Lab rat tests spark TB drug boomerang fear

Isoniazid weakens the body’s capacity to launch an effective immune response against TB bacilli, the study by researchers in India with collaborators in South Africa and the US has found.

“A medicine we’ve taken for granted as a very important first-line drug against TB appears to hold a nasty surprise,” said Gobardhan Das, an immunologist at the Centre for Molecular Medicine at the JNU, who led the research.

The findings have been published in the Journal of Biological Chemistry.

Under standard treatment guidelines for drug-sensitive TB, patients have to take four drugs — rifampicin, isoniazid, pyrazinamide and ethambutol — for two months, and then continue with rifampicin and isoniazid for four more months.

The study on mice has suggested that isoniazid triggers the death of a set of white blood cells called CD4+ T cells and renders the mice vulnerable to TB reactivation or re-infection. These cells help activate other arms of the immune system that trap TB bacilli.

The paradoxical findings have left doctors incredulous.

“We should be very careful about such results. These are for now only observations in mice, and we still don’t know whether this will also happen in humans,” said Digamber Behera, professor and head of pulmonary medicine at the Post-Graduate Institute of Medical Education and Research, Chandigarh, who was not a member of the study team.

Doctors have pointed out that isoniazid and the other three drugs have saved millions of patients with TB.

“Until this claimed negative effect of isoniazid is demonstrated in humans, it’ll be difficult for the medical community to accept this,” said Vikas Maurya, a senior consultant in respiratory medicine at the BLK Super Speciality Hospital, New Delhi, who was not associated with the study.

Das said the observations on laboratory mice warranted follow-up studies to determine whether isoniazid has a similar effect in humans.

“This is particularly important because isoniazid is even used as a preventive medicine, at times prescribed to healthy persons in close contact with TB patients,” he said.

The World Health Organisation recommends a preventive six-month course of isoniazid therapy to children under six years who are close contacts of a TB patient.

A medical review, published earlier this year in the journal BMC Infectious Diseases, had found that preventive isoniazid therapy reduces the risk of children developing TB by 60 per cent.

“But our results question the wisdom of giving isoniazid to healthy persons,” said Das, who had initiated the study while he was at the International Centre for Genetic Engineering and Biotechnology, New Delhi.

Infectious disease experts estimate that nearly a third of the world’s population is infected with TB bacilli. But most people do not develop symptoms of the disease because the immune system keeps the bacilli under check.

But if the effect observed in mice also works in humans, the probability of healthy but infected people developing the disease may increase after a course of preventive isoniazid therapy.

A senior scientist not associated with the study said the results provided “compelling evidence” that isoniazid acts both on TB bacilli and on sets of T cells.

It is known that patients who have received anti-TB drugs are vulnerable to re-infection or reactivation, but the specific mechanism for this vulnerability is yet unknown, the scientist said. This study attempts to unravel the mechanism through research on mice.

Research scholars and scientists at the University of Calcutta, University of Kwazulu-Natal in South Africa, and Vanderbilt University in the US collaborated in the study.

Source: The Telegraph