This part of the document presents practical considerations for introducing the Xpert MTB/RIF assay. The considerations are based on experiences reported to WHO, and reports from countries and partners that were presented and discussed in a series of implementers' meetings convened by WHO in 2011, 2012 and 2013.
7.1. Operational considerations
7.1.1. Checklist: key prerequisites to be met before implementing the Xpert MTB/RIF
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| Category | Prerequisite |
|---|
| Epidemiological data |
Data must be available on the prevalence of MDR-TB and HIV-associated TB to allow for decision-making on prioritizing placement of the technology and optimizing the use of Xpert MTB/RIF in targeted patient groups.
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| Diagnostic policy reform |
- 2.
Plans should be made to modify diagnostic algorithms as part of the national TB programme's strategy to introduce Xpert MTB/RIF.
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| Laboratory network |
- 3.
Sufficient capacity and appropriate referral networks (in both the public and private sectors) must be available to provide quality assured laboratory services with: culture and DST to determine resistance to first-line and second-line anti-TB drugs at the central level (at least); these laboratories must be quality assured through an established link with a TB Supranational Reference Laboratory; sputum-smear microscopy for TB testing and for monitoring responses to treatment; culture to monitor responses to treatment for MDR-TB.
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| Laboratory workload |
- 4.
There must be a sufficient potential number of specimens to be tested using Xpert MTB/RIF in the facility where the technology will be placed to justify implementation of the test and to ensure that utilization of the new technology will be optimal (the capacity of the GeneXpert IV instrument is 12-16 a day or 3000-4000 tests annually).
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| Infrastructure |
- 5.
The electricity supply must be stable in the facilities where the test will be implemented or sufficient measures must be taken to the supply remains uninterrupted supply (for example an uninterrupted power supply unit may be used with additional batteries, a generator or solar panels) - 6.
Premises must be secure to prevent theft of the GeneXpert unit and the computer/laptop. - 7.
Adequate storage space must be provided for the cartridges, which must be stored at the recommended temperature range (2-28°C). - 8.
Appropriate measures must be taken to prevent ambient temperatures from rising above 30°C or falling below 15°C in the room where the equipment will be installed (for example some form of the ventilation, or air conditioning may be necessary).
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| Biosafety |
- 9.
Biosafety requirements must be implemented similar to those for direct sputum-smear microscopy.
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| Personnel |
- 10.
Each site will need 1-2 staff with basic computer literacy and knowledge of laboratory registers; these staff will need to be trained to perform the test and maintain the equipment.
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| Treatment capacity |
- 11.
Sufficient capacity to treat patients of identified with TB and MDR-TB should be available and treatment should follow WHO's recommendations.
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| Financing |
- 12.
Funding should be secured from national budget, donors or partners.
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| Procurement |
- 13.
Importation procedures must allow for reliable procurement of both equipment and consumables (through either regulatory registration or waiver), and the exchange of modules for calibration, swap or repair in case of module failure. Developing efficient, integrated supply chains and distribution systems will ensure a regular supply of consumables with sufficient shelf-life.
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7.1.2. Checklist: Key actions necessary for implementation of Xpert MTB/RIF
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| Category | Action |
|---|
| Policy reform |
Incorporate Xpert MTB/RIF testing into the national diagnostic strategy and algorithms; this should include placing Xpert MTB/RIF at the appropriate level of the diagnostic network. Appropriate pre-test screening strategies should be identified where necessary.
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| Logistics |
- 2.
Identify adequate premises for the equipment (as described in prerequisites 5-10 above). - 3.
Allocate storage space for cartridges (as described in prerequisite 7). - 4.
Identify procedures for cartridge disposal (for example, incineration) as part of each laboratory's waste disposal plan.
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| Procurement |
- 5.
Register the GeneXpert system and Xpert MTB/RIF assay OR obtain a waivr for importation. - 6.
Forecast needs based on the expected demand and period of implementation. - 7.
Calculate the first and subsequent orders for the period of implementation. - 8.
Quantify the buffer stock necessary to cover at least 3 months of expected workload, taking into account the shelf-life of cartridges, and possible delays in procurement and importation. - 9.
Place an order for equipment and cartridges directly with the manufacturer or with a certified distributor; insist on preferential pricing where relevant.
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| Financing |
- 10.
Secure sustainable funding from the national budget, donors or partners to ensure the continued use of Xpert MTB/RIF testing, as well as continued training, maintenance and calibration.
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| Training |
- 11.
Identify and train staff to perform the Xpert MTB/RIF assay. - 12.
Train clinicians and other health-care workers on the utility of Xpert MTB/RIF and the groups of patients that should be targeted and referred for testing; train clinicians and health-care workers how to interpret test results. Offer refresher training for healthcare workers about how to collect a good quality specimen from patients. - 13.
Train staff to ensure that patients are referred in a timely manner and receive proper treatment, train staff in infection control measures and contact tracing.
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| Reporting |
- 14.
Adapt request and reporting forms and patient registers to include results from Xpert MTB/RIF. - 15.
Develop systems for reporting to the clinic on the same day that results become available.
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| Verification |
- 16.
Verify that the GeneXpert platform is working as expected by testing known positive and negative specimens at the time of installation and after each calibration of the modules.
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| Maintenance |
- 17.
Order remote calibration cartridges before the end of each year of testing, and perform calibration in a timely manner. - 18.
Order an extended warranty or budget appropriately for potential repairs.
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| Monitoring |
- 19.
Setup a system for monitoring the implementation of Xpert MTB/RIF.
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7.1.3. Testing capacity
The range of GeneXpert instruments includes systems with 1, 2, 4, 16, 48 or 80 modules. Modules function independently so that batching is not required and individual tests can be started at different times. Results become available for each test in less than 2 hours, so a GeneXpert instrument with four modules (that is, the GeneXpert IV instrument) has the capacity to perform up to 16 tests in an 8-hour working day. Experience from sites using the platform has shown that during the initial 6-12 months of use, while laboratory staff and clinicians grow accustomed to the test, throughput may be only up to 8 tests a day; therefore, cartridge orders should be planned carefully to prevent cartridges from expiring before they are used.
For sites that initially expect low throughput but are unsure whether this will increase later, a GeneXpert IV can be ordered with fewer than four modules, leaving the remaining bays empty. This allows for the possibility of increasing throughput later by installing additional modules, which can be ordered separately from the manufacturer. If additional instruments are required in a laboratory to increase throughput, instruments may be spliced together with a cable to allow data to be stored on a single computer.
7.1.4. Operation and storage conditions
Xpert MTB/RIF cartridges and the specimen reagent should be stored at 2–28 °C, following the manufacturer's recommendations, although it has been stated by the manufacturer that the cartridges are stable if kept at 2-45 °C for less than 6 weeks at 75% relative humidity. The cartridges are bulky when packed and require substantial storage space. An average household refrigerator can hold the supplies needed for 2 weeks at a laboratory performing 12–16 tests per day. The shelf life of the Xpert MTB/RIF cartridges may pose challenges in relatively inaccessible areas that have complex customs clearance procedures. When an order is placed, the shelf life of the cartridges being purchased should be requested from the manufacturer. Planning is essential to prevent stock-outs and cartridges from expiring before they are used; orders should be based on the number of cartridges that have been used, the shelf-life of the cartridges, the lead-time for delivery and the expected time needed to clear customs.
The manufacturer's recommended ambient operating temperature for the GeneXpert instrument is between 15 °C and 30 °C, which is not different from the operating temperatures recommended for a wide range of other laboratory equipment, household appliances, computers and mobile phones. The room where the test is performed may need air conditioning or heating to ensure that the ambient temperature is maintained in the recommended range. Ignoring the recommended temperature range may increase error rates because extreme temperatures interfere with thermo-cycling during the test.
7.1.5. Biosafety
Both the preparation of specimens and the running of the Xpert MTB/RIF test require the same biosafety conditions as are used for conventional direct sputum-smear microscopy35.
7.1.6. Calibration and maintenance
Since April 2012, new GeneXpert instruments have an initial 2-year warranty that is conditional upon modules being regularly calibrated. If the machine is not calibrated after first year, the second year of the warranty is invalidated. The warranty covers repairs of the instrument and any parts. An optional extension of the warranty may be purchased annually or as a 3-year extension (preferential prices are available from the manufacturer for the countries listed in Annex 1).
The GeneXpert modules require annual calibration. A remote calibration option uses a kit containing special cartridges that can be run on each module (without specimens) when calibration is due. During this run, which lasts about 20 minutes, the instrument will be automatically calibrated. However, in some cases remote calibration will not be sufficient, and at the end of the run the user will be informed that a module needs to be exchanged (or swapped); in this case, a replacement module will be sent from Cepheid and the original module must be returned for calibration. In 2014, the calibration kit could be ordered at the preferential price of USD$ 450 per kit; each kit is sufficient to calibrate up to 4 modules. Delivery costs can be minimized by ordering calibration lit at the same time as test cartridges are ordered.
A detailed commercial sales contract and customer support plan should be negotiated with the supplier, guaranteeing an ample and continual supply of cartridges, facilitating customs clearance, maintenance and calibration, and repair and replacement, as necessary.
7.1.7. Power supply
The GeneXpert instrument requires a stable electric power supply: even a short-term interruption in power may cause results to be lost, cartridges to be wasted, and the need to obtain another specimen. An unstable supply of electricity may also damage the electronics of the instrument and the computer, which may not be covered by the manufacturer's warranty. Therefore, a power line stabilizer and an uninterrupted power supply unit (UPS) are recommended for the GeneXpert instrument.
If the electricity is unstable and if power outages occur, then it is important to have an uninterrupted supply unit with additional batteries; the cost of the solution to the problem of power outages will vary depending on the setting and the duration of outages. The budget for the UPS unit will increase significantly if the unit will also act as a back up source of power for a longer period; the cost of and UPS depends on the duration of time that back-up will be needed, the power consumption of the diagnostic instrument and the capacity of the internal battery in the unit. For example, if power outages never exceed a few minutes, a small unit will be sufficient to ensure that the test cycle is not interrupted, and will prevent cartridges from being wasted and protect the equipment. When longer outages are possible, it is prudent to have a supply unit with external battery packs that can provide power for both the instrument and the computer for the average duration of the test – that is, 2 hours. The cost for such a unit depends on the choice of the unit and the availability of local solutions using external batteries and power inverters.
Several countries have reported back-up solutions ranging from custom-made battery arrays with a power inverter to solar-power installations36.
7.1.8. Reporting results
A printer may be installed to print the test results if required for medical filing or test reports. Mechanisms for rapidly reporting results from Xpert MTB/RIF to clinicians and for providing timely access to appropriate treatment must be established so that patients benefit from early diagnosis. Electronic systems for reporting results using text or SMS messaging have been developed by various organizations, including Abt Associates (GXAlert)37 and Interactive Research and Development (XpertSMS)38. The GeneXpert instruments can also be interfaced with most laboratory information systems and the delivery of results can be followed with an SMS message or other means of delivering the results.
7.1.9. Quality assurance
The Xpert MTB/RIF assay includes several internal quality controls that verify specimen processing, success of PCR and cartridge integrity.
Each cartridge includes a sample processing control (SPC), which contains non-infectious spores in the form of a dry spore cake that is included in each cartridge to verify adequate processing of MTB to:
verify that lysis of MTB has occurred if the organisms are present,
verify that the specimen processing is adequate,
detect specimen associated inhibition of the real-time PCR assay
SPC should be positive in a negative sample and SPC can be negative or positive in a positive sample.
The Probe Check Control is a check undertaken before the start of the PCR reaction. The system measures the fluorescence signal from the probes to monitor bead rehydration, reaction-tube filling, probe integrity and dye stability.
There is currently no consensus on the need nor the requirements for performing any additional periodic blinded testing using quality assurance panels. As an interim recommendation to fill this gap, the Global Laboratory Initiative recommends the following minimum requirements for quality assurance of the Xpert MTB/RIF assay.
Instrument verification
Each module in the GeneXpert instrument should be evaluated as being “fit for purpose” through verification with known positive or negative material prior to commencing routine testing of clinical specimens. A single verification test should be performed per module upon instrument installation and following calibration of instrument modules.
Verification panels are now routinely distributed by Cepheid with each new instrument and with recalibrated modules. The format of the verification panels is a card containing 5 Dried Culture Spots (DCS) of a known concentration of whole inactivated Mycobacterium tuberculosis (Rifampicin sensitive) bacilli.
Performance indicator monitoring
Each instrument should be monitored using the following minimum set of indicators to evaluate proper use:
number of tests performed per month per module,
number and proportion of MTB positive results,
number and proportion of MTB positive rifampicin resistant results,
number and proportion of errors (disaggregated by type of error),
number and proportion of indeterminate results,
number and proportion of invalid results.
7.2. Preferential pricing and eligible countries
The manufacturer makes Xpert MTB/RIF cartridges available to the public sector in eligible countries at the cost of US$ 9.98 each, plus shipping (Annex 1). The buyers eligible for preferential pricing in eligible countries are defined as follows:
governments or government-funded Institutions such as ministries of health, national or regional TB centres, government-associated hospitals, institutions associated with the armed forces, the prison services;
non-governmental organizations and United Nations related organizations working for or in eligible countries, such as International Organization for Migration and United Nations High Commissioner for Refugees;
non-profit welfare organizations helping eligible countries to improve diagnosis such as Médecins Sans Frontières, and other humanitarian organizations such as UNICEF, Save the Children and the International Committee of the Red Cross;
donor agencies such as UNITAID, PEPFAR, the United States Agency for International Development, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and Government agencies based outside the country but that support local implementation such as the United States Centers for Disease Control and Prevention CDC (USA);
non-profit private organizations whose mission is in keeping with humanitarian principles, such as private charities or private non-profit hospitals and clinics.
The preferential price for cartridges is a result of a unique buy-down arrangement agreed among the manufacturer, the United States Government (through USAID and PEPFAR), the Bill and Melinda Gates Foundation and UNITAID.
In early 2014, the negotiated price of a GeneXpert 4-module unit for the public sector in eligible countries excluding shipping was:
GeneXpert System 4-module unit with desktop computer – US$ 17000
GeneXpert System 4-module unit with laptop computer – US$ 17500
The manufacturer should be contacted directly to obtain prices for other variants – for example a 4-module instrument shell containing 2 modules, or a 16-module instrument.
In 2014, a calibration kit that can be used for up to 4 modules could be ordered for US$ 450 plus shipping. The manufacturer has also updated the preferential pricing for module exchange:
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for 1 module, US$ 900
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for 2 modules, US$ 1200
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for 3 modules, US$ 1500
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for 4 modules, US$ 1800.
For the 4-module instrument, shipping costs average close to US$ 1000 and about US$ 1 per cartridge, but both costs vary according to the distance and the number of units or cartridges being shipped.
Contact details
Cepheid HBDC SAS, Vira Solelh,
81470 Maurens-Scopont, France
Telephone: +33 563 825 333
Fax +33 563 825 301
7.3. Implementation costs
7.3.1. Sample budget
provides a sample calculation of a budget based on purchasing a 4-module GeneXpert instrument that will run at full capacity during an 8-hour work day. This sample budget will need to be customized according to each setting's requirements. As described in Section 7.1.6, the throughput of machines during the initial 6-12 months of use may be significantly below maximum capacity, while laboratory staff and clinicians grow accustomed to the new technology.
Sample annual itemized budget.
Other costs not included in the table but that should be considered and budgeted for if applicable are:
customs and other clearance fees for imported goods;
the costs of transportation from the port of entry to the final destination in the country;
Infrastructure costs, and costs for security, appropriate space and air conditioning or heating, where relevant;
Training for test operators and health-care workers at different levels of the health-care system, including clinicians.
7.4. Public health impact of Xpert MTB/RIF
The most frequently used test for detection of TB, sputum-smear microscopy, presents a low-cost option, but it seriously lacks sensitivity. As a result, health services miss many TB patients or identify them only when their disease is at an advanced stage. The diagnostic accuracy of smear microscopy depends on the proficiency of the personnel conducting the test and the rigour of the quality assurance programme. Smear microscopy cannot be used to identify drug resistance, and it doesn't differentiate between M. tuberculosis and NTM. Conventional solid culture and liquid culture methods for DST are slow, requiring weeks or months to generate results, and demand high proficiency from personnel as well as costly infrastructure to ensure sufficient biosafety conditions in the containment laboratory.
New TB diagnostics, and Xpert MTB/RIF in particular, largely alleviate many of these constraints. Xpert MTB/RIF provides higher sensitivity than microscopy, has a sensitivity close to solid culture, and is highly specific. The infrastructure requirements for the Xpert MTB/RIF assay are the same as for smear microscopy. The experience of those who have been early adopters of the Xpert MTB/RIF assay shows an increase in the number of bacteriologically-confirmed TB patients diagnosed by around 30-40% when compared with sputum-smear microscopy. Moreover, reports from some settings with a high prevalence of HIV have shown an up to threefold increase in case detection39.
Diagnosing drug resistance remains a particular challenge for laboratory systems in many low-income and middle-income countries. The capacity to diagnose resistant TB is limited in the places where it is needed most. As a result, only a fraction of the estimated cases of MDR-TB have a laboratory-confirmed diagnosis. The use of more sensitive and rapid diagnostics will increase the number of patients who are reliably diagnosed with TB and drug-resistant TB, and may place a higher demand on health services. Additional human and financial resources will be needed to address the increase in workload and to allow these new tests to be used efficiently and for the convenience of patients.
The introduction of early and rapid diagnosis creates opportunities for improvement in TB programmes, provided that test results are responded to rapidly. For example, if treatment delays continue to occur despite the rapid availability of results because there are other problems within the programme, then the introduction of new diagnostic platforms will have little effect on outcomes for patients and the programme. The implementation of new, more accurate and rapid diagnostics can result in a swift increase in the number of patients diagnosed with TB and drug-resistant TB, which may exert pressure on managers who are unprepared or programmes that lack adequate capacity. Improving diagnostic capacity requires the strengthening of treatment capacity. If efforts to improve treatment capacity are neglected or delayed, then treatment will lag and the problem of having patients on waiting lists, which is already prevalent in many affected countries, may be exacerbated. This problem touches on numerous ethical, financial and public-health issues, and it is important to highlight several frequently overlooked points.
Diagnosing TB or drug-resistant TB does not increase the number of people with TB or drug-resistant TB, it merely helps to identify them; these people are in the community already, transmitting disease even when they have not been diagnosed.
Even when treatment is not available for all who need it, diagnosing patients with TB and resistant TB is ethically sound and has more advantages than disadvantages
40. Providing a diagnosis in the absence of treatment can ensure that individuals with resistant TB are not inappropriately treated with first-line anti-TB agents, which can harm both the patient and public health; providing a diagnosis may help individuals make life plans, inform their behaviour in terms of infection control; diagnosing patients will also provide information on the actual burden of disease in an area, and may stimulate policy-makers and donors to scale-up treatment services.
If more patients have a bacteriological diagnosis then fewer patients will be treated empirically, which means fewer individuals will be given unnecessary treatment or receive incorrect or suboptimal treatment.
Although the availability of new diagnostics reduces the need for conventional laboratory services, sputum-smear microscopy and culture laboratories are still needed within TB programmes to monitor treatment. However, reductions in the demand for these services will help to optimize the workload, and culture laboratories will be able to focus on DST for first-line and second-line anti-TB agents other than rifampicin.
The widespread introduction of new diagnostic testing platforms will allow TB to be diagnosed early and accurately. Less advanced forms of TB will be diagnosed; treatment delays will be reduced; disease transmission will decrease; case-fatality rates will decrease; adverse sequelae will be prevented; and patients' outcomes will improve.
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Rachow A, et al. Increased and Expedited Case Detection by Xpert MTB/RIF Assay in Childhood Tuberculosis: a Prospective Cohort Study. Clinical Infectious Diseases. 2012;54:1388–1396. [PubMed: 22474220] [CrossRef].
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