Report of Expert Consultations on Rapid Molecular Testing to Detect Drug-Resistant Tuberculosis in the United States

Possible scenarios and scope of testing for a molecular DR testing service

A phased approach to developing and implementing a molecular DR testing service would be prudent. In the initial phase, testing might be offered for TB patients or suspects at high-risk of having MDR TB and situations deemed high priority by the program (judicious use testing). A long-range goal should be to offer testing for all TB patients and suspects (universal testing). In addition to molecular DR tests, the resources of the molecular DR laboratory might be leveraged to provide other services for state and local TB programs and laboratories. The scope of any additional service, such as NAA testing for detection or culturing or second-line drug susceptibility testing, must be clearly defined and adequately funded.

Judicious use testing would concentrate on testing (a) samples for which the test result would alter case management or TB Control decisions, outbreak or contact investigations, preventive therapy in immunocompromised contacts, infection control, or Do Not Board lists; (b) samples from persons at risk of having drug-resistant TB (persons exposed to an MDR-TB case, from a population with a high rate of MDR TB, or failing or having failed therapy with first-line anti-TB drugs); and (c) respiratory specimens or isolates that can not be tested easily with conventional methods (non-viable specimens; mixed or contaminated cultures). Given that there are 100 to 150 new cases of MDR-TB reported to CDC each year and many new TB cases are persons from populations with a high prevalence of MDR TB, one would estimate that a judicious use molecular DR testing program would entail the testing of about 2500 samples per year. One or two regional molecular DR testing laboratories would be needed. The estimated cost of this is $300,000 to $400,000 plus the cost of shipping (~$70,000) and initial equipment.

Universal testing would involve molecular DR testing one AFB smear-positive or NAA-positive respiratory specimen or one M. tuberculosis culture from each TB patient or TB suspect. About 5000 AFB-smear positive pulmonary TB cases were reported to CDC in 2007. An approximately equal number of patients were AFB-smear positive due to the presence of non-tuberculous mycobacteria (NTM) in the respiratory specimen. About 7,400 pulmonary and ~3000 extrapulmonary culture-confirmed TB cases were reported to CDC in 2007. Thus, universal testing would entail testing 10,000 to 20,000 samples per year. Up to four regional molecular DR testing laboratories would be needed to handle this work load. The estimated cost of a universal molecular DR testing service is 1.2 million to $2 million dollars plus the cost of shipping ($250,000 to $500,000) and initial equipment.

Variations of the molecular DR testing options described above may allow CDC to address the needs of programs for NAA testing for detection as well as molecular DR testing. However, linking NAA testing for detection with molecular DR testing must be carefully thought through to determine if it is a cost-effective, reliable approach to providing molecular DR testing services to state and local TB programs.

1. Option 1: only samples shown to be NAA-positive for TB would be accepted by the molecular DR testing laboratory. In this case, universal testing would involve 7000 to 9000 samples because NAA tests detect 70% to 90% of pulmonary TB cases that are ultimately culture confirmed. This approach (a) would delay sample submission to the molecular DR testing laboratory by 1–2 days, although a positive NAA result at the local laboratory might prompt earlier initiation of therapy; (b) would increase the cost of the molecular DR testing service to the TB program to include the cost of NAA testing at the local laboratory; (c) might complicate the submission process for private- and public-sector laboratories and programs that do not have access to NAA testing, although this requirement might be an incentive for local laboratories to offer NAA testing; and (d) might reduce shipping costs if leftover DNA from the NAA testing were shipped. If NAA testing were required prior to submission, a phased implementation of this requirement would be essential to ensure that all programs have access to molecular DR testing when needed, perhaps by allowing programs to submit samples from patients meeting the judicious use criteria.
2. Option 2: the molecular DR testing laboratory would conduct NAA testing for detection as well as molecular DR testing. For AFB-smear positive specimens, the available molecular DR tests can reliably detect M. tuberculosis DNA, so a separate test for detection is not needed. For AFB-smear negative samples, an optimized NAA test for detection could be coupled with a molecular DR test to increase reliability of the molecular DR test. However, the performance of molecular DR tests with AFB-smear negative, NAA positive specimens is not known. This approach would (a) provide access to NAA testing for detection to local and state TB programs; (b) increase the cost of the molecular DR testing service to include the cost of NAA tests for detection; (c) allow use of a specimen processing method optimized for molecular DR testing; and (d) require strict criteria for submitting AFB-smear negative specimens to avoid inappropriate ordering of NAA tests for patients who are unlikely to have TB.

For any of the scenarios, a phased approach would be prudent. At a minimum, it would be essential to provide molecular DR testing services for TB patients or suspects at high-risk of having MDR TB and those deemed high priority by the program. This could be accomplished by providing sufficient new funding to existing, proficient molecular DR testing laboratories to expand their capacities to meet this need. If done through supplements to existing cooperative agreements, this might be done quickly. Such an interim service could serve as pilot projects and would allow time to (a) compare the performances and costs of currently available tests and select one or more for use in the molecular DR testing service; (b) assess and overcome potential obstacles and barriers to a regional approach to diagnostic testing such as local regulations regarding out-of-state testing, reporting requirement, and need for memoranda of agreement; (c) develop a strategy to coordinate or integrate services provided by the molecular DR testing and genotyping laboratories to avoid unnecessary duplication of efforts and shipment of isolates; (d) develop a strategy for implementing the molecular DR testing service to include informing potential service users of the availability of the service, how to access the service, and the appropriate use and interpretation of molecular DR tests for TB; (e) design a molecular DR testing service to meet the needs of local and state TB control programs; and (f) develop, compete, and award a contract to provide the services.