Rifapentine-based treatment of tuberculosis infection in Spanish adolescents

Abstract

Introduction

Tuberculosis infection (TBI) in adolescents carries a high risk of progression to tuberculosis disease, yet treatment adherence remains a challenge.

Methods

Case series description.

Results

We describe a real-world experience of implementing a 12-dose weekly regimen of isoniazid (INH) and rifapentine (RPT) under video-observed therapy (VOT) in four adolescent diagnosed with TBI in a contact tracing study. This approach was chosen due to logistical and adherence concerns that made daily regimens and directly observed therapy (DOT) unfeasible. RPT was requested as a foreign medication and approved within three weeks. All patients completed treatment with 100% adherence and good tolerance.

Conclusions

Our experience supports the feasibility, tolerability, and high adherence of VOT-based weekly INH-RPT regimens in adolescents, despite regulatory barriers limiting RPT access in Europe. Broader availability of RPT and innovative adherence strategies like VOT are urgently needed to optimize TB preventive treatment in this age group.

.

Resumen

Introducción

En el adolescente, la infección tuberculosa (ITB) conlleva un alto riesgo de progresión a enfermedad y la adherencia al tratamiento es un reto.

Métodos

Descripción de una serie de casos.

Resultados

Presentamos una experiencia real de implementación de un régimen semanal de 12 dosis de isoniazida (INH) y rifapentina (RPT) bajo observación directa por vídeo (VOT) en cuatro adolescentes diagnosticados de ITB en un estudio de contactos. Esta estrategia se seleccionó debido a barreras logísticas y dificultades de adherencia que impedían la administración diaria y la observación directa presencial (DOT). RPT se solicitó como medicación extranjera y fue aprobada en un plazo de tres semanas. Todos los pacientes completaron el tratamiento con una adherencia del 100% y buena tolerancia.

Conclusiones

Nuestra experiencia respalda la viabilidad, tolerabilidad y alta adherencia del régimen semanal de INH-RPT administrado mediante VOT en adolescentes, a pesar de las barreras regulatorias que limitan el acceso a RPT en Europa. Es urgente ampliar la disponibilidad de RPT y adoptar estrategias innovadoras de apoyo a la adherencia, como VOT, para optimizar el tratamiento preventivo de la ITB en este grupo de edad.

Introduction

Young children and adolescents with tuberculosis infection (TBI) are at a higher risk of progressing to tuberculosis disease (TB) than adults.¹ TBI screening strategies and provision of TB preventive treatment (TPT) are a critical part of the World Health Organization (WHO) consolidated guidelines aimed at reducing TB morbidity and mortality among children and adolescents.² Shorter rifamycin-based TPT regimens are preferred over isoniazid (INH) monotherapy due to higher adherence rates and comparable efficacy and toxicity. Rifapentine (RPT) is a rifamycin with a longer half-life than rifampicin (RIF; 13 h compared to 2–3 h, respectively), that is bactericidal against both intracellular and extracellular Mycobacterium tuberculosis organisms by inhibiting DNA-dependent RNA polymerase. RPT has been incorporated into various TPT and TB treatment regimens over the past decade but is not routinely available in Europe.^3,4 We report our experience with RPT-based TPT regimens in Spanish adolescents and discuss its indications and accessibility.

Case series description

A previously healthy 17-year-old boy was diagnosed in January 2024 with pleuropulmonary TB involving the left lower lobe and bronchogenic dissemination, following a 2-week history of symptoms including cough, fever, and progressive dyspnea. He was initiated on the standard 6-month anti-TB treatment regimen. Gastric aspirate cultures later confirmed a pansensitive M. tuberculosis strain. Five siblings (household contacts) and two cousins (non-household contacts) were referred for contact tracing, and all were asymptomatic (Fig. 1). Three sisters, aged 15, 12, and 10 years, along with a 15-year-old female cousin, were diagnosed with TBI based on normal chest X-rays (posteroanterior and lateral views) and positive results from the QuantiFERON-TB Gold Plus assay (Cellestis/Qiagen, Hilden, Germany). In accordance with national guidelines, daily treatment with INH and RIF for 3 months was recommended.⁵ However, several barriers to daily treatment were identified, including the patients being adolescents, the mother's early work schedule preventing her from supervising medication intake, and a history of incomplete adherence to a contact tracing study back in 2022. Directly observed treatment (DOT) was declined due to incompatibility with school hours. Finally, a consensus was reached with the family to implement a 12-dose weekly regimen of INH and RPT under video-based DOT (VOT). Individual clinical reports requesting RPT as a foreign medication were submitted to the Spanish Agency of Medicines and Medical Devices (AEMPS).⁶ The AEMPS promptly approved the request, enabling the arrival of RPT tablets within 3 weeks. The Hospital Pharmacy subsequently dispensed the medication to the family at no cost. Treatment was administered on Saturdays on an empty stomach, with patients recording themselves taking the medication and submitting the videos to physicians via an app. All patients and their guardians provided informed consent to use VOT as part of their treatment and data monitoring strategy. All patients took the pills whole, except for the 10-year-old girl, who dissolved them in water. Adherence was 100%, and the treatment was well tolerated. Only the 12-year-old girl reported mild, self-limited nausea at the start of treatment. One year after completing TPT, all patients remain clinically stable, with no evidence of progression to TB.

Fig. 1.

Family cluster of adolescents treated for tuberculosis infection with weekly isoniazid and rifapentine for 12 weeks. Squares represent males and circles represent females. Filled symbol indicates the index case with tuberculosis disease. The table below the pedigree diagrams summarizes the weekly dosage (in mg) and pill burden for each treated individual.

Discussion

A 3-month regimen of weekly INH and RPT (12 doses) was first recommended by the WHO for the treatment of TBI in children ≥2 years and adults in 2018, ideally via DOT.² The later availability of generic formulations of RPT, including a dispersible child-friendly 150 mg tablet and an adult fixed-dose combination of INH and RPT (300 mg each) made the programmatic use of this regimen more feasible, and extended the recommendation to children < 2 years of age and the weight-band dosage down to 3 kg.⁷ The currently recommended doses in children according to weight bands and the available formulations are summarized in Table 1. This recommendation is supported by two clinical trials that demonstrated its equivalence to 9 months of INH monotherapy in preventing TB, with higher treatment completion rates, both in adults and children aged 2–17 years.^8,9 Furthermore, in the pediatric trial, no differences between arms were observed in grade ≥3 toxicity or in discontinuation rates due to adverse events, and no cases of hepatotoxicity were reported.⁹ Daily RPT plus INH for 30 days is approved as well as TPT in patients aged ≥13 years living with human immunodeficiency virus infection.¹⁰ RPT is also part of the 4-month regimen for the treatment of drug-susceptible pulmonary TB in nonpregnant patients (age ≥12 years, body weight ≥40 kg), in the absence of extrapulmonary involvement, together with INH, pyrazinamide and moxifloxacin.¹¹

Table 1.

Recommended doses according to weight bands and available formulations of the 3-month regimen of weekly isoniazid and rifapentine (12 doses) for the treatment of tuberculosis infection in children and adolescents; directly observed treatment is preferred.⁷

	Doses	Formulations
Isoniazid	3–6 kg and <3mo: 60 mg (6 mL)^a3–6 kg and ≥3mo: 70 mg (7 mL)^a6–10 kg and <6mo: 100 mg6–10 kg and ≥6mo: 150 mg10–15 kg: 250 mg15–20 kg: 300 mg20–30 kg: 450 mg30–40 kg: 600 mg40–50 kg: 750 mg≥50 kg: 900 mg maximum	50, 150 and 300 mg tablets, coformulated with pyridoxine (15, 25 and 50 mg); Chiesi, Spain100 mg dispersible tablets; McLeods, India10 mg/mL suspension; different manufacturers^c
Rifapentine	3–6 kg and <3mo: 75 mg (5 mL)^b3–6 kg and ≥3mo: 105 mg (7 mL)^b6–10 kg: 225 mg10–15 kg: 300 mg15–20 kg: 450 mg20–30 kg: 600 mg30–35 kg: 750 mg≥50 kg: 900 mg maximum	150 mg tablets; Sanofi, France^c300 mg tablets; Lupin, India and McLeods, India^c150 mg dispersible tablets; Lupin, India and McLeods, India^c
Coformulated isoniazid and rifapentin	(See previous doses)	300 + 300 mg tablets; Lupin, India and McLeods, India^c

a

Suspension with a concentration of 10 mg/mL (one 100 mg isoniazid dispersible tablet in 10 mL water).

b

Suspension with a concentration of 15 mg/mL (one 150 mg rifapentine dispersible tablet in 10 mL water).

c

Not routinely available in Spain.

Since RPT is not routinely available in Europe,^3,4 the recommended regimens in Spain are INH and RIF for 3 months, RIF for 4 months and INH for 6–9 months, with similar efficacy but better adherence and lower toxicity in shorter regimens.⁵ In adolescents, factors such as the desire for autonomy, prioritization of short-term social benefits, engagement in health-compromising behaviors, and stigma can undermine adherence to TPT.¹² In this particular case, adherence was a shared concern for both the mother and the physicians, and DOT was not considered a feasible option. Therefore, it was agreed to initiate the 12-dose weekly regimen of INH and RPT with adherence monitored through VOT.¹³ Administration of weekly INH and RPT via DOT or VOT is preferable to maximize adherence and to review for side effects. In contexts where DOT implementation is challenging, the adoption of VOT presents a valuable alternative, since the use of mobile technologies aligns better with daily adolescents practice. Recent evidence demonstrates the non-inferiority of VOT compared to DOT regarding adherence and patient satisfaction.¹⁴

RPT tablets were easily obtained as a foreign medication. Adherence was 100% despite the pill burden (10–12 tablets per dose), and the treatment was well tolerated. The mild, self-limited nausea reported by one of the girls could be attributed to both INH and RPT; other uncommon adverse effects that have been attributed to the INH and RPT 12-week regimen are cutaneous reactions and flu-like syndrome.⁹ We chose to administer the treatment in a fasting state to optimize INH absorption; however, RPT absorption is known to increase with high-fat meals, though this may be associated with reduced tolerance.¹⁵ Both tablets can be crushed and mixed with water or food if swallowing difficulties arise. Like other rifamycins, RPT is a strong inducer of the cytochrome P450 system and may cause significant drug to drug interactions, and produces an orange-red discoloration of body fluids.

Despite its potential to shorten and simplify current treatment regimens for TBI and TB, improve adherence, and ultimately enhance patient acceptability and outcomes, access to RPT has long been a global concern. While the availability of generic formulations and international pricing agreements have improved access in some regions, RPT is still not routinely accessible in Europe.¹⁶ In fact, the French manufacturer does not intend to submit RPT for registration with the European Medicines Agency, despite persistent advocacy from scientific societies, TB organizations, and clinicians.⁴ In light of this regulatory deadlock, alternative importation pathways are urgently needed. In Spain, the AEMPS successfully facilitated access to unregistered, WHO-prequalified pediatric dispersible fixed-dose combinations of first-line tuberculosis drugs through the “Medicamentos en Situaciones Especiales” procedure.¹⁷ These formulations were initially imported via the Global Drug Facility and, since July 2023, have been dispensed free of charge through hospital pharmacies nationwide.¹⁸ Ongoing social and scientific advocacy, together with the success of this temporary access model, ultimately prompted the European Medicines Agency to support a €5 million tender aimed at expediting the formal registration of the pediatric fixed-dose combinations (https://hadea.ec.europa.eu/news/prior-information-notice-tender-speed-development-availability-and-access-anti-tuberculosis-2023-11-21_en). The fact that similar mechanisms are not being pursued for RPT is unacceptable. A coordinated and urgent response is needed at the European level to ensure equitable access to essential TB medicines across the continent.

Authors’ contributions

AN-J led the conceptualization, supervision, and drafting of the manuscript. AN-J, MR, CG-R and CF participated in patient management and contributed to data curation, analysis, and manuscript editing. CL and MP coordinated pharmaceutical logistics and drug access. All authors reviewed and revised the manuscript, approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Ethics statement

The study was approved by the local Ethics Committee (ref. ART-02-25). Informed consent was obtained from parents and patients.

Artificial intelligence involvement

During the preparation of this work the authors used ChatGPT-4 in order to enhance language quality and ensure the accuracy of the manuscript. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Funding

This work was partially supported by a research grant from the Carlos III Institute of Health, Ministry of Economy and Competitiveness of Spain [PI22/00766 to A.N-J.], and by the Spanish Society of Pneumology and Thoracic Surgery [169-2022 to A.N-J.].

Conflicts of interest

The authors have no conflicts of interest to disclose.