One golden wish in TB care and control is surely around early diagnosis of all forms of TB. New rapid diagnostic tools have come on board over the past years such as Liquid Culture, Line Probe Assay (LPA), and Xpert MTB/RIF among others in addition to conventional gold standard solid culture and drug susceptibility testing (DST). At the 4th Union Asia Pacific Region Conference on Lung Health in Hanoi, Viet Nam, national TB programmes of different countries shared their experience of using WHO – recommended Xpert MTB/RIF in Programmatic Management of Drug-resistant TB (PMDT) over the past few years.
WHAT IS XPERT MTB/RIF?
The Xpert MTB/RIF test is a cartridge-based fully automated NAAT (nucleic acid amplification test) for TB case detection and rifampicin (RIF) resistance testing, suitable for use in disease-endemic countries. It purifies, concentrates, amplifies (by rapid, real-time PCR) and identifies targeted nucleic acid sequences in the TB genome, and provides results from unprocessed sputum samples in less than 2 hours, with minimal hands-on technical time (Source: Technical FAQs on Xpert MTB/RIF Assay, produced by Initiative for Promoting Affordable and Quality TB Tests – IPAQT).
XPERT, RIFAMPICIN RESISTANCE AND MDR-TB
According to the World Health Organization (WHO), multidrug-resistant TB (MDR-TB) is defined when TB bacteria becomes resistant to the most effective anti-TB drugs (isoniazid and rifampicin). MDR-TB results from either infection with organisms which are already drug-resistant or may develop in the course of a patient’s treatment.
Most people who are resistant to Rifampicin are also found resistant to Isoniazid. Mono-resistance to Rifampicin is fairly uncommon. That is the rationale for interpreting a positive diagnosis for TB and Rifampicin resistance from Xpert MTB/RIF as a surrogate marker for Isoniazid resistance. That is why WHO recommends doing a confirmatory test using culture and DST before initiating treatment.
Dr Nguyen Viet Nhung, Deputy Manager of Viet Nam’s National TB Programme and Vice Director of National Lung Hospital in Hanoi, Viet Nam, said to Citizen News Service – CNS: “If the positive predictive value (PPV) is high then it indicates the patient is at high risk of MDR-TB. For example, patients who are previously treated for TB come in this category. In such a patient, a positive rifampin (RIF) resistance result of Xpert MTB/RIF is sufficient to initiate MDR-TB treatment. Viet Nam does not delay MDR-TB treatment in such patients rather alongside starting MDR-TB treatment we also send a sample for culture and DST. When the DST results come back, the MDR-TB regimen can be modified/customized, based on DST profile. If the patient has no history of previous TB treatment and no known contact with a MDR-TB case, then a positive RIF resistance result of Xpert MTB/RIF could be a false-positive, and must therefore be confirmed with another test (culture and DST) before MDR-TB treatment is started.”
“In Indonesia no patient is put on MDR-TB treatment despite Xpert MTB/RIF’s positive diagnosis of rifampicin resistance and we have to do a confirmatory culture and DST” said Dr Roni Chandra, microbiologist from Indonesia. However Indonesian PMDT treatment algorithm has recently been updated to align itself with the one followed in Viet Nam and other countries.
Cambodia too does not begin MDR-TB treatment right after a positive diagnosis for rifampicin resistance from Xpert MTB/RIF. Only after a confirmatory culture and DST patients are started on MDR-TB treatment, said Dr Seak Kunrath from Cambodia.
WAIT FOR CONFIRMATORY TEST: YES OR NO?
Dr Chen-Yuan Chiang from International Union Against Tuberculosis and Lung Disease (The Union) questioned the public health rationale of doing Xpert MTB/RIF in patients of presumptive MDR-TB when we have to do a confirmatory culture and DST anyways? Dr Chiang argued in favour of (his theoretical and yet to be evaluated approach) of doing a repeat Xpert MTB/RIF with a different sample in patients who test positive for Rifampicin resistance with Xpert MTB/RIF earlier (instead of conventional culture and DST). Testing a different sample is extremely important in this approach of repeat Xpert MTB/RIF. There is a clear need to test Dr Chiang’s proposal as it may reduce the time between a confirmed diagnosis of MDR-TB and initiation of treatment drastically from few months or weeks to a few hours or days perhaps! Early diagnosis, initiation of right treatment regimen and successful completion of treatment are indeed key to TB care and control.
EXPERT MTB/RIF IN VIET NAM, INDONESIA, CAMBODIA
Out of 27 Gene Xpert MTB/RIF machines currently in use in Viet Nam, 17 were funded by TB CARE I, 5 by TB REACH, 2 by Canadian International Development Agency (CIDA), 1 by Oxford University Clinical Research Unit (OUCRU), 1 by PANTHER, 1 by Foundation for Innovative New Diagnostics (FIND). Viet Nam is currently planning and making efforts to mobilize more resources from The Global Fund to Fight AIDS, Tuberculosis and Malaria (The Global Fund) to establish 26 additional Gene Xpert MTB/RIF machines, and another 9 Gene Xpert MTB/RIF machines from a possible support from UNITAID.
Similarly Indonesia and Cambodia too reported scaling up of Xpert MTB/RIF in their respective PMDT programmes. It is likely that China may roll out 800 Xpert MTB/RIF machines soon.
Increased and rapid diagnosis of TB and rifampicin resistance; and early treatment initiation for TB and drug-resistant TB; were some of the key benefits shared by most countries that are using Xpert MTB/RIF significantly in their respective PMDT programmes. The case detection of MDR-TB patients and those enrolled in PMDT in different countries have all been on the rise, thanks to new approaches and strengthening PMDT.
Roni Chandra from Indonesia said that stock out problems due to delayed procurement process was a major obstacle in introducing and rolling out Xpert MTB/RIF. This delay was because the funding Indonesia receives from the Global Fund to Fight AIDS, Tuberculosis and Malaria (The Global Fund) cannot be used to pay Cepheid directly for Xpert MTB/RIF. Uninterrupted availability of Xpert MTB/RIF cartridges was another major challenge. Roni Chandra shared that in the previous year they had asked for 6000 cartridges but so far have received half of their requirement. Roni Chandra said that limited number of quality assured culture and DST laboratories to support confirmation of Xpert MTB/RIF result was another factor slowing down the gains made by introduction of rapid diagnostic techniques and delaying the onset of treatment. “Three sites in Indonesia reported problems with one of their modules of Xpert MTB/RIF and one site could not function at all till end of February 2013 due to database connection error” said Roni Chandra.
Calibration of Xpert MTB/RIF was a common issue reported by Indonesia, Cambodia and Viet Nam.
Cambodia has 12 Xpert MTB/RIF machines functional in the country. Dr Seak Kunrath from Cambodia highlighted some challenges with rolling out Xpert MTB/RIF that included: 3 modules of Xpert MTB/RIF were “broken and needed replacement”; they were unable to interpret results in some cases; machines needed temperature control, electricity, and other requirements which makes them impractical to be used in the field; and “preparing samples hurriedly causes error.” There was a request for Cepheid to establish in-country partners to help with procurement, after-sale services and maintenance in countries such as Indonesia.
SLOW BUT FIRM: NO SCOPE FOR MISSING A STEP
Drug-resistant TB is a man-made problem. Dr Chen-Yuan Chiang from The Union, could not have summarised this any better: “A poor drug-resistant TB programme is worse than no programme.” He said this while referring to a paper co-authored by him which was published recently.
Dr Nguyen Viet Nhung, who was a key member of APRC 2013’s organizing committee reflected while in a conversation with CNS: “Viet Nam is expanding PMDT, slowly but firmly.” With strengthening laboratory capacity across the country, training PMDT team members and related providers, establishing standards of procedure (SOPs), reliable reporting and recording systems, procuring second-line drugs (SLDs) for PMDT in Viet Nam to ensure uninterrupted supply of quality-assured standard drugs, quality sputum collection and timely transportation, quality counseling for adherence, and helping people on MDR-TB treatment to successfully get cured, are some of the many ways Dr Nhung mentioned PMDT is deepening roots in the country.
Strengthening laboratory capacity was one of the key plans in the revised Global Plan to Stop TB (2011-2015) – which undoubtedly is one of the most significant steps ahead as PMDT rolls out in high burden MDR-TB countries globally.