Prevention of Early Mortality by Presumptive Tuberculosis Therapy Study: An Open Label, Randomized Controlled Trial

Abstract

Abstract. Early mortality after initiation of antiretroviral therapy (ART) occurs in 9-39% of patients in sub-Saharan Africa. A significant proportion of deaths are attributable to tuberculosis (TB). Low baseline CD4 T-cell count and low body mass index (BMI) are strongly associated with early mortality. We hypothesized that initiation of ART concurrent with presumptive anti-TB chemotherapy in high-risk patients would reduce mortality within the first 6 months by treating unrecognized TB. From October 2011 to December 2012, ART-naive, smear-negative participants with a CD4 T-cell count < 50 cells/μL and BMI < 18 kg/m 2 were randomly assigned to undergo either empiric four-drug anti-TB treatment followed 2 weeks later by efavirenz-based ART (N = 23) (ART + TB) or ART only (N = 20). This open-label, 1:1 randomized, controlled trial took place in Uganda, Mozambique, and Gabon and was stopped prematurely by the sponsor for slow recruitment. Overall, the 43 participants had a median CD4 of 22 (interquartile range [IQR]: 9-35) cells/μL and a median BMI of 17.5 (IQR: 16.6-18.0) kg/m 2 . The mortality was 14% (95% confidence interval [CI]: 5.3-27.9); two (10.0%) participants (ART-only group), and four (17.4%; ART + TB group). The associated hazard ratio (HR) for all-cause mortality was 1.6 (95% CI: 0.30-8.90). Despite limited enrollment, the study did not suggest that empiric TB treatment in severely immunosuppressed patients with low BMI decreased mortality and, had an HR in the opposite direction than expected. Notably, two participants in the ART + TB group died with autopsy-confirmed drug-induced hepatotoxicity. Improved TB diagnostics sensitive in immunosuppressed patients presenting late to care are urgently needed for more targeted interventions.

Role of empiric treatment in hospitalized patients with Xpert MTB/RIF-negative presumptive pulmonary tuberculosis: A prospective cohort study

“…Unfortunately, empiric treatment of Xpert-negative patients in our study was not associated with a reduction in mortality as 5.6% of empirically treated patients and 4.8% of those untreated died. Our result extend the observations of no survival benefit of empiric TB treatment among people living with HIV (Hosseinipour et al, 2016;Grant et al, 2020;Manabe et al, 2016) to the population of all people (independent of HV status) with presumptive TB admitted to a referral hospital in a high TB burden country.…”

“…While empiric treatment (i.e. initiation of TB treatment without bacteriological confirmation) is beneficial for patients who truly have TB (Katagira et al, 2016;Theron et al, 2014;Kendall et al, 2019), a randomized controlled trial showed that empiric TB treatment does not reduce overall mortality in people living with advanced HIV disease (Hosseinipour et al, 2016) and some studies found that empiric treatment may even increase the risk of death when other diagnoses are overlooked in people living with HIV (Grant et al, 2020;Manabe et al, 2016).…”

Algorithm-guided empirical tuberculosis treatment for people with advanced HIV (TB Fast Track): an open-label, cluster-randomised trial

“…20 The PROMPT trial individually randomised individuals in four countries in Africa with CD4 less than 50 cells per µL and no evidence of tuberculosis on sputum smear or chest radiography to presumptive tuberculosis treatment or control; it was stopped early because of slow recruitment. 21 The STATIS trial found no difference in death or invasive bacterial disease by 24 weeks among adults with CD4 <100 cells per µL individually randomised to ART plus extensive tuberculosis investigation versus ART and empirical tuberculosis treatment. 22 The LAM assay is feasible for PHClevel use but, as elsewhere, its sensitivity in our study was too low to be used in isolation.…”

Rapid antiretroviral therapy initiation in low- and middle-income countries: A resource-based approach

“…In an outpatient setting in 4 countries in SSA, the TB Fast Track Trial did not show a mortality benefit from empiric 4-drug anti-TB regimens in patients identified as being at high TB risk in the absence of CD4 testing [31]. The PROMPT study showed autopsy evidence of disseminated TB even among patients empirically treated with 4-drug anti-TB regimens prior to ART initiation and provides further evidence that empiric anti-TB therapy in the severely immunosuppressed does not improve outcomes [32]. In addition to isoniazid, across CD4 strata cotrimoxazole prophylaxis also reduces mortality and risk of serious bacterial infections and malaria within endemic regions [11,12] and is recommended regardless of CD4 count in areas with a high prevalence of severe bacterial infections and/or malaria [33].…”