Rising Prevalence of Isoniazid-Resistant TB Should Be Factor in Treatment Decisions

By Will Boggs MD

February 05, 2020

NEW YORK (Reuters Health) - The increasing global prevalence of isoniazid-resistant tuberculosis should influence individual treatment decisions, researchers say.

"Rifampicin and isoniazid are both major first-line medicines used in the treatment of TB, but most of the efforts towards preventing the spread of drug-resistant TB focus on the detection of rifampicin resistance," said Dr. Anna S. Dean of the World Health Organization's Global TB Program, in Geneva.

"We found that resistance to isoniazid is actually more common, yet we do not have the same availability of rapid diagnostic tools," she told Reuters Health by email.

An estimated 3.4% of new TB cases and 18% of previously treated TB cases have rifampicin-resistant TB. Less is known about resistance to isoniazid, the most commonly used medicine for preventive therapy.

Dr. Dean and colleagues describe the global prevalence of isoniazid-resistant, rifampicin-susceptible (Hr-)TB, with and without resistance to other anti-TB medicines, as well as molecular markers of isoniazid resistance, in a report in PLoS Medicine.

Among the countries and territories for which data were available, the global prevalence of Hr-TB was 7.4% among new patients, 11.4% among previously treated TB patients and 8.4% among all TB patients, with significant variance across and within WHO regions.

The overall prevalence of any resistance to isoniazid, regardless of rifampicin resistance, was 10.7% among new TB patients and 27.2% among previously treated TB patients.

The prevalence of resistance to either levofloxacin or pyrazinamide was low among Hr-TB cases except in Pakistan, where 12.6% of new Hr-TB patients had resistance to at least one of these drugs.

Among the isolates with isoniazid resistance, 78.6% had resistance-conferring mutations in the katG gene, compared with 6.8% that had only resistance-conferring mutations in the inhA promoter region.

"Many cases of drug-resistant TB are being missed," Dr. Dean said. "These patients have a lower chance of being cured and therefore will continue to transmit drug-resistant TB. This hampers efforts to tackle the TB epidemic at the global level."

"Patients who are not responding as expected to their TB treatment should be investigated for underlying drug resistance that has not been diagnosed from the outset, and their treatment regimen should be adjusted accordingly," she said.

"The analysis of drug resistance patterns should ideally be linked to patient treatment outcome data, to better understand the clinical relevance of laboratory testing results and contribute to global policy for clinical decision-making," the authors conclude.

Dr. Madhukar Pai of McGill University, in Montreal, Canada, and Manipal Academy of Higher Education, in Manipal, India, who co-authored a linked editorial, told Reuters Health by email, "For decades, people working in TB knew that monoresistance to INH (isoniazid) was common. But as long as the bacteria were sensitive to RIF (rifampicin), everyone thought standard 6-month therapy would work fine. We cannot condone this approach anymore."

"Countries now need to think of how they can go beyond rifampicin screening to include other drugs and come up with a more comprehensive drug-susceptibility testing (DST) for patients," he said. "Countries will also need to offer INH-resistant TB patients the correct alternative regimen."

According to 2018 WHO guidance, patients with Hr-TB should receive a six-month course of rifampicin, pyrazinamide, ethambutol, and levofloxacin. The addition of a higher dose of isoniazid can be considered if only low-level isoniazid resistance is present, as indicated by specific inhA promoter mutations in the absence of katG mutations.

"Be alert to the possibility of drug-resistant TB, and aim to screen all TB patients for drug resistance," Dr. Pai advised. "Quality TB care must include universal DST, not just rifampin resistance testing, for all individuals with TB, followed by individualized therapy, based on DST results."

He added, "Expanded DST testing requires laboratories that are capable of performing liquid cultures and rapid molecular assays for detecting mutations. So, I would like to see greater emphasis on building stronger, tiered, connected laboratories."

SOURCE:https://bit.ly/2t7WLiy and https://bit.ly/319Emi3 PLoS Medicine, online January 21, 2020.