Canadian Tuberculosis Standards 8th edition: What’s new? And what’s next?

Abstract

On World Tuberculosis (TB) Day 2022, the 8th edition of the Canadian Tuberculosis Standards (at: https://www.tandfonline.com/toc/ucts20/6/sup1) was published by the Canadian Thoracic Society in collaboration with Association of Medical Microbiology and Infectious Disease (AMMI) Canada and the support of the Public Health Agency of Canada. Written by a large and diverse group from across Canada, with expertise in clinical, epidemiologic, pathogenetic, microbiologic and public health aspects of TB, and with important input from community partners, notably from indigenous communities, the TB standards is intended to provide comprehensive and practical guidance for front line providers. After decades of neglect between 1970 and 2000, the last 20 years has seen a surge in new diagnostics, new treatments, and new control strategies for TB. These advances are reflected in the new TB Standards, with major changes in recommendations in many sections. See Table 1 for a summary of some of the most important changes. However, these advances have not yet impacted TB rates—which have barely changed over the last two decades—globally1 and in Canada.2 In fact, as detailed in the first chapter of the Standards, the number of persons diagnosed with TB disease each year in Canada has increased over the last 3 years.2 Clearly, new diagnostics, treatments and strategies are needed, not only as recommendations but in practice. For the diagnosis of TB disease, rapid molecular tests can be used3—to accelerate detection of the disease, and are recommended for the rapid identification of drug resistant strains—such that appropriate and effective therapy can be started promptly. The technology has been available for close to a decade, but implementation has been slow due to cost considerations. Given the risks to patients,4 increased transmission5 and high costs to health systems of delayed or missed diagnoses, the investment to implement these rapid and highly accurate tests seems modest. Isoniazid (INH) has been the mainstay of TB prevention since the first edition of the TB Standards in 1970. Although the long duration (of 6 to 12 months), and potential for serious, even fatal hepato-toxicity were major drawbacks, the evidence for alternate regimens was slow in arriving. However, two rifamycin based regimens have undergone rigorous evaluations in randomized trials and are now recommended as first line regimens for TB prevention.6 One regimen is 4 months daily Rifampin (RIF) (4 R), which has significantly better completion, fewer severe adverse events and noninferior efficacy for TB prevention, compared to 9 months INH (9H) in adults7,8 and children.9 The other is 3 months once weekly INH & Rifapentine (3HP), which has better completion and less hepato-toxicity, and noninferior efficacy compared to 6H or 9H in adults10–12 and children.13 The fact that 3HP has only 12 doses seems appealing, but a drawback is that each dose must be directly observed14; this is not feasible in all settings. Recommended regimens for treatment of TB disease caused by organisms that are susceptible to all TB drugs are unchanged.15 A recent study using high doses of Rifapentine and a fluoroquinolone,16 showed that 4 months of therapy was adequate, compared to the current 6-month standard. However, because of concerns regarding increased toxicity, this regimen has not (yet) been recommended in Canada, until more data regarding its safety is available. However, treatment of drug-resistant TB has been transformed by the introduction of new or repurposed drugs including later generation fluoroquinolones (moxifloxacin or levofloxacin), linezolid, clofazimine and bedaquiline. Although there have been few randomized trials, analysis of individual patient data from many observational studies has demonstrated substantial reductions in mortality and increased cure rates with use of these agents17 for the treatment of multi-drug resistant (MDR) TB. As a result, the new TB Standards have recommended an all-oral regimen with these drugs, replacing prolonged use of injectable drugs such as Amikacin for MDR-TB.18 Additionally, fluoroquinolones are now recommended as part of treatment of INH resistant TB,18 the most common form of drug resistant TB in Canada2 and globally.1,19 However, implementation of these new recommendations will be challenging. Many of the newly recommended regimens for TB prevention or for TB disease require drugs that do not have regulatory approval from Health Canada for treatment of these conditions in Canada. These drugs include rifapentine, bedaquiline and clofazimine. Despite good evidence of their efficacy and safety for treatment of these conditions, including evidence that these agents are substantially superior to drugs17,20 that are currently approved for the same conditions in Canada, and even though they are strongly recommended by the World Health Organization