Clinical predictors of 3-month isoniazid rifapentine (3HP)-related adverse drug reactions (ADR) during tuberculosis preventive therapy (PAnDoRA-3HP study): an observational study protocol

Abstract

Introduction

Tuberculosis (TB) is the leading infectious cause of death globally. Despite WHO recommendations for TB preventive therapy (TPT), challenges persist, including incompletion of treatment and adverse drug reactions (ADRs). There is limited data on the 3-month isoniazid and rifapentine (3HP) pharmacokinetics, pharmacogenomics and their relation with ADRs. Our study aims to describe the pharmacokinetic and pharmacogenomics of 3HP used for TPT, the ADRs and their association with completion rates, and TPT outcomes, providing vital insights for TB control strategies in resource-limited settings.

Methods

This is an observational cohort study with a nested case–control study. We enrolled consecutive patients who had been initiated on TPT using the 3HP regimen. These are followed up biweekly and then monthly during the active phase of treatment and 3 monthly for 2 years following completion of TPT. ADR evaluation includes clinical assessment and liver function tests. Cases are selected from those who experience ADRs and controls from those who do not. Serum isoniazid and rifapentine concentrations are measured and pharmacogenomic analysis for NAT2, AADAC and CYP2E1 polymorphisms are done. Participants are followed up for 2 years to determine TPT outcomes.

Analysis

The safety profile of 3HP will be assessed using descriptive statistics, including proportions of patients experiencing ADRs and grade 3 or above events related to treatment. χ² tests and regression models will determine predictors of ADRs and their impact on treatment completion. Pharmacokinetic-pharmacodynamic modelling will establish population parameters and factors influencing rifapentine and isoniazid concentrations.

Ethics and dissemination

Ethical approval of this study inclusive of all the appropriate documents was obtained from the Infectious Diseases Institute Research and Ethics Committee and the Uganda National Council of Science and Technology. The study adheres to legal, ethical and Good Clinical Practice (GCP) guidelines. Deidentified genotype data from 300 patients will be shared after publication. The protocol and phenotype data will be publicly accessible. Abstracts will be submitted to conferences, and a manuscript will be published poststudy.

Correspondence to Dr Christine Sekaggya-Wiltshire; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The study’s comprehensive scope includes multiple healthcare facilities in Uganda, with a long-term follow-up to robustly evaluate outcomes and adverse events.

• This study will critically evaluate population pharmacokinetics (PK) of adverse events, and the genetic analysis will enhance understanding of individual responses to 3-month isoniazid and rifapentine in Uganda.

• Continuous directly observed therapy is not done in the programmatic setting, potentially causing reporting bias.

Introduction

23% of the people who developed tuberculosis (TB) in 2022 were from the WHO Africa region.¹ In 2019, Africa recorded 2.46 million new TB cases, a quarter of the global cases, with the highest incidence rate worldwide of 231 cases per 100 000.² HIV-TB rates are five times higher in Africa than the worldwide average. The incidence rate of TB in Uganda is among the highest in the world at 200 cases per 100 000 and like the rest of Africa, the rates of HIV-TB are one of the highest (81 cases per 100 000).¹

TB’s global burden extends beyond active cases, with a quarter of the global population harbouring latent TB infection (LTBI).³ Approximately 5%–10% of persons with LTBI progress to active TB disease during their lifetime^4–6; however, TB preventive therapy (TPT) reduces TB incidence by 40%,^{7 8} which is crucial in order to achieve WHO’s goal of ending TB by 2030.⁹

WHO recommends TPT for all persons living with HIV (PLWH) and TB contacts with latent TB.⁴ Uganda recently rolled out TPT using the 3 months of weekly isoniazid and rifapentine (3HP) in 2022.¹⁰ 3HP has better completion rates, as shown by a study in Pakistan where household contacts of all ages were more likely to complete TPT with shorter weekly regimens, in a programmatic setting in a high-burden country.¹¹ 3HP is also non-inferior to the 6 months of isoniazid.^12–16 However, there are limited data on 3HP safety and drug pharmacokinetics in routine clinical settings from Africa, especially in the paediatric and adolescent population.¹⁴

A recent systematic review and meta-analysis that included 175 publications describing TPT-related adverse events in 277 cohorts found that 3HP had the highest incidence of any AE and AE-related treatment discontinuation, although it also had a low incidence of hepatotoxic AEs.¹⁷ Several studies have also demonstrated pharmacokinetic variability of isoniazid and that of rifamycins in people receiving treatment for active TB disease.^18–20 In a recent study evaluating the pharmacokinetics of isoniazid in 30 people living with HIV, high isoniazid exposures were found, however, the adverse drug reactions (ADRs) were not linked to the 3HP. Polymorphisms in NAT-2 are associated with variability in isoniazid concentrations and may contribute to the occurrence of ADRs.²¹ In Taiwan, 22.8% of participants were slow metabolisers of isoniazid and NAT2 rs1041983 polymorphisms were associated with severe ADRs.²² The mechanism underlying some ADRs including isoniazid-induced hepatotoxicity has been referred to as a ‘metabolic idiosyncrasy’ because it is incompletely understood.^{23 24} The reasons for interindividual variability of isoniazid concentrations, especially in LTBI patients, are still poorly described, and how those variable exposures might contribute to ADRs is still unknown.^{18 23–26} Isoniazid and its metabolites may be directly cytotoxic, particularly in the presence of rifampin or similar drugs that induce cytochrome P450. Other molecular mechanisms might contribute to ADRs including immune-mediated processes influenced by HLA immunogenetic markers.²⁷ The effect of recently described HLA genotypes and other drug metabolising enzymes, such as cytochrome 2E1 (CYP2E1) and uridine 5'-diphospho-glucuronosyltransferase, on relative concentrations of isoniazid and rifamycins hepatotoxicity risk in slow vs fast acetylators needs to be elucidated further.

The majority of the data available on 3HP is from clinical trials which we may not be able to entirely extrapolate to the ‘real-life’ settings. This study will review the rate of adverse events resulting from 3HP in Uganda compared with other settings where evaluation and management of adverse events may differ. The study will also generate and compare pharmacokinetic, pharmacogenomic and immunogenetic data from patients in a routine clinical setting experiencing ADR and matched controls without ADR to determine the mechanism underlying interindividual variability of ADR in LTBI patient populations. We, therefore, aimed to describe the safety profile of 3HP among people receiving TPT and the effect of ADRs on TPT completion rates. We also sought to describe the pharmacokinetic and pharmacogenomic determinants of the ADRs. We hypothesise that 3HP-related ADR will be minimal and those who do experience ADRs are more likely to discontinue treatment.

Methods and analysis

Study site

The study is being conducted at the Infectious Diseases Clinic (IDI) at Mulago National Referral Hospital, Kampala, Uganda, where over 8000 HIV-infected patients are managed annually. The study also takes place in Kampala City Council Authority health facilities.

Study population

Patients are enrolled if they meet the following inclusion criteria: (1) individuals greater or equal to 2 years who have been initiated on TPT using the isoniazid/rifapentine regimen according to standard of care, (2) both PLWHIV and HIV-uninfected individuals are eligible and (3) subjects who are willing and are able to comply with study procedures.

Patients are excluded from the study if they meet any one of the following criteria: (1) women who are pregnant at the time of screening and (2) individuals who have already received 3HP for more than 1 month.

Study design

This is a cohort study including 651 participants with a nested case–control study (150 cases and 150 controls). Over 18 months, we enrolled consecutive patients who were already initiated on TPT by the facility clinician as per standard of care. At enrolment, baseline clinical and demographic information are collected including age, sex, HIV status, type of Antiretriviral Therapy (ART) where applicable, weight/body mass index (BMI), concomitant medications and comorbidities, prior history of TB treatment and history of substance abuse. Blood samples for baseline alanine aminotransferase (ALT) and total bilirubin are also drawn as shown in table 1.

Table 1

Study procedures

	Screening	Baseline	Week 2	Month 1	Month 2	Month 3	Months 6–27 (3 monthly)
Patient history and physical examination	x	x	x	x	x	x
Clinical adverse event assessment			x	x	x	x
Pregnancy test	x			x	x	x
ALT/bilirubin		x		x	x	x
Assessment for TB/TB reactivation				x	x	x	X
Witnessed ingestion of 3HP				x	x	x
PK for rifapentine and isoniazid			x *	x *	x *	x *
Genetic analysis (cases and controls)			x **	x **	x **	x **
Adherence counselling		x	x	x	x	x

ALT, alanine aminotransferase; 3HP, 3-month isoniazid and rifapentine; PK, pharmacokinetics; TB, tuberculosis.

The 3HP is provided through standard of care and administered to the patient as a weekly dose of rifapentine and isoniazid for up to 12 doses (3 months). Treatment is self-administered at home except on the study visit where treatment will be given as directly observed therapy and in order to conduct the pharmacokinetic analysis. The majority of the participants living with HIV were on dolutegravir-based regimens and participants who experience any antiretroviral drug interactions with 3HP are managed accordingly in addition to discontinuation of the 3HP. We assess adherence by self-report and review of the TPT card. A number of doses missed are recorded.

Nested case–control study

Cases are selected from patients within the cohort study who have developed adverse events that are related to the drug based on the Naranjo score. Controls are selected by incidence density sampling from those within the cohort study who do not develop any ADR related to drug. Cases and controls are matched by duration on 3HP, sex and age.

Follow-up

All enrolled participants are followed up to evaluate for ADRs after 2 weeks from enrolment and then monthly during the 3 months of 3HP treatment. TPT cards are given to every participant to record each dose that has been taken. During every follow-up visit, participants are also required to come with empty sachets of the drugs they have taken before they can be given drugs for the following month. Following completion of 3HP, 3 monthly visits are conducted for 2 years, where one visit will be conducted every 3 months for a total period of 2 years.

Primary outcomes

Our primary outcomes are ADRs and TPT completion.

Adverse drug reactions

ADRs are assessed using clinical history, physical examination and laboratory tests (ALT and total bilirubin). The ALT and bilirubin measurements are performed at the IDI Core laboratory, which is a College of American Pathologists certified laboratory.

Participants who present with symptoms suspected to be ADRs are further evaluated and additional laboratory tests may be performed. ADRs that may have been experienced between visits are also evaluated and recorded. ADRs are assessed for relationship to the drug using the Naranjo scale.²⁸ Follow-up is conducted to determine the outcome of the ADR and whether subsequent doses of TPT are taken or not. Division of AIDS (DAIDS) V.2.2²⁹ is used to grade the severity of ADRs.

TPT completion rates

TPT completion is defined as taking all 12 doses of HP within 16 weeks of starting treatment. For those who undergo interruption of treatment for any reason, the total duration of their TPT is recorded. Interruption and restarting of TPT are in accordance with national treatment guidelines which state that If interruption is within 3 days stick to same day of the week and go back to one’s normal routine. If interruption >3 days; take the next dose on your usual day: This means one has skipped a week and will need to continue the medication for an additional week. 3HP should completed within 4 months or else TPT should be restarted all over again.¹⁰

Secondary outcome

Our secondary outcome is the efficacy of 3HP in terms of TB reactivation or a TB episode following TPT within 2 years of treatment completion

Evaluation for TB after TPT

All participants in the cohort are followed up for 2 years following 3HP initiation. Screening for signs and symptoms of TB is conducted at the monthly and 3-monthly visits using the intensified case finding form.

A gene expert will be done for all presumptive TB patients, and if MTB is not detected, further clinical evaluation including a chest X-ray will be done.

HIV positive adults in whom TB is not picked up by gene expert and are very sick (CD4 less than 100) will be tested for TB using Urine TB LAM test.

Pharmacokinetic analysis

Blood sampling for PK analysis is done for patients (cases and controls) within the nested case–control study to measure rifapentine and isoniazid concentrations. The first PK sampling occurs within 2 weeks of being selected as a case or control. The second PK sampling is performed before or at the month 3 visit. A meal is provided prior to drug intake. Blood samples are drawn predose, at 4 to 6 hours and 24 hours postdose. Time and date of the last dose are noted on these occasions.

Drug concentrations are measured using ultraperformance liquid chromatographic-tandem mass spectrometry or high-performance liquid chromatography.

Pharmacogenomic analysis

Blood sampling is performed for polymorphisms in AADAC and CYP2E1 (rs2070673). In addition, NAT2 acetylator status is determined using a three-single-nucleotide polymorphism panel of 191G>A (rs1801279), 341T>C (rs1041983) and 857G>A (rs1799931).

DNA extraction is performed using commercially available kits according to the manufacturer’s instructions. Genotyping is conducted using real-time PCR allelic discrimination using the TaqMan assay (Applied Biosystems, Warrington, U.K.) at the IDI Translational laboratory.

HLA genotyping for class 1 will be performed using PCR. Allele-specific PCR, using sequence-specific primers will be performed according to the protocol and recommendations of the manufacturer.

Patient and public involvement

In the exploration of adverse events associated with 3HP within Uganda’s routine clinical setting, the patient and public involvement section stands as a testament to our dedication to inclusivity and collaboration. At the outset, patients and the public were intimately involved in shaping the study’s direction, with their insights guiding the formulation of research questions. Drawing from their lived experiences, preferences and priorities, our study aims to resonate deeply within the community it serves. Throughout the design and execution phases, patients and the public have been indispensable partners. Their input has steered decisions concerning study design, the selection of outcome measures and the crafting of recruitment strategies. Furthermore, their ongoing engagement extends to critical decisions regarding the plans for disseminating study findings. By fostering this level of meaningful engagement, our study not only amplifies the voices of those affected by TB but also ensures that our findings are both accessible and actionable within Uganda’s healthcare landscape, contributing to more effective TB control strategies in resource-limited settings.

Sample size determination for cohort study

In this study, the primary endpoint for primary objective 2 is the proportion of patients who complete treatment. We aim to compare the completion rates among patients who experience ADR versus those who do not experience ADR. Using a difference in proportions, TPT completion rates of 87.3% among patients who do not experience ADR and assuming 70% completion among patients with ADR, type I error of 5% and 90% power, design effect of 2.0 to account for between cluster correlation, we will enrol a total of 614 study participants.

Subjects may withdraw from the study at any time at their own request, or they may be withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioural reasons, or the inability of the participant to comply with the protocol required schedule of study visits or procedures. Participants who are withdrawn from the study can be replaced.

Sample size calculation for case–control study

In a study by Meng Rui et al, the mean drug concentration among patients who experienced ADR was 0.25 (SD 0.10). In our study, we assume that patients who do not experience ADR will have a 15% lower drug concentration. Using a difference in means as the primary endpoint, assuming a 5% type 1 error, 80% power, we will need to enrol 129 cases and 129 controls. The sample sizes for both groups have been adjusted for missing data and incomplete observations and a final sample size of 150 cases and 150 controls will be enrolled.

Analysis of outcomes

Description of safety profile

Safety profile of 3HP will be described using descriptive statistics including proportions. We will determine the proportion of patients who had any ADR and those with grade 3 and above events with their relatedness to the treatment.

Effect of ADRs on TPT completion

We will use χ² tests to compare the proportion of patients with ADR who completed 3HP versus those who did not experience ADR. Additional comparisons of TPT completions will be made based on differences in demographic characteristics and risk categories including (HIV+, children <5 years and gender), behavioural risk factors like substance abuse, comorbid conditions and health facility. We will use univariable and generalised linear models to determine the factors associated with 3HP completion and these characteristics and calculate adjusted risk ratios. We will use robust SEs to account for correlation within health facilities. In a sensitivity analysis and given the availability and completeness of all participants’ visits, we will conduct a Kaplan-Meier survival analysis to estimate the time to drop out from 3HP treatment and compare across different variables, for example, sex, HIV status, BMI category and others using log-rank tests. All analyses will be performed by using STATA V.14.0.

Pharmacokinetic-pharmacodynamic modelling

Non-linear mixed effects modelling technique will be used develop a model to establish the population parameters for rifapentine and isoniazid and the variability around these parameters. Using this approach, we will then determine the PK parameters: area under the concentration-time curve and maximum concentrations of rifapentine and isoniazid and the factors that affect these PK parameters including age, sex and pharmacogenomic variants in NAT-2, AADAC and CYP2E1.

Ethics and dissemination

Ethical approval for this study was sought and approvals were received from the Infectious Diseases Institute Research and Ethics Committee, IREC Ref: 001/2021 and the Uganda National Council of Science and Technology (UNCST), UNCST Folio Number: HS1582ES.

Informed consent is obtained from all participants. Children between 8 and 17 years are requested for assent, in addition to consent from their parents or legally authorised representative. For children less than 8 years, consent is sought from their parents/legally authorised representative. The study is conducted in accordance with good clinical practice and Declaration of Helsinki.

Study status

The study began enrolment in February 2022 and completed recruitment in August 2023. All participants have completed TPT and are undergoing follow-up for TB reactivation. Follow-up will be completed in September 2025.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors This study was conceptualised by CS-W and SZ-M. The study design was conceived by CS-W, SZ-M, EAOL, JM, KED, JP, BC, TS and MPS. IM, RRN, LA, FA, BO, RO, JB and JN assisted with data collection while JP and GB assisted with data analysis. IM, RN and CS-W wrote the manuscript. All authors were involved in drafting the work or reviewing it critically for important intellectual content and all authors have agreed to this publication. All named authors adhere to the 302 authorship guidelines of BMJ Open. CS-W is the guarantor.

Funding The National Institute of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R01AI160434 supported research reported in this publication. KED is supported by NIAID K24AI150349.

Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Competing interests None declared.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

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