New DNA Test Quickly Identifies Multidrug-Resistant Tuberculosis
Physicians will be able to order the correct therapy in as little as two hours after taking a sample for testing
Thomas Morrow, MD
Tuberculosis (TB) is not something people take much time to think about, many very wrongly assuming that it is a defeated disease in the United States. TB has been around for a long time, and although it is significantly reduced in developed countries, still poses a considerable threat to this country.
Evidence of TB in humans has been found in 6,000-year-old skeletal remains, and Egyptian mummies from 3,000 to 2,400 B.C. demonstrated the damage of spinal TB. Hippocrates described TB as the most widespread disease during his lifetime. In the Americas, evidence has been found dating from the time of Jesus.
Tubercles, fibrous infected masses of active TB bacillus and white cells found in lungs in the pulmonary form of the disease, were described by Dr. Richard Morton in 1689, eventually leading to the name tuberculosis. Robert Koch, a German doctor, discovered the bacillus Mycobacterium tuberculosis (MTB) in 1882, which led to a Nobel Prize two decades later. During his lifetime in Europe, TB accounted for one in four deaths!
The primary means of transmission of TB is through the inhalation of airborne organisms: As few as 10 bacteria can cause an infection. A single sneeze from an infected person can expel 40,000 droplets, each droplet capable of containing enough active bacteria to cause an infection.
Fortunately, most people with TB develop a latent form of the infection that is not typically contagious to others. But about 10% of those with latent TB will eventually progress to the infectious active form of TB, typically when their immune system deteriorates because of age, other diseases, immunosuppressive medications.
Classic symptoms of TB include fever and chronic cough, often associated with blood-tinged sputum and night sweats. If the bacillus infects other organs, a number of other symptoms can exist, which can confuse the diagnosis. In days past, TB was often called “consumption” because of the weight loss associated with untreated, advanced infection.
Although only about 5% to 10% of people in the United States test positive for having had contact with the disease, in some places, such as parts of Asia and Africa, upward of 80% of the population test positive. Immigrants from these areas are a major source of TB in the United States.
In active cases, a specific stain (the acid-fast smear) can enable trained clinicians to see the TB bacterium under the microscope. Although this test is rather simple, it depends on having a sufficient number of bacteria in the sputum sample to see the organism.
The microscopic exam thus misses many infections; therefore it is followed by culture, a process that takes weeks. If a sputum sample is found not to contain TB under microscopic examination, but later the culture is found to grow the TB bacillus, it is termed smear-negative. Microscopy also cannot tell whether the organism is resistant to the traditional drugs.
Early TB intervention included separation of infected people from the masses and the creation of TB sanatoriums. A crude vaccine, the BCG vaccine, is used worldwide but is only partially effective.
The first antibiotic used to treat TB, streptomycin, was developed in 1946. Numerous others have been developed, including isoniazide, rifampin, pyrazinamide, ethambutol, amikacin, ethionamide, moxifloxin, and para-aminosalicylic acid. These drugs have been the mainstay of therapy for some time.
But a new threat is becoming a public health nightmare, the development of multidrug-resistant TB (MDRTB). This form of the disease, although not as common, is much more dangerous. One of the major concerns related to MDRTB is the rather long time it takes to actually diagnose the presence of TB and, in particular, the resistant form. Until now, there was not an easy-to-use, reliable, accurate, and fast way of positively identifying TB and, especially, MDRTB.
The other two major human lethal infections, malaria and HIV, both have rather simple and rapid tests capable of being done in primary care settings.
Recently, the FDA approved Xpert MTB/RIF, created by Cephid, a Sunnyvale, Calif., company. It is the first test that can rapidly and simultaneously detect M. tuberculosis and rifampin resistance. Rifampin resistance is associated with a specific gene, the rpoB gene, and is a marker for multidrug resistance.
The test works by using a now common process of amplifying the DNA of the organism with polymerase chain reaction (PCR) technology and detecting whether the genetic markers specific for MTB and/or rifampin resistance are present. The test is also very fast — two hours as opposed to nearly six weeks for culture and sensitivity testing.
The controlled clinical trials leading to approval compared test results from the Xpert MTB/RIF assay to traditional culture and sensitivity testing, the gold standard. In these trials, Xpert MTB/RIF rapidly detected more then 92% of pulmonary TB with a sensitivity of over 97% and a specificity of 99.5%, meaning it detected specifically the form of MTB it was intended to detect. It was also able to detect 72.5% of those forms that are smear-negative.
A subsequent “real-world” study was done in numerous less developed countries (Peru, Azerbaijan, South Africa, Uganda, India, and the Philippines), performed by technicians with little or no computer or laboratory experience — with almost identical results.
The FDA stated that the Xpert MTB/RIF assay “is intended for use with specimens from patients in whom there is clinical suspicion of TB and who have received no anti-TB therapy or less than three days of therapy.” The specimen can be raw sputum or concentrated sediments prepared from induced or expectorated sputum. The specimen is loaded into the Xpert MTB/RIF assay cartridge that is then loaded onto the GeneXpert Instrument System platform that performs the automated sample processing and real-time PCR for detection of DNA.
Since it is detecting the presence or absence of specific genetic material, it uses an algorithm to report these easy-to-understand results:
Presence of Mycobacterium tuberculosis
According to the FDA decision summary, the test “must be used in conjunction with mycobacterium culture to address the risk of false negative results and to recover the organism for further characterization and drug susceptibility testing.”
$300,000 per case
The treatment of drug-resistant TB differs considerably from normal treatment in a number of ways and according to one report (http://bit.ly/19Gl01Y) can cost $300,000 per case! Knowing that the infection is present and whether it is resistant can facilitate accurate and rapid treatment, significantly reducing the chance of spread.
The approval and rollout of the Xpert MTB/RIF test again proves that advances in genetic testing will be a foundation of Tomorrow’s Medicine.
Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. Contact him at TMorrow@ManagedCareMag.com.
The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.