Empirical treatment for TB in HIV: lessons from a cohort study of people living with HIV treated in Recife, Brazil

Albuquerque, Maria Fátima de Pessoa Militão; Coimbra, Isabella; Batista, Joana; Maruza, Magda; Ximenes, Ricardo A. A.; Lacerda, Heloísa Ramos; Miranda-Filho, Demócrito Barros; Santos, Marcela Lopes; Rodrigues, Laura C.

doi:10.1186/1471-2458-14-289

Cited by 7 publications

(7 citation statements)

References 18 publications

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“…We did not find a significant difference in the adjusted hazard for death between those treated for TB with any bacteriologic test (positive or negative) versus no test results in the secondary analysis. This finding is consistent with a study in Brazil which found no difference in mortality risk between PLWH who did or did not undergo TB bacteriologic testing [17]. This argues against the notion that the presence of TB bacteriologic testing is a marker of better-resourced sites (and therefore reduced mortality), as patients with a bacteriologic test would have been expected to have a lower mortality than those who were not tested if that were the case.…”

Section: Discussionsupporting

confidence: 88%

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Mortality among adults living with HIV treated for tuberculosis based on positive, negative, or no bacteriologic test results for tuberculosis: the IeDEA consortium

Humphrey

Mpofu

Pettit

et al. 2019

Preprint

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Background3 In resource-constrained settings, people living with HIV (PLWH) treated for tuberculosis (TB) 4 despite negative bacteriologic tests have a higher mortality than those treated with positive tests. 5 Many PLWH are treated without bacteriologic testing; their mortality compared to those with 6 bacteriologic testing is uncertain. 7 8 Methods 9 We conducted an observational cohort study among PLWH ≥ 15 years of age who initiated TB 10 treatment at clinical sites affiliated with four regions of the International epidemiology Databases 11 to Evaluate AIDS (IeDEA) consortium from 2012-2014: Caribbean, Central and South America, 12 and Central, East, and West Africa. The primary exposure of interest was the TB bacteriologic 13 test status at TB treatment initiation: positive, negative, or no test result. The hazard for death in 14 the 12 months following TB treatment initiation was estimated using the Cox proportional 15 hazard model, adjusted for patient-and site-level factors. Missing covariates were multiply 16 imputed. 17 18 Results 19 Among 2,091 PLWH included, the median age at TB treatment initiation was 36 years, 44% 20 were female, 53% had CD4 counts ≤ 200 cells/mm 3 , and 52% were on antiretroviral treatment 21 (ART). Compared to patients with positive bacteriologic tests, the adjusted hazard for death was 22 higher among patients with no test results (HR 1.56, 95% CI 1.08-2.26) but not different than 4 23 those with negative tests (HR 1.28, 95% CI 0.91-1.81). Older age was also associated with a 24 higher hazard for death, while being on ART, having a higher CD4 count, West Africa region, 25 and tertiary facility level were associated with lower hazards for death. 26 27 Conclusion 28 PLWH treated for TB with no bacteriologic test results were more likely to die than those treated 29 with positive tests, underscoring the importance of TB bacteriologic diagnosis in resource-30 constrained settings. Research is needed to understand the causes of death among PLWH treated 31 for TB in the absence of positive bacteriologic tests. 5 32 Introduction 33 Although tuberculosis (TB) accounted for 300,000 deaths among people living with HIV 34 (PLWH) in 2017, diagnosing TB in resource-limited settings remains a challenge [1]. In 2017, 35 only 56% of the 5.5 million pulmonary TB cases reported to the World Health Organization 36 (WHO) globally were bacteriologically confirmed (i.e. positive for smear microscopy, culture, or 37 nucleic acid amplification test [NAAT]) [1]. Among studies reporting the autopsy prevalence of 38 TB in HIV-related deaths, TB was prevalent in 37% of deaths, but in half of those cases, TB was 39 not diagnosed by the time of death [2]. The rollout of nucleic acid amplification tests (NAAT)40 such as the Xpert® MTB/RIF (Cepheid, Sunnyvale, CA, USA), which are more sensitive and 41 specific than smear microscopy, has helped close this diagnostic gap [3]. However, limited 42 impact on mortality has been observed with the use of Xpert MTB/RIF, in part due to high 43 baseline rates of empiri...

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Section: Discussionsupporting

confidence: 88%

“…Patients may not be able to produce a sputum sample for bacteriologic testing or access TB testing sites (e.g. for serial sputum collection) due to the distance or cost of transport [8, 16, 17].…”

Section: Introductionmentioning

confidence: 99%

Mortality among adults living with HIV treated for tuberculosis based on positive, negative, or no bacteriologic test results for tuberculosis: the IeDEA consortium

Humphrey

Mpofu

Pettit

et al. 2019

Preprint

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“…Prospective studies to investigate outcomes with empiric TB treatment as well as the Determine TB LAM test and treat strategies are on-going in sub-Saharan Africa [39] . One observational study from Brazil showed increased mortality with empiric TB treatment, although no weighted adjustment for selection bias was performed in this study [40] .…”

Section: Discussionmentioning

confidence: 99%

Point-of-Care Lateral Flow Assays for Tuberculosis and Cryptococcal Antigenuria Predict Death in HIV Infected Adults in Uganda

et al. 2014

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BackgroundMortality in hospitalized, febrile patients in Sub-Saharan Africa is high due to HIV-infected, severely immunosuppressed patients with opportunistic co-infection, particularly disseminated tuberculosis (TB) and cryptococcal disease. We sought to determine if a positive lateral flow assay (LFA) result for urine lipoarabinomannan (LAM) and cryptococcal antigenuria was associated with mortality.Methods351 hospitalized, HIV-positive adults with symptoms consistent with TB and who were able to provide both urine and sputum specimens were prospectively enrolled at Mulago National Referral Hospital in Uganda as part of a prospective accuracy evaluation of the lateral flow Determine TB LAM test. Stored frozen urine was retrospectively tested for cryptococcal antigen (CRAG) using the LFA. We fitted a multinomial logistic regression model to analyze factors associated with death within 2 months after initial presentation.ResultsThe median CD4 of the participants was 57 (IQR: 14–179) cells/µl and 41% (145) were microbiologically confirmed TB cases. LAM LFA was positive in 38% (134), 7% (25) were CRAG positive, and 43% (151) were positive for either test in urine. Overall, 21% (75) died within the first 2 months, and a total of 32% (114) were confirmed dead by 6 months. At 2 months, 30% of LAM or CRAG positive patients were confirmed dead compared to 15.0% of those who were negative. In an adjusted model, LAM or CRAG positive results were associated with an increased risk of death (RRR 2.29, 95% CI: 1.29, 4.05; P = 0.005).ConclusionsIn hospitalized HIV-infected patients, LAM or CRAG LFA positivity was associated with subsequent death within 2 months. Further studies are warranted to examine the impact of POC diagnostic ‘test and treat’ approach on patient-centered outcomes.

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“…This suggests that severity of clinical condition may influence clinicians’ decision to treat empirically. In Brazil, HIV-positive patients with cough who were smear and culture negative and received TB treatment had a higher mortality than those who did not [29]. The authors interpreted that even after adjustment, severe HIV disease remained a confounder of the association between empirical TB treatment and mortality.…”

Section: Discussionmentioning

confidence: 99%

Mortality in the first six months among HIV-positive and HIV-negative patients empirically treated for tuberculosis

Huerga¹,

Ferlazzo

Wanjala

et al. 2019

BMC Infect Dis

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BackgroundEmpirical treatment of tuberculosis (TB) may be necessary in patients with negative or no Xpert MTB/RIF results. In a context with access to Xpert, we assessed mortality in the 6 months after the initial TB consultation among HIV-positive and HIV-negative patients who received empirical TB treatment or TB treatment based on bacteriological confirmation and we compared it with the mortality among those who did not receive TB treatment.MethodsThis prospective cohort study included consecutively adult patients with signs and symptoms of TB attending an outpatient TB clinic in Western Kenya. At the first consultation, patients received a clinical exam and chest X-ray. Sputum was collected for microscopy, Xpert and Mycobacterium tuberculosis complex (MTB) culture. Patients not started on TB treatment were reassessed after 5 days. All patients bacteriologically confirmed (positive Xpert or culture) received TB treatment. Empirical treatment was defined as a decision to start TB treatment without bacteriological confirmation. Patients were reassessed after 6 months.ResultsOf 606 patients included, 344/606 (56.8%) were women. Median age was 35 years [Interquartile Range (IQR):27–47] and 398/594 (67.0%) were HIV-positive. In total, 196/606 (32.3%) patients were Xpert- or culture-positive and 331/606 (54.6%) started TB treatment. Overall, 100/398 (25.1%) HIV-positive and 31/196 (15.8%) HIV-negative patients received empirical treatment. Mortality in the 6 months following the first consultation was 1.6 and 0.8/100 patient-months among HIV-positive and HIV-negative patients respectively. In the multivariate analyses, TB treatment - whether empirical or based on bacteriological confirmation- was not associated with increased mortality among HIV-positive patients (aHR:2.51, 95%CI:0.79–7.90 and aHR:1.25, 95%CI:0.37–4.21 respectively). However, HIV-negative patients who received empirical treatment had a higher risk of mortality (aHR:4.85, 95%CI:1.08–21.67) compared to those not started on treatment. HIV-negative patients treated for TB based on bacteriological confirmation did not have a different risk of mortality (aHR:0.77, 95%CI:0.08–7.41).ConclusionsOur findings suggest that in a context with access to Xpert, clinicians should continue using empirical TB treatment in HIV-positive patients with signs and symptoms of TB and negative Xpert results. However, differential diagnoses other than TB should be actively sought before initiating empirical TB treatment, particularly in HIV-negative patients.

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Empirical treatment for TB in HIV: lessons from a cohort study of people living with HIV treated in Recife, Brazil

Cited by 7 publications

References 18 publications

Mortality among adults living with HIV treated for tuberculosis based on positive, negative, or no bacteriologic test results for tuberculosis: the IeDEA consortium

Mortality among adults living with HIV treated for tuberculosis based on positive, negative, or no bacteriologic test results for tuberculosis: the IeDEA consortium

Point-of-Care Lateral Flow Assays for Tuberculosis and Cryptococcal Antigenuria Predict Death in HIV Infected Adults in Uganda

Mortality in the first six months among HIV-positive and HIV-negative patients empirically treated for tuberculosis

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