This Week in TB R&D – 04 May 2010

isoniazid structure
isoniazid structure

Over the last month, a few reports about new positive TB cases have surfaced from FL, involving students at a couple of high schools and at a college.

Information was not made available as to how the original infected TB individuals contracted TB. Furthermore, it is not clear whether any of the newly identified TB positive individuals have developed active TB or latent TB (LTBI) since the diagnoses used the skin test, which only reveals exposure to TB.

LTBI treatment, however, carries its own inherent risks and raises questions about the best treatment in situations and environments such as in a classroom where the risk of TB transmission is higher .

Treatment for active TB verses LTBI is different: active TB requires a combination regimen of up to four different antibiotics to combat and eliminate infection, whereas recommended treatment for LTBI generally requires only one drug. In the US, recommended treatment for latent TB is a 9 month course of Isoniazid (INH).

While INH is a venerable treatment, its use to treat LTBI is now being called into question. INH inhibits an enzynme, InhA, which is involved in fatty acid synthesis. A recent Morbidity and Mortality Weekly Report (MMWR) published in the Journal of the American Medical Association (JAMA) by the CDC reports the incidence of severe liver toxicity in patients receiving INH treatment for LTBI.

From 2004-2008, state health departments voluntarily provided information to the CDC on severe adverse events, of which liver toxicity is a major adverse event. Seventeen patients, which included two children, aged 11 and 14, ranging in age from 19-63 years old developed severe liver toxicity. Five of these patients had to receive liver transplants, including one of the children. Unfortunately, five adult patients of the seventeen died, including one of the liver transplant patients.

Apparently, patients developed symptoms related to hepatic injury such as jaundice, nausea, and abdominal pain just to name a few, prior to laboratory tests confirming toxicity. INH treatment was halted for all patients once signs of hepatic injury were confirmed by laboratory tests. The report further encouraged that all patients should be advised to immediately discontinue treatment at the first experience of any symptoms related to liver toxicity.

Interestingly, the report mentions that people on INH can develop liver injury without displaying the symptoms mentioned above. These observations underscore the unmet need to develop safer, shorter regimens not only for active TB, but also for LTBI.

The report mentions other countries, such as UK use a different and shorter regimen for LTBI which contains INH and rifampin, should the US modify their current regimen? What are the incidence rates of liver toxicology in patients on these other LTBI treatment regimens?

If only a small percentage of people infected with LTBI will ever develop active TB, should suspected LTBI patients such as those in FL noted above, be monitored instead of treated with INH due to the risk of developing liver toxicity? Should there be a different protocol for treating children? Should parents be able to refuse treatment for their children at the recommendation of the school? Should schools and communities be concerned if parents refuse treatment children?

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