GeneXpert: The first five years

In December 2010 the World Health Organisation recommended that countries start using a breakthrough new TB test called Xpert MTB/RIF (commonly referred to as GeneXpert). South Africa rapidly embraced this scientific advance and made significant investments in rolling out GeneXpert. But how much has really changed five years down the line?

The GeneXpert is a fully automated diagnostic test for TB, which offers several advantages compared to the traditional methods of diagnosing TB.

GeneXpert is able to detect the presence of TB bugs within a much shorter turn-around time and requires far fewer TB bugs (130 per ml of sputum) for testing. In comparison, sputum smear microscopy requires many TB bugs (tens of thousands per ml of sputum) to detect the presence of one bacterium. GeneXpert is therefore considerably (at least 25 percent) more sensitive than smear microscopy.

A further advantage of this technology is that the operation of the machine requires minimal training and, under ideal conditions, results are available to health workers within two hours. Because of this ease of operation, the instrument can be located in a clinic rather than a laboratory, making it suitable as a point of care (POC) diagnostic test.

While not yet on a par with a culture test, which is widely recognised as the gold standard for TB diagnosis, improved versions of the test that are likely to have accuracy comparable to that of a culture test, are in the pipeline. Furthermore, the GeneXpert is able to detect resistance to rifampicin, a key drug that forms part of the standard first-line treatment for TB. By detecting rifampicin-resistant TB strains, the test serves as a reliable proxy for MDR-TB directly from sputum specimens – if someone is resistant to rifampicin they are typically also resistant to isoniazid and therefor have MDR-TB. Newer versions of the technology to be launched in 2016/17 are expected to be able to detect resistance to additional TB drugs.

The ability of GeneXpert to detect both drug-sensitive and rifampicin-resistant TB in a much shorter time period significantly improves the chances of timely, effective treatment initiation for many TB patients whose treatment would otherwise be delayed. An additional benefit is the ability of the GeneXpert to detect smear-negative TB, which provides a significant advantage – especially in patients with HIV co-infection,who tend to have low levels of TB bacteria in their sputum. Such patients are at risk of becoming missed TB cases – although even the GeneXpert still misses roughly three out of ten TB cases in HIV-positive people. With children, in whom it is notoriously difficult to detect TB with traditional techniques because of difficulties in obtaining sputum, the increased sensitivity of GeneXpert has yielded promising results.

Until recently, the sputum culture method that has been used for more than a century and which involves growing and detecting bacteria using a microscope, was the only method available for many developing countries. This method has the additional limitation of requiring centralised laboratories with specialised facilities.

Testing for MDR-TB is another cumbersome process of growing the MTB bugs, over several weeks or months, in addition to requiring extensive infrastructure. During this period, the infected person poses a threat not only to themselves but also to their families, the community and the general public, as the drug-resistant MTB strains are spread just like ordinary TB – via the air from person to person.

The GeneXpert has therefore been widely regarded as ‘a game changer’, mainly because it eliminates the long turnaround around time for results associated with conventional testing methods, allowing for a rapid diagnosis, and early treatment initiation, which has great potential to impact on the transmission rates of the disease. If this point-of-care technology is located at a community health centre, the chain of care and speedy delivery of test results means that the period from diagnosis of TB to treatment for TB can potentially be significantly reduced. South Africa has made massive investments in the GeneXpert and today GeneXpert machines can be found in most major healthcare centres across the country. However, significant questions remain as to whether this investment has been worthwhile and whether there have been any notable improvements as a result of the implementation of this technology.

Early evidence of the impact of GeneXpert has shown varying results, depending on the setting. A University of Cape Town study demonstrated clear benefits from the provision of GeneXpert testing, compared to smear microscopy. This study showed that a higher proportion of TB patients in the GeneXpert arm had a confirmed TB diagnosis and that these patients were more likely to initiate treatment, compared to those in the routine arm. Another clear benefit of GeneXpert from this study was shortened times to treatment, leading to significant improvements in the overall treatment initiation rates and the proportion of patients successfully treated for TB, particularly in HIV-positive patients.

Another study, called the TB-Neat study, showed that GeneXpert outperformed smear microscopy in diagnosing smear-negative TB cases. There appears to be some consensus across studies that the greatest effect and value of the GeneXpert assay to date has been seen in difficult-to-access communities.
Yet, whether GeneXpert is actually saving lives or not is unclear. A study by Gavin Churchyard found that people who were tested with the GeneXpert were no less likely to have died six months after being tested than people who were tested using sputum microscopy. Another study found that, despite the rapidity of GeneXpert results, only about 70 percent of TB patients were actually initiated onto treatment one month after testing. These results show that while early diagnosis and better tools such as GeneXpert is important, equally important is facilitating better linkage to care. An optimally functioning healthcare system is clearly essential for the full benefits of GeneXpert or any other new tools to be realised.

In conclusion, we note that while the laboratory turnaround time has been reduced in many settings as a result of the GeneXpert, the effect has not been as dramatic as anticipated. In order to optimise and realise the full potential of the GeneXpert, several health system factors need attention. Issues within the healthcare system, such as early diagnosis and treatment; proper sputum collection procedures; TB patient follow-up to support treatment adherence and treatment success; treatment support and ensuring patient retention in care, will all need to be addressed in order for the full benefits of GeneXpert to be fully realised. In a fragile health system, even the most sophisticated tool is bound to underperform.