Empiric TB Treatment of Severely Ill Patients With HIV and Presumed Pulmonary TB Improves Survival

Katagira, Winceslaus; Walter, Nicholas D.; Boon, Saskia den; Kalema, Nelson; Ayakaka, Irene; Vittinghoff, Eric; Worodria, William; Cattamanchi, Adithya; Huang, Laurence; Davis, J. Lucian

doi:10.1097/qai.0000000000000970

Cited by 27 publications

(21 citation statements)

References 22 publications

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“…First, clinician attitudes in urban settings and thresholds for empiric TB treatment initiation in patients with low CD4 changed during the course of our clinical trial. 27 These treatment decisions were likely driven by data from SSA showing TB as a key cause of mortality after ART initiation 2,4,28 and high rates of prevalent TB in patients initiating ART in a high-burden setting. In this study, 6.5% of the screened patients had smear-positive TB before ART, slightly lower than previously reported rates of prevalent TB in HIV-infected patients in SSA (15-25% in South Africa 29,30 and 10-15% for other sub-Saharan African countries 23,31 ).…”

Section: Discussionmentioning

confidence: 99%

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

Manabe

Worodria

Leth

et al. 2016

The American Society of Tropical Medicine and Hygiene

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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.

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Section: Discussionmentioning

confidence: 99%

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

Manabe

Worodria

Leth

et al. 2016

The American Society of Tropical Medicine and Hygiene

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“…Developing a strong evidence base for predictors of poor outcomes in seriously ill inpatients could result in improved treatment and diagnostic algorithms. Empiric antituberculosis treatment improved 8-week survival of inpatients with WHO danger signs and negative sputum smears, but had no effect on survival in inpatients without danger signs in a Ugandan study; [ 4 ] which indicates that the danger signs have prognostic value.…”

Section: Introductionmentioning

confidence: 99%

Prognostic indicators in the World Health Organization’s algorithm for seriously ill HIV-infected inpatients with suspected tuberculosis

et al. 2018

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BackgroundCriteria for the 2007 WHO algorithm for diagnosing tuberculosis among HIV-infected seriously ill patients are the presence of one or more danger signs (respiratory rate > 30/min, heart rate > 120/min, temperature > 39 °C, and being unable to walk unaided) and cough ≥ 14 days. Determining predictors of poor outcomes among HIV-infected inpatients presenting with WHO danger signs could result in improved treatment and diagnostic algorithms.MethodsWe conducted a prospective cohort study of inpatients presenting with any duration of cough and WHO danger signs to two regional hospitals in Cape Town, South Africa. The primary outcome was all-cause mortality up to 56 days post-discharge, and the secondary outcome a composite of any one of: hospital admission for > 7 days, died in hospital, transfer to a tertiary level or tuberculosis hospital. We first assessed the WHO danger signs as predictors of poor outcomes, then assessed the added value of other variables selected a priori for their ability to predict mortality in common respiratory opportunistic infections (CD4 count, body mass index (BMI), being on antiretroviral therapy (ART), hypotension, and confusion) by comparing the receiver operating characteristic (ROC) area under the curve (AUC) of the two multivariate models.Results484 participants were enrolled, median age 36, 66% women, 53% had tuberculosis confirmed on culture. The 56-day mortality was 13.2%. Inability to walk unaided, low BMI, low CD4 count, and being on ART were independently associated with poor outcomes. The multivariate model of the WHO danger signs showed a ROC AUC of 0.649 (95% CI 0.582–0.717) for predicting 56-day mortality, which improved to ROC AUC of 0.740 (95% CI 0.681–0.800; p = 0.004 for comparison between the two ROC AUCs) with the multivariate model including the a priori selected variables. Findings were similar in sub-analyses of participants with culture-positive tuberculosis and with cough duration ≥ 14 days.ConclusionThe study design prevented a rigorous evaluation of the prognostic value of the WHO danger signs. Our prognostic model could result in improved algorithms, but needs to be validated.Electronic supplementary materialThe online version of this article (10.1186/s12981-018-0192-0) contains supplementary material, which is available to authorized users.

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“…The lack of association between post-XP empirical treatment or microbiologically confirmed treatment and the risk of death was also found by three recent studies among both ambulant and hospitalized ART naïve patients [18, 28–30]. However, a recent systematic review on the impact of tuberculosis nucleic amplification tests, such as Xpert® MTB/RIF, concluded that the evidence has been of limited scientific rigour and from a relatively small number of settings, limiting its validity and generalisability [13].…”

Section: Discussionmentioning

confidence: 55%

Treatment decisions and mortality in HIV-positive presumptive smear-negative TB in the Xpert® MTB/RIF era: a cohort study

et al. 2017

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BackgroundThe Xpert® MTB/RIF (XP) has a higher sensitivity than sputum smear microscopy (70% versus 35%) for TB diagnosis and has been endorsed by the WHO for TB high burden countries to increase case finding among HIV co-infected presumptive TB patients. Its impact on the diagnosis of smear-negative TB in a routine care setting is unclear. We determined the change in diagnosis, treatment and mortality of smear-negative presumptive TB with routine use of Xpert MTB/RIF (XP).MethodsProspective cohort study of HIV-positive smear-negative presumptive TB patients during a 12-month period after XP implementation in a well-staffed and trained integrated TB/HIV clinic in Kampala, Uganda. Prior to testing clinicians were asked to decide whether they would treat empirically prior to Xpert result; actual treatment was decided upon receipt of the XP result. We compared empirical and XP-informed treatment decisions and all-cause mortality in the first year.ResultsOf 411 smear-negative presumptive TB patients, 175 (43%) received an XP; their baseline characteristics did not differ. XP positivity was similar in patients with a pre-XP empirical diagnosis and those without (9/29 [17%] versus 14/142 [10%], P = 0.23). Despite XP testing high levels of empirical treatment prevailed (18%), although XP results did change who ultimately was treated for TB. When adjusted for CD4 count, empirical treatment was not associated with higher mortality compared to no or microbiologically confirmed treatment.ConclusionsXP usage was lower than expected. The lower sensitivity of XP in smear-negative HIV-positive patients led experienced clinicians to use XP as a “rule-in” rather than “rule-out” test, with the majority of patients still treated empirically.

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Empiric TB Treatment of Severely Ill Patients With HIV and Presumed Pulmonary TB Improves Survival

Cited by 27 publications

References 22 publications

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

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

Prognostic indicators in the World Health Organization’s algorithm for seriously ill HIV-infected inpatients with suspected tuberculosis

Treatment decisions and mortality in HIV-positive presumptive smear-negative TB in the Xpert® MTB/RIF era: a cohort study

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