Treatment of isoniazid-resistant tuberculosis: closing evidence gaps on safety, effectiveness, and pharmacokinetics of the standard regimen

Socios En Salud Sucursal Peru, Lima

Investigators

Abstract

PROJECT SUMMARY. Tuberculosis (TB) is a dangerous disease that, prior to the advent of COVID-19, was the leading cause of death from an infectious agent. M. tuberculosis resistance to anti-TB drugs worsens clinical outcomes and poses a serious threat to global TB control. Resistance to isoniazid, the first-line drug with the most potent early bactericidal activity, is the most common form of resistant TB and reduces the efficacy of standard 6-month treatment. Based on a meta-analysis of observational reports, the WHO, the US CDC, and several scientific societies, have recommended an alternative regimen for isoniazid-mono-resistant TB that substitutes levofloxacin for isoniazid and includes a 6-month course of levofloxacin along with rifampicin, ethambutol, and pyrazinamide (6Lfx-REZ regimen). To date, this is a weak recommendation because it is based on evidence rated as very low quality. It is also acknowledged that the prolonged administration of pyrazinamide entails a considerable risk of liver toxicity, and it may be necessary to increase the dose of rifampicin and levofloxacin to boost efficacy, within sufficient safety criteria, because it lacks the bactericidal action of isoniazid. The prevalence of isoniazid-mono-resistant TB in Peru is significant; in Lima, 20% of TB cases are isoniazid-resistant but half of them are still sensitive to rifampicin. Additionally, the 6Lfx-REZ regimen is being applied across the nation following new national TB guidelines. Here, we propose a study to fill in some of the gaps in the evidence supporting the safety, tolerability, effectiveness, and drug dosages of this regimen. We will recruit patients in primary health care centers throughout metropolitan Lima and use rapid molecular and phenotypic tests to identify 218 isoniazid-resistant and rifampicin-sensitive TB participants who receive the 6Lfx-REZ regimen. Through active pharmacovigilance of these patients with phone calls every two weeks and periodic medical examinations with laboratory tests, we will assess the safety and tolerability of the regimen. We will measure sustained effectiveness up to 12 months post-enrollment with periodic sputum cultures and assess the acquisition of additional resistance in individuals who fail treatment or relapse. We will also determine pharmacokinetic (PK) and pharmacodynamic (PD) parameters of levofloxacin and rifampicin at week 8 in a subset of participants, oversampling those who fail to convert their culture to negative to determine the minimum inhibitory concentrations of both drugs in baseline isolates. We believe that this study will offer useful information about the regimen used to treat the most prevalent type of drug-resistant TB. The data will be transferable to environments with a high prevalence of resistant TB. Finally, we believe that this prospective cohort design will provide high-quality evidence promptly while also strengthening the clinical research capabilities of the participating Peruvian institutions.