Greg J. Fox

Reassessment of the positive predictive value and specificity of Xpert MTB/RIF: a diagnostic accuracy study in the context of community-wide screening for tuberculosis

BACKGROUND Community-wide screening for tuberculosis with Xpert MTB/RIF as a primary screening tool overcomes some of the limitations of conventional screening. However, concerns exist about the low positive predictive value of this test in screening settings. We did a cross-sectional assessment of this diagnostic test to directly estimate the actual positive predictive value of Xpert MTB/RIF when used in the setting of community-wide screening for tuberculosis, and to draw an inference about the specificity of the test for tuberculosis detection. METHODS Field staff visited households in 60 randomly selected villages in Ca Mau province, Vietnam. We included people aged 15 years or older who provided written informed consent and were able to produce 0·5 mL or more of sputum, irrespective of reported symptoms. Participants were tested with Xpert MTB/RIF, then those with positive results had two further sputum samples tested for smear microscopy and culture, and underwent chest radiography at the provincial TB Health Center. The positive predictive value of Xpert MTB/RIF was compared against two reference standards for tuberculosis diagnosis-a positive sputum culture for Mycobacterium tuberculosis, and a positive sputum culture or a chest radiograph consistent with active pulmonary tuberculosis. We then calculated the specificity of Xpert MTB/RIF for tuberculosis detection on the basis of these positive predictive values and disease prevalence in this setting. FINDINGS 43 435 adults consented to screening with Xpert MTB/RIF. Sputum samples of 0·5 mL or greater were collected from 23 202 participants, producing 22 673 valid results. 169 participants had positive Xpert MTB/RIF results (0·39% of those screened and 0·75% of those with valid sputum results). The positive predictive value of Xpert MTB/RIF was 61·0% (95% CI 52·8-68·7) when compared against a positive sputum culture and 83·9% (76·8-89·2) when compared against a positive sputum culture or chest radiograph consistent with active tuberculosis. On the basis of these positive predictive values, the specificity of Xpert MTB/RIF was determined to be between 99·78% (95% CI 99·71-99·84) and 99·93% (99·88-99·96). INTERPRETATION The positive predictive value and specificity of Xpert MTB/RIF in the context of community-wide screening for tuberculosis is substantially higher than that predicted in previous studies. Our findings support the potential role of Xpert MTB/RIF as a primary screening tool to detect prevalent cases of tuberculosis in the community. FUNDING Australian National Health and Medical Research Council.

Household-Contact Investigation for Detection of Tuberculosis in Vietnam

BACKGROUND Active case finding is a top priority for the global control of tuberculosis, but robust evidence for its effectiveness in high‐prevalence settings is lacking. We sought to evaluate the effectiveness of household‐contact investigation, as compared with standard, passive measures alone, in Vietnam. METHODS We performed a cluster‐randomized, controlled trial at clinics in 70 districts (local government areas with an average population of approximately 500,000 in urban areas and 100,000 in rural areas) in eight provinces of Vietnam. Health workers at each district clinic or hospital were assigned to perform either household‐contact intervention plus standard passive case finding (intervention group) or passive case finding alone (control group). In the intervention districts, household contacts of patients with positive results for tuberculosis on sputum smear microscopy (smear‐positive tuberculosis) were invited for clinical assessment and chest radiography at baseline and at 6, 12, and 24 months. The primary outcome was the cumulative incidence of registered cases of tuberculosis among household contacts of patients with tuberculosis during a 2‐year period. RESULTS In 70 selected districts, we enrolled 25,707 household contacts of 10,964 patients who had smear‐positive pulmonary tuberculosis. In the 36 districts that were included in the intervention group, 180 of 10,069 contacts were registered as having tuberculosis (1788 cases per 100,000 population), as compared with 110 of 15,638 contacts (703 per 100,000) in the control group (relative risk of the primary outcome in the intervention group, 2.5; 95% confidence interval [CI], 2.0 to 3.2; P<0.001); the relative risk of smear‐positive disease among household contacts in the intervention group was 6.4 (95% CI, 4.5 to 9.0; P<0.001). CONCLUSIONS Household‐contact investigation plus standard passive case finding was more effective than standard passive case finding alone for the detection of tuberculosis in a high‐prevalence setting at 2 years. (Funded by the Australian National Health and Medical Research Council; ACT2 Australian New Zealand Clinical Trials Registry number, ACTRN12610000600044.)

Group 5 drugs for multidrug-resistant tuberculosis: individual patient data meta-analysis

The role of so-called “group 5” second-line drugs as a part of antibiotic therapy for multidrug-resistant tuberculosis (MDR-TB) is widely debated. We performed an individual patient data meta-analysis to evaluate the effectiveness of several group 5 drugs including amoxicillin/clavulanic acid, thioacetazone, the macrolide antibiotics, linezolid, clofazimine and terizidone for treatment of patients with MDR-TB. Detailed individual patient data were obtained from 31 published cohort studies of MDR-TB therapy. Pooled treatment outcomes for each group 5 drug were calculated using a random effects meta-analysis. Primary analyses compared treatment success to a combined outcome of failure, relapse or death. Among 9282 included patients, 2191 received at least one group 5 drug. We found no improvement in treatment success among patients taking clofazimine, amoxicillin/clavulanic acid or macrolide antibiotics, despite applying a number of statistical approaches to control confounding. Thioacetazone was associated with increased treatment success (OR 2.6, 95% CI 1.1–6.1) when matched controls were selected from studies in which the group 5 drugs were not used at all, although this result was heavily influenced by a single study. The development of more effective antibiotics to treat drug-resistant TB remains an urgent priority. A meta-analysis of patient data found that group 5 drugs have limited benefit in treating patients with MDR-TB http://ow.ly/TIrH304QBci

Passive case finding for tuberculosis is not enough

Current World Health Organisation targets calling for an end to the global tuberculosis (TB) epidemic by 2035 require a dramatic improvement in current case-detection strategies. A reliance on passive case finding (PCF) has resulted consistently, in over three million infectious TB cases per year, being missed by the health system, leading to ongoing transmission of infection within families and communities. Active case finding (ACF) for TB has been recognized as an important complementary strategy to PCF, in order to diagnose and treat patients earlier, reducing the period of infectiousness and therefore transmission. ACF may also achieve substantial population-level TB control. Local TB epidemiology and the resources available in each setting will influence which populations should be screened, and the types of ACF interventions to use for maximal impact. TB control programs should begin with the highest risk groups and broaden their activities as resources allow. Mathematical models can help to predict the population-level effects and the cost-effectiveness of a variety of ACF strategies on different risk populations.

Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis

Abstract Objective To assess the effectiveness of decentralized treatment and care for patients with multidrug-resistant (MDR) tuberculosis, in comparison with centralized approaches. Methods We searched ClinicalTrials.gov, the Cochrane library, Embase®, Google Scholar, LILACS, PubMed®, Web of Science and the World Health Organization’s portal of clinical trials for studies reporting treatment outcomes for decentralized and centralized care of MDR tuberculosis. The primary outcome was treatment success. When possible, we also evaluated, death, loss to follow-up, treatment adherence and health-system costs. To obtain pooled relative risk (RR) estimates, we performed random-effects meta-analyses. Findings Eight studies met the eligibility criteria for review inclusion. Six cohort studies, with 4026 participants in total, reported on treatment outcomes. The pooled RR estimate for decentralized versus centralized care for treatment success was 1.13 (95% CI: 1.01–1.27). The corresponding estimate for loss to follow-up was RR: 0.66 (95% CI: 0.38–1.13), for death RR: 1.01 (95% CI: 0.67–1.52) and for treatment failure was RR: 1.07 (95% CI: 0.48–2.40). Two of three studies evaluating health-care costs reported lower costs for the decentralized models of care than for the centralized models. Conclusion Treatment success was more likely among patients with MDR tuberculosis treated using a decentralized approach. Further studies are required to explore the effectiveness of decentralized MDR tuberculosis care in a range of different settings.

Tuberculosis and mental health in the Asia-Pacific

Objective: This opinion piece encourages mental health researchers and clinicians to engage with mental health issues among tuberculosis patients in the Asia-Pacific region in a culturally appropriate and ethical manner. The diversity of cultural contexts and the high burden of tuberculosis throughout the Asia-Pacific presents significant challenges. Research into tuberculosis and mental illness in this region is an opportunity to develop more nuanced models of mental illness and treatment, while simultaneously contributing meaningfully to regional tuberculosis care and prevention. Conclusions: We overview key issues in tuberculosis and mental illness co-morbidity, highlight ethical concerns and advocate for a regional approach to tuberculosis and mental health that is consistent with the transnational challenges presented by this airborne infectious disease. Integrating tuberculosis and mental health services will go a long way to addressing the needs of vulnerable populations and stopping the transmission of one of the world’s biggest infectious killers.

Screening for tuberculosis in migrants and visitors from high-incidence settings: Present and future perspectives

In most settings with a low incidence of tuberculosis (TB), foreign-born people make up the majority of TB cases, but the distribution of the TB risk among different migrant populations is often poorly quantified. In addition, screening practices for TB disease and latent TB infection (LTBI) vary widely. Addressing the risk of TB in international migrants is an essential component of TB prevention and care efforts in low-incidence countries, and strategies to systematically screen for, diagnose, treat and prevent TB among this group contribute to national and global TB elimination goals. This review provides an overview and critical assessment of TB screening practices that are focused on migrants and visitors from high to low TB incidence countries, including pre-migration screening and post-migration follow-up of those deemed to be at an increased risk of developing TB. We focus mainly on migrants who enter the destination country via application for a long-stay visa, as well as asylum seekers and refugees, but briefly consider issues related to short-term visitors and those with long-duration multiple-entry visas. Issues related to the screening of children and screening for LTBI are also explored. TB screening of migrants from high to low TB incidence settings contributes to national and global TB elimination http://ow.ly/ZuRi30kb4bs

Recurrence of tuberculosis among patients following treatment completion in eight provinces of Vietnam: A nested case-control study

BACKGROUND Patients completing treatment for tuberculosis (TB) in high-prevalence settings face a risk of developing recurrent disease. This has important consequences for public health, given its association with drug resistance and a poor prognosis. Previous research has implicated individual factors such as smoking, alcohol use, HIV, poor treatment adherence, and drug resistant disease as risk factors for recurrence. However, little is known about how these factors co-act to produce recurrent disease. Furthermore, perhaps factors related to the index disease means higher burden/low resource settings may be more prone to recurrent disease that could be preventable. METHODS We conducted a case-control study nested within a cohort of consecutively enrolled adults who were being treated for smear positive pulmonary TB in 70 randomly selected district clinics in Vietnam. Cases were patients with recurrent TB, identified by follow-up from the parent cohort study. Controls were selected from the cohort by random sampling. Information on demographic, clinical and disease-related characteristics was obtained by interview. Treatment information was extracted from clinic registries. Logistic regression, with stepwise selection, was used to develop a fully adjusted model for the odds of recurrence of TB. RESULTS We recruited 10,964 patients between October 2010 and July 2013. Median follow-up was 988 days. At the end of follow-up, 505 patients (4.7%) with recurrence were identified as cases and 630 other patients were randomly selected as controls. Predictors of recurrence included multidrug-resistant (MDR)-TB (adjusted odds ratio 79.6; 95% CI: 25.1-252.0), self-reported prior TB therapy (aOR=2.5; 95% CI: 1.7-3.5), and incomplete adherence (aOR=1.9; 95% CI 1.1-3.1). CONCLUSIONS Index disease treatment history is a leading determinant of relapse among patients with TB in Vietnam. Further research is required to identify interventions that will reduce the risk of recurrent disease and enhance its early detection within high-risk populations.

Better than a pound of cure: preventing the development of multidrug-resistant tuberculosis

Diagnostic and treatment delays contribute to increased death and disability among the 490,000 adults and children who develop multidrug-resistant (MDR) tuberculosis every year. Since the treatment of MDR tuberculosis is complex, costly and often toxic, tuberculosis control programs should prioritize strategies to prevent drug-resistant tuberculosis. Opportunities to limit transmission and prevent disease progression in close contacts of MDR tuberculosis cases are often neglected. Effective MDR tuberculosis preventive strategies could minimize the costs for patients and healthcare systems. This review characterizes the biological basis for the development of MDR tuberculosis, outlines the evidence for strategies to reduce transmission and highlights programmatic approaches to the management of patients infected with drug-resistant strains of Mycobacterium tuberculosis.

Response to: Socio-political prescriptions for latent tuberculosis infection are required to prevent reactivation of tuberculosis

The importance of addressing the conditions that predispose individuals and populations to develop tuberculosis is increasingly being recognized. Accurate quantification of the protective effect of preventive therapy and the provision of pragmatic guidance for clinical care and public health interventions is important. However, this approach must be nested within a socio-political context that addresses associated disadvantage and inequality.