By Dean L. Winslow, MD, FACP, FIDSA

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: In an open-label trial, adults with latent tuberculosis infection were randomized to either four months of treatment with rifampin or nine months of treatment with isoniazid. The four-month rifampin regimen was non-inferior to nine months of isoniazid for prevention of active tuberculosis. It also was associated with a higher treatment completion rate and superior safety.

SOURCE: Menzies D, Adjobimey M, Ruslami R, et al. Four months of rifampin or nine months of isoniazid for latent tuberculosis in adults. N Engl J Med 2018;379:440-453.

Adult patients with latent tuberculosis infection (LTBI) from nine countries were assigned randomly to either a four-month regimen of rifampin (RIF) at a dose of 10 mg/kg/day (maximum dose 600 mg) vs. a nine-month regimen of isoniazid (INH) at 5 mg/kg/day (maximum dose 300 mg). Patients considered to be at high risk for development of neuropathy also received vitamin B6.

Of the 3,443 patients randomized to RIF, confirmed active tuberculosis (TB) developed in four patients and clinically diagnosed TB developed in four patients during 7,732 person-years of follow up, compared to development of confirmed active TB in four patients and clinically diagnosed TB in five patients among the 3,416 patients in the INH arm.

Seventy-nine percent of the RIF patients completed their course of treatment compared to 63% of the INH patients. One hundred sixty-two patients (5.8%) in the INH arm and 80 patients (2.8%) in the RIF arm experienced adverse events, with 1.7% of the INH patients experiencing grade 3 or 4 hepatotoxicity and 0.3% of RIF patients experiencing grade 3 or 4 hepatotoxicity.

COMMENTARY

This is an important clinical trial, which clearly will change practice in both the developed and developing world. The shorter and better-tolerated RIF regimen proved as effective as INH in preventing development of active TB, and a significantly higher proportion of patients completed their treatment. However, a big limitation of RIF (since it is a potent inducer of many cytochrome P450 isoforms) is the many problematic drug interactions. In view of this, a careful review of all patients’ concomitant medications by a clinical pharmacist would seem to be prudent in many cases before initiating RIF. In many of these patients, INH will need to be used instead.

This bit of excellent news comes quickly on the heels of the release of a meta-analysis and CDC recommendations to consider the 12-week regimen of once-weekly INH plus rifapentine (3HP) given by either directly observed therapy or self-administered treatment in persons 2 years of age and older for LTBI.1 The authors of the CDC meta-analysis reported a 5% drug discontinuation rate (largely due to systemic drug reactions often associated with fever, headache, and myalgias). While rifapentine probably is not quite as potent of a cytochrome P450 inducer as rifampin is, drug interactions are still potentially problematic.

REFERENCE

  1. Borisov AS, Bamrah Morris S, Njie GJ, et al. Update of recommendations for use of once-weekly isoniazid-rifapentine regimen to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2018;67:723-726.