Poor tuberculosis treatment outcomes in Southern Mozambique (2011–2012)

This study is one of the few operational research studies assessing TB treatment outcomes
and mortality burden attributable to TB in Mozambique. We found an extremely high
fatality rate among patients on TB treatment (15.1 %), much higher than recent figures
from neighboring sub-Saharan African countries 15]–17]. Moreover, the general contribution of TB to the overall causes of mortality in our
district is very high (6.5 %), skyrocketing up to one out of every five deaths among
young adult females and males in their mid-thirties.

Tuberculosis was an important cause of death in both 2011 and 2012, especially among
middle age groups. Although the analysis approach does not allow comparison among
other diseases, it is very likely that TB ranks among the leading causes of death.
In South Africa, during 2013, tuberculosis was the leading cause of death, accounting
for 8.8 % of all deaths, and of 9.8 % of all deaths for natural causes 18]. As in South Africa, our study shows that the proportion of deaths due to tuberculosis
among all deaths by natural causes was higher for males (7.8 %) compared to females
(5.4 %). Due to the difficulty of ascertaining the actual cause of deaths of TB patients,
we have defined death due to tuberculosis as a death occurring during TB treatment.
This certainly overestimates the true TB attributable deaths among patients on treatment,
since dying during TB treatment does not equal dying of TB. However, since our analysis
is based on deaths among notified TB cases only and WHO estimated a case detection
rate of 34 % in the country during 2012, it is very likely that it underestimated
the true TB contribution to the death burden. To accurately ascertain cause of death
by TB, the only acceptable method would be the postmortem evaluation of those cases
19], 20].

The treatment success rate (which includes those cured or who completed treatment)
in the district of Manhiça for the period 2011–2012 was 71.2 %, and 76.6 % among those
laboratory confirmed TB patients. More than 50 % of the cases who did not achieve
treatment success died (defaulting, treatment failure and transfer out cases account
for the other cases). These results are far below the 87 % treatment success target
set by the Stop TB partnership for the year 2015 and even further away from the new
target (90 %) of the Global Plan to Stop TB 2011–2015 5]. Although at a country level Mozambique reported treatment success rates of 87 %
among new cases 1] for the year 2013 (no data are available for 2012), the lower figures obtained in
the district of Manhiça might have different explanations. HIV prevalence among TB
cases in the district of Manhiça has been reported to be higher than national level
estimates 6]. Our study and the literature repeatedly report a higher proportion of poorer outcomes
among HIV-infected individuals 15], 21]–24]. Among HIV patients, the proportion of patients on ART (at any time during treatment)
was very low (41.0 %). This contributes to the overall poor outcomes 17], 25]. The reason behind better treatment outcomes in 2012 than 2011 is driven primarily
by a higher proportion of patients on ART (the difference disappears after adjusting
for HIV infection and ART status in the multivariable regression model). Interestingly,
there is substantial 4 % additional mortality from 6 month to 1 year after treatment
initiation (when most patients have already finished treatment). This could be attributable
to clinical conditions related to HIV/AIDS, although cannot explain all the additional
mortality after 6 month treatment, since some of those deaths occurring 6 months after
treatment initiation were in HIV negative individuals. High defaulting treatment rate
(10 %) and poor adherence to TB treatment (which would translate into longer treatment
periods), but not necessarily defaulting, could also be another factor for low success
rate, although the length of TB treatment was not assessed in our study.

Those TB cases who were not laboratory confirmed with smear microscopy had a higher
odds of dying during treatment than those who were just clinically diagnosed (Table 1 and Fig. 2b). This might have two different explanations. Some may have been misdiagnosed with
TB, thus antituberculous therapy was useless and could have delayed or prevented access
to the correct treatment for their condition. Another explanation would be that HIV
positive individuals have higher immunosuppression (lower CD4 counts) and are often
paucibacillary, thus less likely to have a positive smear. This may have led to diagnostic
delays, contributing to the poorer outcomes 26]. Although several studies have shown that re-treatment cases are more likely to have
a poor outcome 26], mostly as a consequence of higher rates of defaulting and higher MDR rates, we could
not show this association in our study. A potential explanation for this is that information
on previous TB treatment might have not been properly recorded (patients’ recall bias
or lack of adequate history taking). Only 10 % of patients were classified as retreatment,
while, for example, in Cape Town, South Africa, retreatment cases consistently account
for 30 % of notified TB cases 27], 28].

Although TB/HIV patients not on antiretroviral treatment were significantly more likely
to have a fatal outcome than those taking ART (20.3 % vs 12.5 %, p??0.001), we expected to find a greater difference 29]. Kaplan Meier survival analysis, although conducted on a smaller sample, did not
show statistical differences between both groups. Besides the small numbers, this
might be due to the fact that patients who received ART were also those at highest
risk of dying (because they had low CD4 counts or other opportunistic infections).
An alternative explanation could be the poor reporting on ART status before February
2012, when the HIV/TB one-stop model was implemented in the district (HIV treatment
during TB treatment being provided and monitored by the NTP officers). In fact the
proportion of HIV infected TB patients on ART increased sharply from 2011 to 2012
(20 % to 62 % respectively). Thus, some patients might have started HIV treatment
during TB treatment also in 2011, but this information may have been poorly or not
registered on the TB registry books. In fact, a recent study in Manica Province (Central
Mozambique), reported that only 73 % of data on ART use in the TB registry were correct
30].

This study had several limitations. The linking of the NTP registry book with the
HDSS dataset could only be done to a subset of patients belonging to the study area,
limiting the sample size for the survival analysis. The reasons for this are the different
names used by patients, handwriting errors on the matching variables and the impossibility
of verification on those without a perfect matching. That said, we believe there are
no sources of selection bias in the sample used for this analysis. Second, we could
not assess the impact of other important variables/comorbidities on mortality, such
us malnutrition, diabetes, occupation or immunosuppression (CD4 counts), which would
provide further characterization of TB mortality factors. Third, the aforementioned
potential misreporting of use of ARTs or TB type (new case or retreatment) calls for
cautious interpretation of the magnitude of association of mortality and these two
variables. Fourth, during the study period, culture was not routinely performed, thus
some false positive smear results, due to non tuberculous mycobacteria (NTMs) could
have occurred. However, this might have had limited impact on treatment outcomes,
since the proportion of NTMs among positive smears from adult population is below
2 % (unpublished data). Lastly, due to the lack of reliable information on dates of
death and defaulting and very few deaths on the subsample that could be linked to
HDSS, Cox regression, a preferred analysis strategy for analysis factors associated
to mortality, was not performed.