Impact on Patients’ Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial

<div><p>Introduction</p><p>The impact on treatment outcomes of XpertMTB/RIF, a molecular-based test that provides rapid diagnosis of tuberculosis (TB) and rifampicin resistance with high accuracy, has not been reported despite its adoption in a few countries. We here report treatment outcomes in a step-wedged cluster randomized trial for patients diagnosed with XpertMTB/RIF compared to patients diagnosed with sputum smear examination in public health facilities in Brazil.</p><p>Methods</p><p>Treatment outcome data were added to the trial database of patients diagnosed from 4 February to 4 October 2012, and crosschecked with data from the national mortality and the drug-resistant TB registers. Treatment outcomes in the intervention (n=2232) and baseline (n=1856) arms were compared using a multilevel regression model.</p><p>Results</p><p>Unfavourable outcomes were frequent in both arms, mainly due to loss to follow-up (16%). Overall unfavourable outcomes were not reduced in the intervention arm (29.6% versus 31.7%, OR=0.93; 95%CI=0.79-1.08). However, the overall TB-attributed death rate was lower in the intervention arm (2.3% vs. 3.8%). Adjusted for HIV status, age group and city, the intervention resulted in a 35% decrease in TB-attributed deaths (OR=0.65, 95%CI=0.44-0.97).</p><p>Conclusions</p><p>The proportion of patients successfully treated did not increase with Xpert MTB/RIF implementation, with high loss to follow-up rates in both arms. We did observe a 35% reduction in TB-related mortality, which we hypothesize may be explained by less advanced disease among the smear-negative patients diagnosed by Xpert. In conclusion, XpertMTB/RIF introduction did not improve TB treatment outcomes in Brazil.</p><p>Trial Registration</p><p>clinicaltrials.gov <a href="https://www.clinicaltrials.gov/ct2/show/NCT01363765?term=NCT01363765&rank=1" target="_blank">NCT01363765</a></p></div

Characteristics associated with unfavourable outcomes in a multilevel logistic regression model.

<p>*Positive smear in baseline arm and positive Xpert in intervention arm.</p><p>^§Negative smear in baseline arm and negative Xpert in intervention arm.</p><p>^†Unfavourable = loss to follow up, death from any cause, transfer out and resistance.</p><p>Characteristics associated with unfavourable outcomes in a multilevel logistic regression model.</p

Patients’ characteristics in the baseline and intervention arms.

<p>*Statistically significant difference between column proportions at the 0.05 p-value level</p><p>*Positive smear in baseline arm and positive Xpert in intervention arm</p><p>^†Negative smear in baseline arm and negative Xpert in intervention arm</p><p>Patients’ characteristics in the baseline and intervention arms.</p

Flowchart of patients included in the present analyses.

<p>Flowchart showing study inclusion in baseline (smear examination) and intervention (Xpert MTB/RIF) arm.</p

Characteristics associated with TB-attributed death in a multilevel logistic regression model.

<p>OR = odds ratio, aOR = adjusted odds ratio</p><p>*Positive smear in baseline arm and positive Xpert in intervention arm</p><p>^§ Negative smear in baseline arm and negative Xpert in intervention arm</p><p>Characteristics associated with TB-attributed death in a multilevel logistic regression model.</p

Notifications of pulmonary tuberculosis by laboratory according to arm (baseline versus intervention).

<p>The numbers of the laboratories reflect the sequence of introduction of the Xpert intervention (two labs at a time).</p><p>Notifications of pulmonary tuberculosis by laboratory according to arm (baseline versus intervention).</p

Flowchart showing study inclusion in baseline (smear examination) and intervention (Xpert MTB/RIF) arms.

<p>Bold arrows indicate cross-linkage between databases.</p

Cluster-averaged notification rates, rate differences, and rate ratios for laboratory-confirmed TB, TB with negative test result, TB with no testing, and overall pulmonary TB.

<p>Notification rate ratio is for intervention (Xpert) compared to baseline (smear examination) arm.</p>a<p>Notification rate ratio adjusted for sex, age, municipality, and baseline smear-positive rate, quasi-likelihood population-averaged method.</p>b<p>ITT analysis assuming availability of back-up smear examination.</p><p>Cluster-averaged notification rates, rate differences, and rate ratios for laboratory-confirmed TB, TB with negative test result, TB with no testing, and overall pulmonary TB.</p

Positive laboratory test result for tuberculosis, irrespective of notification.

<p>Overall notification rates: number of notified cases divided by population size, multiplied by 100,000. Cluster-averaged rates: mean of cluster-specific notification rates.</p>a<p>Laboratory-specific rate of positive smear examinations in the first study month, per 100,000 population per year.</p><p>Positive laboratory test result for tuberculosis, irrespective of notification.</p

Notifications of pulmonary tuberculosis despite negative laboratory test.

<p>Overall notification rates: number of notified cases divided by population size, multiplied by 100,000. Cluster-averaged rates: mean of cluster-specific notification rates.</p>a<p>Laboratory-specific rate of positive smear examinations in the first study month, per 100,000 population per year.</p><p>Notifications of pulmonary tuberculosis despite negative laboratory test.</p