Tuberculosis and HIV : evaluation of new tests for diagnostic accuracy, cost-effectiveness and effect on treatment of tuberculosis in Smear-Negative HIV-positive patients in Uganda

Background: 

Despite tremendous progress in the control of the global tuberculosis (TB) epidemic during the past decade, it is
still a major health problem even today. The burden of TB is particularly severe in sub-Sahara Africa where TB
and HIV co-infection is common, especially in those who are smear-negative. Such patients are twice more
likely to die from TB than their counterparts because of delayed diagnosis and treatment. This thesis focuses on
the evaluation of currently available new tests which have been developed to facilitate rapid diagnosis and early
treatment of TB. 



Aims: 

The purpose of this thesis was to increase knowledge about the diagnostic accuracy, cost-effectiveness and
effect on treatment of TB of the new tests in smear-negative HIV-positive patients in a context where resources
are limited. 



Methods: 

In study I, a systematic review was performed to summarize and compare the over-all accuracy for smearnegative
TB of the existing traditional TB tests (WHO 2007 TB algorithm) and two new tests: Xpert MTB/Rif
test (a molecular-based method) and Microscopic Observation Drug Susceptibility test (a culture-based
method). In study II, a cross-sectional study was performed to collect primary laboratory data on the diagnostic
accuracy for smear-negative TB of Xpert MTB/Rif (GeneXpert), Microscopic Observation Drug Susceptibility
test (MODS) and Nitrate Reductase Assay (NRA) in HIV-positive patients. The results of the three tests were
compared with traditional solid Löwenstein-Jensen (L-J) TB culture and a new conventional liquid (MGIT) TB
culture method. In study III, we modelled the cost-effectiveness of using MODS or GeneXpert-based algorithm
for diagnosis of pulmonary TB in HIV-positive patients. Finally, in study IV, we investigated how best to treat
patients with presumptive pulmonary TB who were both Smear and GeneXpert negative. 



Results: 

From study I, we found that the sensitivity of the tests for smear-negative TB was moderate (61-73%). The
specificity was high for both GeneXpert (98%) and MODS (91%) but moderate for the WHO 2007 TB
algorithm (69%). From study II, we found that GeneXpert, MODS and NRA had low sensitivity for smearnegative
TB in HIV-positive patients (24-49%). However, the specificity of all three tests was high (92-98%).
From study III, we found that utilizing a MODS-based algorithm for diagnosis of pulmonary TB in HIVpositive
patients was more cost-effective than utilizing a GeneXpert-based algorithm (US$ 34 versus US$ 71
per TB patient diagnosed). From study IV, we found that a smear and GeneXpert-negative test result had a high
negative predictive value for TB. Thus, despite the low-moderate sensitivity of GeneXpert for smear-negative
TB, a majority of patients (88%) responded fully to antibiotic treatment and empiric TB treatment was initiated
in only a few (8%) of them. 



Conclusions: 

GeneXpert, MODS and NRA are useful for diagnosis of TB in smear-negative patients including those who are
HIV-positive. The tests could be used to improve the existing WHO 2007 TB algorithm. But since they have
low-moderate sensitivity, additional evaluation for TB is required in those who test negative using these new
tests. The high specificity of GeneXpert, MODS and NRA implies they are highly reliable to initiate TB
treatment in those with positive results. From an economic view point, utilizing a MODS-based algorithm for
diagnosis of TB in HIV patients is more cost-effective than a GeneXpert-based algorithm. Therefore, where
resources are limited, MODS could be used as an alternative to GeneXpert. Using an antibiotic treatment trial in
HIV patients who are both smear and GeneXpert negative could be useful to reduce empiric TB treatment
because of the high negative predicative value for TB of the two combined tests