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

On World Tuberculosis (TB) Day 2022, the 8^th 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.

Table 1. Summary of new or changed Recommendations in 8th edition of the Canadian Tuberculosis Standards.

	“Old recommendation” 7^th Edition (2013)	New/changed recommendation 8^th edition (2022)
TB Disease (“active TB”)
Diagnosis TB Disease	AFB Smear & TB cultures	No change
Treatment TB Disease (Drug susceptible)	2 months INH&RIF&PZA&EMB, then 4 months INH&RIF. Intermittent allowed. Dose of RIF: 10 mg/kg/day; Max: 600 mg	Regimen same. Intermittent only in final 4 months, and not if HIV infected. Dose of RIF: 10 mg/kg/day. No maximum
Treatment support	Emphasis on DOT for support	Emphasis on comprehensive Person-centered care for support
Therapeutic Drug monitoring	Not recommended	Recommended for persons at risk of altered TB drug absorption or metabolism
Post Treatment	No mention	New recommendations for Post TB care
Drug resistant TB disease
Diagnosis Drug Resistance	Phenotypic Drug susceptibility tests	Genotypic (molecular) testing immediately Phenotypic testing to confirm
INH Resistant TB treatment	6 months RIF&PZA&EMB	6 months RIF&PZA&EMB AND Fluoroquinolone (Moxifloxacin or Levofloxacin). Consider stopping PZA after 2 months, if less extensive disease
MDR TB treatment	18-20 months Injectable (Amikacin) for first 6-8 months Oral drugs, at least four to which isolate sensitive.	18-20 months All-oral regimen Core: Bedaquiline, Linezolid, Fluoroquinolone, Clofazimine, Cycloserine
Extra-pulmonary TB disease
Treatment	Standard 6 months course	No Change for most forms For TB Meningitis: High dose RIF (up to 35 mg/kg/day). Plus corticosteroids For TB Pericarditis: Standard therapy. Plus corticosteroids if HIV negative.
TB Infection (“latent TB infection”)
Diagnosis TB Infection	TST or IGRAs	Either TST or IGRA in most situations, except: IGRAs preferred if:  BCG in infancy and age 2-10  BCG at an older age  Expertise to perform TST not available TST preferred if:  Serial testing is planned (eg, Health care workers)
Treatment TB Infection	First Line: INH for 9 months (9H) Alternate: 4 months daily self-administered RIF (4 R).	First Line: 4 R or 3HP (3 months once weekly INH & Rifapentine - preferably by DOT). Alternate: 9H.
BCG Vaccination	Should be given to newborns in communities with evidence of transmission	Unchanged for BCG, but added that newborns in Inuit and First Nations communities should have testing for SCID before receiving BCG
Screening for TB among immigrants and refugees	TB Disease screening: recommended TB Infection testing: only recommended if have medical comorbidities, that increase TB risk.	TB Disease: unchanged TB Infection: See Table 2
Prevention of TB transmission in health care settings
Repeated testing of workers for TB infection	Annually for many health care workers involved in direct patient care in facilities caring for TB patients	No routine periodic TB testing of all HCWs with negative TST, except those at highest risk of exposure
Hospitalization for isolation	No clear guidance	Patients with infectious TB are preferably placed in HOME isolation, not hospitalized
De-isolation Patients considered initially contagious can be taken out of respiratory isolation when:
Initially AFB  Smear  Negative	After 2 weeks of effective therapy	Unchanged
Initially AFB  smear  positive	When AFB Smear conversion occurs (at least 2 consecutive smears are negative)	The earlier of: AFB smear conversion, or, Four weeks of effective therapy
If MDR	When culture conversion occurs	If AFB smear negative: After 4 weeks of effective therapy If AFB smear positive: After AFB smear conversion

Abbreviations (in alphabetic order): AFB, acid fast bacilli; BCG, bacille Calmette-Guerin; DOT, directly observed treatment; EMB, ethambutol; IGRAs, interferon gamma release assays; INH, isoniazid, MDR, multi-drug resistant; RIF, rifampin; PZA, pyrazinamide; SCID, severe combined immune deficiency; TB, tuberculosis; TST, tuberculin skin test.

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 adults^7,8 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 adults^10–12 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 drugs^17,20 that are currently approved for the same conditions in Canada, and even though they are strongly recommended by the World Health Organization (WHO)²¹ and now the Canadian TB Standards,¹⁸ Health Canada has not approved their use. Approval of a drug for a condition in Canada is time-consuming and expensive. Given the small number of persons in Canada who would receive these drugs each year, pharmaceutical companies would have to absorb substantial financial losses to license these drugs. As a result, these TB drugs languish in a regulatory no-man’s land; this creates a major barrier for what should be first line therapy. Ironically, most low- and middle-income countries have streamlined access to these life-saving drugs, through the Global Drug Facility (GDF). Established by the WHO, this facility procures quality assured medications, including ensuring that manufacturing sites selected to provide medications comply with the applicable International Organization for Standardization (ISO) norms and Quality Management System (QMS) requirements, as well as Good Manufacturing Practices (GMP) standards through a formal WHO pre-qualifications process.²² The stringent regulatory authorities in Australia and Sweden (ie, equivalent agencies to Health Canada) have accepted the use of the GDF mechanism for supply of these TB drugs, rather than their own review and approval.

There are many other changes in other chapters. A new chapter co-written by Indigenous authors²³ is a must-read for providers of TB services to Inuit or First Nations communities. Also new is a chapter on TB and co-morbidities²⁴—an increasing problem in Canada’s aging population. Much greater testing and treatment of TB infection among immigrants and refugees arriving in Canada is now recommended;²⁵ these recommendations are summarized in Table 2. The final chapter in the new Standards proposes a framework and indicators for evaluation of TB programs.²⁶ The indicators were selected to be simple and use readily available data to ensure it would be feasible to measure and report in all jurisdictions. They include indicators that treatment is adequate and timely, or that important public health measures, such as contact investigation, are timely. Not rocket science. In fact, not new; many other countries, including the United States and United Kingdom have introduced monitoring and performance frameworks of similar indicators some years ago and have demonstrated incremental but steady improvement in these indicators over time. These indicators will be useful for any program, at any level. However, national implementation will require federal leadership and strong buy-in by provincial and territorial public health officials, for this to make a meaningful contribution to TB control in Canada.

Table 2. Summary of recommendations for tuberculosis (TB) infection testing.

		TB incidence in country of origin
Risk of developing active TB	Age	<50	50-200	>200
Very high risk*	All ages	Yes	Yes	Yes
High risk*	≤65	No	Yes	Yes
	>65	No	Consider	Consider
Low/Moderate risk*	≤65	No	Consider	Consider
	>65	No	Consider	Consider
Refugees†	≤65	No	Yes	Yes
	>65	No	Consider	Consider

Notes: Source: Chapter 13: Tuberculosis Surveillance and Tuberculosis Infection Testing and Treatment in Migrants.²⁵

* Very high risk, eg, HIV, TB contacts, silicosis; High risk, eg, advanced CKD ± dialysis, solid/hematologic transplantation, immunosuppressive drugs, active cancer; Moderate risk, eg, diabetes, heavy tobacco, heavy ETOH; low risk, no risk factors.

† Refugees within two years of arrival.

¶ Within 5 years of arrival.

In summary, the 8^th edition of the Canadian TB Standards has a lot that is new. Many Canadian TB researchers have contributed importantly to the evidence underlying the new and changed recommendations. An even larger group of Canadian TB experts have contributed to reviewing that evidence, working with stakeholders and crafting what we hope is useful guidance for TB providers across Canada. The biggest challenge is still ahead—changing practice. Experience from the COVID-19 pandemic suggests that this can be done rapidly when there is a broad commitment from governments at all levels.²⁷ This requires knowledge mobilization on many levels, and action by governments, to invest in new drugs and diagnostics, and to facilitate access to these new tools needed for TB elimination in Canada.

Disclosure statement

All author(s) in this paper declare that they have no conflict of interest.

Funding

Dr Menzies received salary support from a Canada Research Chairs (Tier 1) award.