 % of HIV infected TB patients and 9 % of HIV uninfected TB patients had alternate diagnoses to TB [36]. In HIV uninfected TB patients, these diagnoses included post-TB bronchiectasis, pulmonary silicosis, bacterial sepsis and lung cancer [37]. Smear negative disease could also reflect alternate illnesses such as sarcoidosis and lymphoma where inappropriate therapy could be fatal.

Among those infected with HIV, we found no association between smear results and death. Studies have found conflicting results with both smear positive and smear negative TB disease being associated with death [3, 9, 32]. TMP-SMX chemoprophylaxis has been shown to reduce mortality in HIV-infected patients [38, 39]. In our study, TMP-SMX chemoprophylaxis was not associated with reduced mortality. However, we were unable to assess the impact of this intervention on mortality because more than 95 % of our HIV-infected TB cases received TMP-SMX chemoprophylaxis.

Our study has several limitations. Loss to follow-up occurred in 10.5 % of cases and likely led to under-ascertainment of deaths [40]. Our study is retrospective, so our findings may be subject to random error, bias, and confounding. We minimized random error by utilizing a large surveillance population of over 16,000 TB cases. Also, trained health care personnel used a standardized data form during the study period, which likely reduced bias. Lastly, confounding was minimized by employing multivariate regression analyses including variables such as age, gender, HIV status, CD4 count if HIV-infected, TB smear result at TB diagnosis, history of prior TB, anatomic site of TB, and concurrent TMP-SMX and antiretroviral treatment during TB treatment. These variables have been shown to affect mortality during TB treatment [41]. We acknowledge that we did not have data on variables that may have influenced mortality, such as AIDS-defining illnesses; non-infective co-morbid illnesses; isoniazid prophylaxis therapy, nutritional factors; anemia; baseline performance status; socio-economic factors; smoking, alcohol and substance misuse; duration of symptoms prior to TB diagnosis; treatment adherence and drug-resistant strains; and HIV viral load [41]. We also were unable to correlate chest x-ray findings with mortality. Mortality during TB treatment may correlate with the extent of TB disease as evidenced by chest X-ray involvement and the presence or absence of cavity formation.

Despite these limitations, our study’s large sample size, standardized data collection and careful inputting of missing data add value to current literature. Our study identifies several easily recognizable factors that could be targeted to reduce TB mortality. Firstly, HIV testing should be performed for all TB patients. Secondly, we recommend a triple strategy among those infected with HIV. This triple strategy would include immediate (same day) CD4 counts at HIV diagnosis, expedited referral to HIV clinics for ART initiation and prioritization of ART for those of advancing age and of female gender. In HIV infected and HIV uninfected TB patients, our study identified those with advancing age as an independent risk factor for death. By identifying increasing age as a predictor of death, further research is now needed to determine whether excess TB deaths are due to age-related co-morbid illnesses or due to dysfunctional intracellular processes, such as autophagy [42]. Age related co-morbid illnesses such as ischemic heart disease, stroke, lower respiratory infections, diabetes and chronic obstructive pulmonary disease are listed in the top twenty causes of death in South Africa [43]. Importantly, a substantial proportion of TB patients have co-morbid illnesses such as hypertension (37 %) and diabetes (12 %) in this community [44]. If these co-morbid illnesses contribute to TB-related deaths, interventions would need to be implemented at TB diagnosis to diagnose and treat them.

In a surveillance population of over 16,000 adults with active TB, several important predictors of death during TB treatment were recognized. In those not infected with HIV, the risk of death increased with advancing age but decreased with smear-positive disease. In those infected with HIV, the risk of death increased with advancing age and female gender but decreased with a higher CD4 count and ART. In a region of high TB incidence and high HIV prevalence with scarce resources, stratification at TB diagnosis by age, gender, HIV status and smear result would enable targeted interventions to reduce TB-related deaths.