Comparing Incidence Rate of Systemic Drug Reactions Under 3HP and 1HP Regimen for Latent Tuberculosis Infection Treatment: a Pragmatic Multicenter Randomized Control Trial

Tuberculosis (TB) remains one of the deadliest infectious diseases, with an estimated 10.0 million new cases and 1.6 million deaths in 2017. The World Health Organization (WHO) has set the goal of eliminating TB as a public health problem, aiming to achieve 90% and 95% reductions in the TB incidence and number of TB deaths by 2035. Latent tuberculosis infection (LTBI), a status of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without clinically manifest active TB, has a 10% risk of progressing to active TB and has thus emerged as a critical target for improving TB control and elimination.

The effectiveness of LTBI programmes has long been limited. In 1999, real-world data obtained from an inner-city population in Atlanta, Georgia in the United States revealed that only 27% of subjects receiving isoniazid (INH) preventive therapy completed their treatment. A 2016 meta-analysis including 748,572 subjects in 58 studies also found poor completion of LTBI programmes, with a 60% treatment completion rate. With the introduction of rifapentine (RPT), a rifamycin with much longer half-life than rifampin, the duration of a modern preventive regimen termed 3HP comprising RPT and INH could be shortened to 12 doses administered weekly, with the completion rate approaching 90%. However, 3.8% of those receiving 3HP experience systemic drug reactions (SDRs). The risks of severe adverse event (AE) and SDRs are even higher among subjects >35 years old.

To date, little has been discovered regarding the risk factors or predictors of SDRs due to 3HP therapy. In a pharmacokinetics study of once-weekly RPT treatment in 35 TB patients during continuation phase therapy, serious AEs were not linked with a higher area under the plasma concentration-time curve (AUC0~∞) of RPT. Furthermore, no studies have reported on plasma INH levels after once-weekly INH treatment or the association between plasma INH level and AE development. Under the support of the Taiwan Centers for Disease Control (TCDC), a prospective multicenter observational study was conducted in Taiwan since 2016 to investigate the correlation between SDRs and plasma concentrations of INH, RPT and their major metabolites - acetyl-isoniazid (AcINH) and desacetyl-rifapentine (DeAcRPT). Preliminary results from 129 LTBI cases showed that those with SDRs and those without SDRs had similar plasma concentrations of the 4 compounds at either post-dose 6 or 24 hours (C6 or C24), except that the C24 plasma INH concentration was significantly higher in the SDRs group. Furthermore, generalised estimating equation (GEE) model revealed that C24 plasma INH level was associated with a higher risk of SDR development (OR [95% CI]: 1.61 [1.15-2.25], p = 0.006). By contrast, C24 plasma RPT level was not associated with a higher risk of SDR development (OR [95% CI]: 1.01 [1.00-1.02], p = 0.218).

The 3HP regimen is among the four regimens for LTBI that is recommended by the WHO and is also probably the most promising regimen because of its convenience, with only 12 doses requried. With its effectiveness well established, the major remaining concern regarding 3HP may be its AEs. Studies have estimated that 4.9% to 9.1% of those in close contact with patients with open TB and who received 3HP failed to complete the regimen because of the side effects.8,10 While on the 3HP regimen, SDRs have generally been linked with RPT, which has a well-known side effect: flu-like syndrome. Additionally, RPT is a newer agent, making it a possible contributor to SDRs given that a higher SDR rate was observed compared with other INH-containing regimens. Some scholars, however, have argued against this point. First, one study using the 3HP regimen demonstrated that rechallenge with RPT did not necessarily lead to SDRs. In the same study, rifapentine was better tolerated than isoniazid upon rechallenge. In another study involving 1200 mg of RPT once weekly as continuation therapy for active TB, no SDRs were linked with RPT. Finally, in a study of 162 pulmonary TB patients receiving RPT with a dosage of more than 15mg/kg daily, no patients developed SDRs. In literature review, we discovered that among reports describing an association between RPT and flu-like symptoms, RPT was commonly coadministered with INH. Furthermore, in cases describing an association between INH and flu-like symptoms, the associations were all proven with rechallenge.

Although a less well-known effect than that of RPT, INH can also lead to flu-like syndrome. Of the patients with active TB who were receiving INH, usually with a dose of 300 mg/day, 1%-9.8% developed flu-like syndrome. Case reports describing the association between INH and flu-like syndrome have also been published. In the 3HP regimen, INH dosage is 900 mg/week, and no data exist regarding the proportion of cases developing SDRs under a single INH dosage higher than this.