Rollout Of Xpert Research Articles

Paediatric tuberculosis – new advances to close persistent gaps

Young children are most vulnerable to develop severe forms of tuberculosis (TB) and are over-represented among TB deaths. Almost all children estimated to have died from TB were never diagnosed or offered TB treatment.Improved access to TB preventive treatment (TPT) requires major upscaling of household contact investigation with allocation of adequate resources. Symptom-based screening is often discouraged in adults for fear of generating drug resistance, if TB cases are missed. However, the situation in vulnerable young children is different, as they present minimal risk of drug resistance generation. Further, the perceived need for additional diagnostic evaluation presents a major barrier to TPT access and underlies general reluctance to consider pragmatic decentralised models of care.Widespread roll-out of Xpert MTB/RIF Ultra® represents an opportunity for improved case detection in young children, but attaining full impact will require the use of non-sputum specimens. The new Fujifilm SILVAMP TB LAM® urine assay demonstrated good diagnostic accuracy in HIV-positive and malnourished children, but further validation is required. Given the limited accuracy of all available tests and the excellent tolerance of TB drugs in children, the global community may have to accept some over-treatment if we want to close the persistent case detection gap in young children.

Fujifilm SILVAMP TB LAM Assay on Cerebrospinal Fluid for the Detection of Tuberculous Meningitis in Adults With Human Immunodeficiency Virus.

Tuberculous meningitis (TBM) has a high fatality rate, with inadequate diagnostic tests being a major contributor. The rollout of Xpert MTB/Rif and Xpert MTB/RIF Ultra (Xpert Ultra) have improved time-to-diagnosis with sensitivities similar to culture, yet test availability and sensitivity are inadequate. The TB lipoarabinomannan lateral flow assay (AlereLAM) offers ease of use, but its low sensitivity in cerebrospinal fluid (CSF) limits clinical utility for TBM. The Fujifilm SILVAMP TB LAM (FujiLAM) assay has excellent sensitivity in urine, but performance on cerebrospinal fluid is uncertain. We conducted a prospective cohort study at Kiruddu National Referral Hospital in Kampala, Uganda, enrolling patients suspected to have TBM. CSF was tested using AlereLAM, Xpert Ultra, culture, and FujiLAM. Results were compared with 2 reference standards: probable and definite TBM or definite TBM alone by the uniform TBM case definition. Of 101 patients enrolled (95/101 HIV-positive), 34 had definite TBM and 24 had probable TBM. FujiLAM sensitivity on CSF was 52% (30/58) for definite or probable TBM compared with 55% (32/58) for Xpert Ultra. AlereLAM had lower sensitivity than FujiLAM in the subgroup of patients tested with both assays (14% [4/28] vs 50% [14/28]; P < .01). FujiLAM specificity was 98% (42/43) for patients without probable or definite TBM. FujiLAM showed higher sensitivity than AlereLAM, with sensitivity potentially approaching that of Xpert Ultra. FujiLAM could improve time-to-treatment-initiation, especially in settings where the more technical Xpert Ultra system might not be feasible. Large confirmatory studies are needed.

Modeling the patient and health system impacts of alternative xpert\xae MTB/RIF algorithms for the diagnosis of pulmonary tuberculosis in Addis Ababa, Ethiopia

BackgroundTo reduce global tuberculosis (TB) burden, the active disease must be diagnosed quickly and accurately and patients should be treated and cured. In Ethiopia, TB diagnosis mainly relies on spot-morning-spot (SMS) sputum sample smear analysis using Ziehl-Neelsen staining techniques (ZN). Since 2014 targeted use of xpert has been implemented. New diagnostic techniques have higher sensitivity and are likely to detect more cases if routinely implemented. The objective of our study was to project the effects of alternative diagnostic algorithms on the patient, health system, and costs, and identify cost-effective algorithms that increase TB case detection in Addis Ababa, Ethiopia.MethodsAn observational quantitative modeling framework was applied using the Virtual Implementation approach. The model was designed to represent the operational and epidemiological context of Addis Ababa, the capital city of Ethiopia. We compared eight diagnostic algorithm with ZN microscopy, light emitting diode (LED) fluorescence microscopy and Xpert MTB/RIF. Interventions with an annualized cost per averted disability adjusted life year (DALY) of less than the Gross Domestic Product (GDP) per capita are considered cost-effective interventions.ResultsWith a cost lower than the average per-capita GDP (US$690 for Ethiopia) for each averted disability adjusted life year (DALY), three of the modeled algorithms are cost-effective. Implementing them would have important patient, health system, and population-level effects in the context of Addis Ababa❖ The full roll-out of Xpert MTB/RIF as the primary test for all presumptive TB cases would avert 91170 DALYs (95% credible interval [CrI] 54888 – 127448) with an additional health system cost of US$ 11.6 million over the next 10 years. The incremental cost-effectiveness ratio (ICER) is $370 per DALY averted.❖ Same day LED fluorescence microscopy for all presumptive TB cases combined with Xpert MTB/RIF targeted to HIV-positive and High multidrug resistant (MDR) risk groups would avert 73600 DALYs( 95% CrI 48373 - 99214) with an additional cost of US$5.1 million over the next 10 years. The ICER is $169per DALY averted.❖ Same-day LED fluorescence microscopy for all presumptive TB cases (and no Xpert MTB/RIF) would avert 43580 DALYs with a reduction cost of US$ 0.2 million over the next 10years. The ICER is $13 per DALY averted.ConclusionsThe full roll-out of Xpert MTB/RIF is predicted to be the best option to substantially reduce the TB burden in Addis Ababa and is considered cost effective. However, the investment cost to implement this is far beyond the budget of the national TB control program. Targeted use of Xpert MTB/RIF for HIV positive and high MDR risk groups with same-day LED fluorescence microscopy for all other presumptive TB cases is an affordable alternative.

Tuberculosis Diagnostics: State of the Art and Future Directions.

Rapid and accurate diagnosis is critical for timely initiation of anti-tuberculosis (TB) treatment, but many people with TB (or TB symptoms) do not have access to adequate initial diagnosis. In many countries, TB diagnosis is still reliant on sputum microscopy, a test with known limitations. However, new diagnostics are starting to change the landscape. Stimulated, in part, by the success and rollout of Xpert MTB/RIF, an automated, molecular test, there is now considerable interest in new technologies. The landscape looks promising with a pipeline of new tools, particularly molecular diagnostics, and well over 50 companies actively engaged in product development, and many tests have been reviewed by WHO for policy endorsement. However, new diagnostics are yet to reach scale, and there needs to be greater convergence between diagnostics development and the development of shorter TB drug regimens. Another concern is the relative absence of non-sputum-based diagnostics in the pipeline for children, and of biomarker tests for triage, cure, and latent TB progression. Increased investments are necessary to support biomarker discovery, validation, and translation into clinical tools. While transformative tools are being developed, high-burden countries will need to improve the efficiency of their health care delivery systems, ensure better uptake of new technologies, and achieve greater linkages across the TB and HIV care continuum. While we wait for next-generation technologies, national TB programs must scale up the best diagnostics currently available, and use implementation science to get the maximum impact.

Mixed impact of Xpert(®) MTB/RIF on tuberculosis diagnosis in Cambodia.

National Tuberculosis (TB) Program sites in northwest Cambodia. To evaluate the impact of Xpert(®) MTB/RIF at point of care (POC) as compared to non-POC sites on the diagnostic evaluation of people living with the human immunodeficiency virus (PLHIV) with TB symptoms and patients with possible multidrug-resistant (MDR) TB. Observational cohort of patients undergoing routine diagnostic evaluation for TB following the rollout of Xpert. Between October 2011 and June 2013, 431 of 822 (52%) PLHIV with TB symptoms and 240/493 (49%) patients with possible MDR-TB underwent Xpert. Xpert was more likely to be performed when available as POC. A smaller proportion of PLHIV at POC sites were diagnosed with TB than at non-POC sites; however, at POC sites, a higher proportion of those diagnosed with TB were bacteriologically positive. There was poor agreement between Xpert and other tests such as smear microscopy and culture. Overall, the evaluation of patients with possible MDR-TB increased following Xpert rollout, yet for patients confirmed as having drug resistance on drug susceptibility testing, only 46% had rifampin resistance that would be identified with Xpert. Although utilization of Xpert was low, it may have contributed to an increase in evaluations for possible MDR-TB and a decline in empiric treatment for PLHIV when available as POC.

Market assessment of tuberculosis diagnostics in South Africa, 2012-2013.

To assess the current served available market of tuberculosis (TB) diagnostics in South Africa in the public and private sectors. Public and private sector test volumes and unit costs were collected for tuberculin skin tests, interferon-gamma release assays, smear microscopy, culture, speciation, Xpert MTB/RIF, other nucleic acid amplification tests, drug susceptibility testing and adenosine deaminase tests. In 2012, during Xpert scale-up, the public and private sectors performed a total of 9.2 million TB diagnostic tests, at an estimated total value of US$98 million. The public sector accounted for 93% of the overall test volume and value. There were no major differences in the types of tests performed in both sectors, with microscopy and culture accounting for the majority of tests performed (72%). In 2013, the public sector market value increased to US$101 million (a 10% increase over 2012): Xpert volumes increased by 166%, while total TB test volumes decreased by 12% compared to 2012. South Africa has a substantial TB diagnostic market in terms of both volume and value. The roll-out of Xpert provides insights into how markets change in volume and value with the introduction of new tools.

Rollout of Xpert(®) MTB/RIF in Northwest Cambodia for the diagnosis of tuberculosis among PLHA.

To describe the implementation and utilization of the Xpert (®) MTB/RIF (Xpert) assay to diagnose tuberculosis (TB) among people living with the human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS, PLHA) in Cambodia. Following the rollout of Xpert, an evaluation was conducted in four provinces of Cambodia from March to December 2012 to determine the utilization, performance, and turnaround time (TAT) of Xpert among PLHA. Data were collected from paper-based patient registers. Of 497 PLHA with a positive TB symptom screen, 357 (72%) were tested with smear microscopy, and 250 (50%) with Xpert; 25 (10%) PLHA tested with Xpert were positive for TB and none were rifampicin-resistant. The utilization of Xpert increased from 23% to 75%, with a median TAT of 1 day. Across districts, utilization ranged from zero to 85%, while the TAT ranged from zero to 22 days. While early data show increasing utilization of Xpert for PLHA with a positive symptom screen, most patients underwent smear microscopy as an initial diagnostic test. Training delays and challenges associated with specimen referral may have contributed to variability in Xpert uptake and TAT, particularly for sites without onsite Xpert testing. Enhanced programmatic support, particularly for specimen referral and results reporting, may facilitate appropriate utilization.

The importance of implementation strategy in scaling up Xpert MTB/RIF for diagnosis of tuberculosis in the Indian health-care system: a transmission model.

India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited. We developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: -1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: -5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four-module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research. The impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources. Please see later in the article for the Editors' Summary.

A hospital-based tuberculosis focal point to improve tuberculosis care provision in a very high burden setting.

A hospital-based tuberculosis focal point (TBFP) at a tertiary hospital in Johannesburg, South Africa. To describe the possible tasks and impact of a hospital-based TBFP as well as staffing and infrastructure requirements for setting up a hospital-based TBFP. A TBFP can centralize the notification and referral of new TB cases, perform human immunodeficiency virus counseling and testing, assessment of difficult to diagnose TB suspects and management of complicated TB cases, and it can provide an ideal setting for research and health care worker training. The number of TB suspects assessed by sputum initially increased, followed by a decrease starting in 2010, which correlates with the globally decreasing TB incidence. The proportion of TB cases who failed to link to TB care decreased from 23% to 14% between 2009 and 2012. Almost 40% of cases with hepatotoxicity required an adjusted treatment regimen. Roll-out of Xpert(®) MTB/RIF testing and decentralized drug-resistant TB treatment increased the number of rifampicin monoresistant and sputum smear-negative multidrug-resistant TB cases treated on an out-patient basis. A hospital-based TBFP complements care at primary care level by coordinating TB care for a vulnerable population of patients diagnosed in a hospital setting, and by coordinating the diagnosis and treatment of complex TB cases.