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WHO's guidelines for TB medications may be too low for patients with HIV

The World Health Organisation's dosage guidelines for two leading tuberculosis medications may be far too low for patients with HIV, allowing them to remain contagious for longer than necessary, The New York Times reports a study has found.

TB, now the leading infectious killer worldwide, takes over 1.5m lives per year. Treatment lasts at least six months and can cause serious side effects, making it difficult for patients to stick to it.

Doctors have been prescribing two TB drugs, rifampicin and isoniazid, for almost half of a century. But a study led by researchers at the Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda, and division of infectious diseases and hospital epidemiology, University Hospital Zurich, University of Zurich, adds to growing evidence that higher doses may kill the deadly mycobacteria faster, curbing transmission.

“I’m not surprised,” said Dr Melvin K Spigelman, the president of the Global Alliance for TB Drug Development. “The recommended doses were really based on the cost of the drug, not on good science that showed it was the right dose. People, understandably, tried to get away with the least amount that seemed like it worked.”

The report says the study focused on about 270 TB patients also infected with HIV. The condition can reduce the amounts of medications absorbed or retained in a patient’s bloodstream. Patients received standard drug doses to treat TB, but concentrations in the blood were found to be jarringly low: 84% of the participants had substandard levels of isoniazid, and 78% fell below targets for rifampicin.

Patients with lower blood concentration levels also bore the infectious bacteria in their sputum for longer periods of time – potentially spreading it by coughing, said Dr Jan S Fehr, one of the study’s lead authors. Such persistent infection could threaten the WHO’s goal of eliminating almost all TB deaths by 2035, he added.

The WHO already has begun reviewing its decades-old treatment regimen. “This study provides one piece of a larger puzzle, and it’s necessary that we have another look,” said Dr Karin Weyer, a TB expert at the WHO.

The study’s findings are a sign that TB research has been chronically underfunded, said Dr Neil Schluger, an epidemiology professor at Columbia University in the report. For decades, few economic incentives have prompted drug companies to update TB treatments, which are primarily needed in poor regions – compared to lucrative therapies for diseases like cancer, he said.

“My real question is, why are we just doing this now?” said Schluger. “These are fundamental questions that should have been answered a long time ago.”

Background: The relationship between concentrations of anti-tuberculosis (TB) drugs, sputum conversion and treatment outcome remains unclear. We sought to determine the association between anti-TB drug concentrations and sputum conversion among TB-HIV co-infected patients on first-line anti-TB drugs.
Method: We enrolled HIV-infected Ugandans with pulmonary TB. Estimation of first-line anti-TB drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of TB treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion.
Results: We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of TB treatment or by the end of follow-up; Hazard ratio (HR) 0.54: 95% confidence interval (CI): 0.37–0.77, P=0.001 and HR: 0.61, 95% CI: 0.44–0.85, P=0.003, respectively. Patients in the highest AUC quartile for rifampicin and isoniazid were approximately two times more likely to experience sputum conversion. Rifampicin and isoniazid concentrations below the thresholds and being in a weight band <55kg were both risk factors for unfavorable TB treatment outcomes. Only 4.4% of the participants had treatment failure.
Conclusion: Although low anti-TB drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications on TB transmission.

Christine Sekaggya-Wiltshire, Amrei von Braun, Mohammed Lamorde, Bruno Ledergerber, Allan Buzibye, Lars Henning, Joseph Musaazi, Ursula Gutteck, Paolo Denti, Miné de Kock, Alexander Jetter, Pauline Byakika-Kibwika, Nadia Eberhard, Joshua Matovu, Moses Joloba, Daniel Muller, Yukari C Manabe, Moses R Kamya, Natascia Corti, Andrew Kambugu, Barbara Castelnuovo, Jan S Fehr

[link url=""]The New York Times report[/link]
[link url=""]Clinical Infectious Diseases abstract[/link]

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