The following 2 regimens are considered equivalent in terms of safety and efficacy, although they have not been directly compared in an RCT. The choice between regimens should be tailored to the patient’s specific circumstances, considering factors such as patient preference, pill burden/number of doses, potential for adverse effects and cost. Local healthcare resources and capacity to ensure high likelihood of completion of treatment should also be considered when deciding on which regimen to use.
3.1.1. Rifapentine and isoniazid once weekly for three months (3HP)
The 3HP (Rifapentine and INH once weekly for three months) regimen, when given as directly observed preventive therapy (DOPT) has been shown to be noninferior to self-administered (SAT) 9H in preventing TB in large RCTs in both children (age 2 to 17) and adults.7,8 Furthermore, recent network meta-analyses confirm efficacy, reduced hepatotoxicity9,10 and improved completion in comparison to longer INH-based regimens.9 Since the publication of the network meta-analysis, one of the largest cohorts assembled to study 3HP in routine healthcare settings in the US demonstrated a completion rate of 87.2% (2867/3288) via DOPT.11 The risk of hepatotoxicity is significantly reduced with 3HP compared to 9H,7,9,12 although the regimen can cause an influenza-like syndrome. For the most part, this is mild and short lived and usually does not result in discontinuation of treatment. Severe events such as syncope and hypotension that resulted in hospitalization have been reported in rare instances (0.1%); however, no long-term sequelae attributable to the regimen have been reported.13,14 Pyridoxine (Vitamin B6) 50 mg should be given at each dose to minimize the risk of neuropathy.
Administration of 3HP should generally be given by DOPT, since administration by SAT is associated with a lower completion rate when compared to DOPT as shown in an RCT comparing these two ways of administering the regimen (SAT’s completion rate was 74%, vs 87% for DOPT). However, a preplanned subgroup analysis in the same study demonstrated that SAT was non-inferior to DOPT in the US sites.15 The Centers for Disease Control and Prevention (CDC)16 and World Health Organization (WHO)2 guidelines consider 3HP given by SAT as an acceptable option; it should be noted, however, that the original efficacy trial7 was based on 3HP given by DOPT.
The 3HP regimen has consistently been found to be cost-effective compared to INH monotherapy.17–19 Within the Canadian context, when analyzed in an Arctic setting, 3HP was both more effective and cost-saving compared to the previous standard of care (DOPT with 9H twice weekly).20
Potential disadvantages of 3HP include a high pill burden, the risk of drug-drug interactions and the influenza-like syndrome. In Canada, 300 mg rifapentine tablets are available, reducing the number of pills to be taken weekly to 7. A rifapentine 300 mg/INH 300 mg fixed dose combination tablet is expected to become available in 2022, which should further reduce pill burden.2
At present, Health Canada has not approved the use of rifapentine. However, the federal government has issued an urgent public health need regulation which allows front-line practitioners to access rifapentine for TPT anywhere in Canada. 3HP is currently the standard of care in Nunavut, and standard operating procedures for 3HP can be obtained from the Government of Nunavut.
3.1.2. Rifampin self-administered daily for 4 months (4 R)
The 4 R regimen — rifampin self-administered daily for 4 months — is only given SAT; this has been shown to be noninferior in preventing TB to SAT 9H in large RCTs in both children (age 6 months to 17) and adults.21 The risk of grade 3-4 adverse events (all types and hepatotoxicity) was also significantly lower with 4 R compared to 9H among adults.21–23 In the trial in children, there were no grade 3-4 adverse events with either 4 R or 9H.22 Network meta-analyses also support efficacy, reduced hepatotoxicity and improved completion of this regimen compared to longer INH-based regimens in all patients.9,10
The 4 R regimen is more cost-effective than 9H in a variety of different settings, including high-income countries such as Canada.24 Potential disadvantages of 4 R include the risk of drug-drug interactions (as with 3HP), as well as the longer duration and greater number of doses compared to 3HP. At present, there is limited evidence of safety and efficacy in human immunodeficiency virus (HIV) patients, particularly those using newer antiretroviral treatments.25
We strongly recommend either once-weekly rifapentine and isoniazid for 3 months (3HP) or daily rifampin for 4 months (4R) for tuberculosis preventive treatment (good evidence).
3.1.3. Drug-drug interactions
All rifamycin-based regimens have important drug-drug interactions because rifamycins are inducers of hepatic metabolizing enzymes, including cytochrome P450 enzymes, which can result in increased elimination of many other medications. Some of the important categories of interacting medications include many antihypertensives, anticoagulants, antifungal drugs, methadone, some immunosuppressive agents, hormonal contraceptives, antiretrovirals and others. These medications may need to be adjusted, stopped or changed to an alternate medication during TPT. In the case of oral contraception, an alternative form of contraception such as a barrier contraceptive or an intrauterine device should be used during treatment. Practitioners can check for drug-drug interactions with Lexicomp and Micromedex, the two main professional-level tools for doing so. Both are widely used (license required).
Good practice statement
Interactions between patients’ baseline medications and the prospective tuberculosis preventive treatment regimen should be considered through an up-to-date drug decision support tool prior to treatment initiation.
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