Several factors need to be considered when deciding on the implementation of this regimen: DST, treatment support, pill burden, cost of medicines, administration of the shorter regimen with food, training of health care workers and criteria guiding the choice of regimen. These factors are discussed below.
DST
Although DST use must, in principle, be universal, it is not yet available in all settings. However, rapid DST for key medicines, including isoniazid, rifampicin and the fluoroquinolones, is rapidly expanding. WHO recommends rapid genotypic testing for TB and RR-TB as an initial test at diagnosis; if DST for the fluoroquinolones and isoniazid can be performed at the same time, this can make it easier to allocate the most appropriate regimen, although the testing has implications for costs, logistics and laboratory workload.
In practical terms, although highly desirable, baseline DST for fluoroquinolones would not be necessary for patients with confirmed rifampicin-susceptible TB by a reliable, WHO-recommended rapid molecular diagnostic test. The prevalence of fluoroquinolone resistance in patients without confirmed rifampicin resistance is usually low (6-10) but can reach 15% in patients with documented DR-TB (5). In settings where the prevalence of resistance to fluoroquinolones in patients with DS-TB is higher because of their widespread use for other conditions, DST for the fluoroquinolones would be highly recommended at baseline to exclude fluoroquinolone resistance (5).
Treatment support
In Study 31, patients received treatment 7 days per week. At the early stages of the introduction of this regimen, treatment support with observation may be important given the current pill burden and the lack of an FDC formulation. Current WHO recommendations support the use of observation but also other forms of patient support; overall, even though this regimen is shorter, patient support remains a key element of TB programming.
Pill burden
Currently, the overall pill burden will be high for patients who receive this 4-month regimen, because there is no FDC tablet for this regimen. This may affect acceptability by patients; however, this situation may change as uptake of this regimen improves, creating a demand for the regimen and its component medicines.
Cost of medicines
Currently, the cost of the shorter regimen is substantially higher than that of the 6-month 2HRZE/4HR regimen, mainly due to the inclusion of rifapentine. Again, this situation may change as uptake of this regimen improves, creating a demand for the regimen and its component medicines. Several pharmaceutical companies are ready to bring quality-assured rifapentine to the market, including generic forms. The availability of rifapentine for this regimen may also depend on the uptake of rifapentine-containing regimens for TB prevention.
Administration of the shorter regimen with food
In some settings, administration of the shorter regimen with food may present a challenge. In Study 31, a flat dose of 1200 mg of rifapentine was given daily, with food. Pharmacokinetic and pharmacodynamic modelling predicted that a rifapentine dose of 1200 mg without food would yield an area under the curve (AUC) similar to that of a rifapentine dose of 900 mg with a high fat meal. Given that the target rifapentine AUC lies somewhere between that achieved with a very high fat meal and a rifapentine dose of 900–1200 mg, the strategy proposed was a rifapentine dose of 1200 mg with a modest food requirement, the rationale that a very high fat meal may not be feasible under routine TB care conditions, whereas dosing with food may be feasible. For some medicines (e.g. moxifloxacin), food may delay absorption.
Training of health care workers
Training will be necessary when introducing the 4-month regimen into a programmatic setting. However, this is a requirement for any new programmatic intervention, and the ability to shorten treatment and potentially treat more patients may offset the initial investments in training.
Criteria guiding the choice of regimen
Eligibility criteria for the regimen, age and patient preference should guide the choice between the 6-month and 4-month regimens. Other local factors can be important, such as the availability and cost of rifapentine.