The emerging crisis of multidrug-resistant tuberculosis is a “personal and health system catastrophe” that’s occurring half a million times a year in the form of new cases, Eric Nuermberger said at an IDWeek session on HIV-related opportunistic diseases. Not only is it an intensively difficult disease to treat, requiring up to two years of therapy with very toxic and expensive drugs with poor efficacy, “we continue to learn it’s even worse than we may have first thought,” he said.
“We’re creating worse drug resistance problems for one out of every ten patients we try to treat,” he said, referring to an article published this month in Clinical Infectious Diseases.
Nuermberger said when it comes to new TB drug development, we want to see the following: more potent drugs to rapidly resolve symptoms, reduce transmission, shorten and simplify treatment, and prevent resistance to companion drugs. New drugs should have good tolerability and safety, and have no interactions with antiretrovirals or other TB drugs, he said.
There are three areas where new drugs are coming from, he said: repurposing existing agents that have been used to treat other diseases, improving existing TB drugs like rifamycins, and developing new chemical agents, of which there are 6 new agents that have moved into phase II of clinical development, including bedaquiline and delaminid.
“But I don’t want you to leave with a false sense of security that we have this robust, rich TB drug development pipeline,” he said. With very few new drugs in late stage development in the pipeline and no drugs in the early pre-clinical phase, “there’s likely to be a good 5-10 years before we have more new drugs to be working into regimens,” he said.
“More advanced fluoroquinolones could open the door to shorter regimens,” he said. Animal models suggest rifamycin exposure drives sputum conversion, he added, with mice showing quicker recovery from TB with higher rifamycin exposure.
Bedaquiline, which has received accelerated approval, hastens sputum conversion and prevents resistance to companion drugs for MDR-TB, he said, but is prone to drug-drug interactions and must complete a phase III study to better examine efficacy and safety.
Linezolid has shown early success in salvage therapy, he said, and sutezolid has shown early bacteriacidal activity in TB patients.
In addition to new drugs, there is some progress in developing new diagnostics for TB. Yukari Manabe described the Alere Determine TB LAM Ag test, a new point-of-care diagnostic for TB. The urine-based test delivers results in 25 minutes, is non-invasive, can be stored at room temperature, comes in individualized foil, strip packaging, and is easy to transport, she said.
The test has highest sensitivity in patients living with HIV, but poor accuracy in children, she said. Studies show the test may have additive value with sputum smear microscopy, with one study showing sputum smear alone finds 66 percent of cases detected, and 81 percent of cases with the LAM test. In addition, GeneXpert plus LAM detected 93 percent of cases.
Manabe said there are a currently a number of studies further investigating the test.