Isoniazid preventive therapy doesn't increase risk of resistant TB

Michael Carter
Published: 13 April 2010

Treatment with isoniazid preventive therapy does not lead to the development of drug-resistant tuberculosis, South African investigators report in the April 24th edition of AIDS.

Drug susceptibility was monitored in gold miners who developed active tuberculosis (TB). Results showed that patients who received isoniazid preventive therapy did not have an increased risk of developing TB which was resistant to the drug.

Isoniazid preventive therapy has been shown to halve the risk of developing TB in people with HIV.

However concerns about the emergence of resistance in patients who already have undiagnosed active TB are a major obstacle to the implementation of isoniazid preventive therapy programmes in many resource-limited settings.

The incidence of TB is especially high amongst South African gold miners, due in part to the high prevalence of HIV amongst this population.

It is estimated that most (89%) gold miners in South Africa have latent TB. The Thibela TB study was therefore designed to evaluate the effectiveness of isoniazid preventive therapy in this population.

Individuals were randomised to receive preventive treatment with isoniazid for nine months, or to be provided with routine TB control.

Analysis was then restricted to patients who developed active TB. Drug susceptibility was compared between those who received isoniazid and those who did not. A laboratory sub-study was also performed, involving individuals who presented with active TB and who had no history of TB therapy.

A total of 23,095 individuals were included in the study, and 126 of these developed active TB despite receiving isoniazid.

These patients had a median age of 43, and 99% were men. The median duration of isoniazid preventative therapy was 105 days, and 22% of patients had completed the full nine months of treatment with the drug.

The HIV status of 103 patients was known, and most (83%) were HIV-positive. Only a quarter of these individuals were taking antiretroviral therapy, and median CD4 cell count was 196 cells/mm3.

For 75% of patients, this was their first episode of TB, and in 69% of cases it affected the lungs.

At the time the authors wrote their study, TB therapy had been completed by 108 patients. Treatment failure or interruption was observed in two patients, with a further 31% being transferred or lost to follow-up. Nine patients died, eight of whom were HIV-positive.

Drug susceptibility test results were available for 71 individuals.

These showed that 12% of patients experiencing their first episode of TB had resistance to isoniazid.

This was comparable to the 6% prevalence of resistance to this drug which the investigators observed in the control arm. Moreover, the prevalence of isoniazid resistance was 18% amongst patients in the laboratory sub-study.

Amongst patients with recurrent TB, the prevalence of isoniazid resistance was 8% amongst those who received preventive treatment with the drug and 19% amongst individuals in the control arm.

“Concern about generating isoniazid resistance is a major obstacle to wider implementation of isoniazid preventative therapy. These data do not support this concern”, comment the investigators. “Drug resistance was no more prevalent than in the comparison groups.”

They conclude, “TB disease among mostly HIV-infected people previously exposed to isoniazid preventative therapy had treatment outcomes typical of this setting and a similar prevalence of isoniazid resistance to background. Concerns about generating drug resistance should not impede implementation of isoniazid preventive therapy.”


van Halsema CL et al. Tuberculosis outcomes and drug susceptibility in individuals exposed to isoniazid preventative therapy in a high HIV prevalence setting. AIDS 24: 1051-55, 2010.

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