Surey et al. BMC Infectious Diseases (2021) 21:90 https://doi.org/10.1186/s12879-021-05766-9 RESEARCH ARTICLE Open Access An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study J. Surey1,2* , H. R. Stagg3, T. A. Yates1,4, M. Lipman5, P. J. White6,7, A. Charlett6, L. Muñoz8, L. Gosce1, M. X. Rangaka1, M. Francis1, V. Hack1, H. Kunst9,10 and I. Abubakar1 Abstract Background: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. Methods: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/ isoniazid (‘intervention’) or a daily combination of rifampicin/isoniazid (‘standard’), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. Results: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7–91.4), compared with 19 of 25 (76.0%, CI 54.9–90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. Conclusion: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. Trial registration: The trial was funded by the NIHR, UK and registered with ISRCTN (26/02/2013-No.04379941). Keywords: Tuberculosis, Latent tuberculosis treatment, Randomised controlled trial, Rifapentine * Correspondence: j.surey@ucl.ac.uk 1 Institute for Global Health, University College London, London, UK 2 Faculty of Medicine, Universidad Autónoma Madrid, Madrid, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. 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BMC Infectious Diseases (2021) 21:90 Page 2 of 8 Keypoints preventive treatment; and provision of informed This pilot trial assessed treatment completion and the consent. feasibility of treating LTBI in the UK using a weekly rifa- We excluded pregnant and breast-feeding women; per- pentine and isoniazid regimen versus daily rifampicin sons weighing less than 45 kg;; and individuals unable to and isoniazid, both self-administered for twelve weeks. receive study drugs due to allergy, liver disease or any Treatment completion was comparable between the two medical condition contraindicating the use of a rifamy- regimens. cin or isoniazid; individuals who needed concomitant medications that could not be safely taken with study Background drugs and those with HIV infection. For this pilot study, Despite the availability of effective treatment for drug we were concerned that patients on antiretroviral ther- susceptible tuberculosis (TB), it is estimated that a total apy might have to have their medication changed if there of 1.5 million individuals died of the disease worldwide were randomised to the rifampicin arm due to the drug- in 2018 [1]. In the UK, the majority of TB occurs in mi- drug interaction. grants, and arises largely through the reactivation of in- DOT is not standard of care for LTBI treatment in the fection acquired overseas [2]. Screening for latent UK. Individuals whose social circumstances would ne- tuberculosis infection (LTBI) is thus an essential element cessitate enhanced adherence support and DOT - such of any TB elimination strategy [3]. as homelessness, history of mental health problems, in- In 2011, Sterling et al. described a 12-dose weekly regi- carceration, or problematic drug use - were also men of rifapentine/isoniazid (3HP) with a relatively low excluded. likelihood of drug-related hepatotoxicity (0.4%) [4]. This After enrolment, individuals were randomised cen- regimen was shown to be non-inferior at preventing the trally using Sealed Envelope’s web-based Simple Ran- development of active TB to nine months of isoniazid in domisation Service by a member of the study team in a randomised controlled trial (RCT). Within that trial, the recruitment clinic. There was no stratification and adherence could not be evaluated as patients placed on the ratio of individuals in the intervention to standard the 3HP arm had treatment with directly observed ther- care arm was 1:1. Recruited individuals were randomised apy (DOT), but those in the control arm did not. Fur- to receive either 3HP (weekly) in the intervention arm thermore, one might expect higher rates of completion or 3HR (daily) in the standard of care arm. Dosing was with a shorter 12-dose regimen of 3HP than nine weight dependant with patients being weighed at each months of treatment. visit and dosing adjusted accordingly (see Add- In light of the promising results from that RCT [4] itional File 1, Appendix 1 for dosing schedule). Both and the absence of RCTs comparing 3HP to the UK arms self-administered treatment without direct obser- standard of care of daily rifampicin/isoniazid for three vation and recruits were educated on how to take the months (3HR), a randomised pilot trial between the two medication as well as the main side effects of treatment. regimens was designed with self-reported treatment Treatment was initiated following an eligibility assess- completion as the primary outcome. We enrolled adults ment at baseline (week 0). Subsequent medication was aged between 16 and 65 years and did not use DOT dispensed at clinic visits at weeks 2, 4 and 8 following an (treatment was self-administered). Secondary outcomes adherence and AE check as per the study flow chart sought to assess adherence to the regimens using an ad- below. Extra visits were possible if a patient presented herence tool (MARS), as well as the frequency with with any symptoms related to the study medication or which adverse events (AEs) were observed in the two had a mild derangement of liver function tests (see study arms. The results of this trial aim to inform the below in AEs). feasibility of a larger, fully powered, trial assessing the non-inferiority of treatment completion on 3HP com- Outcomes assessments pared to 3HR. Primary outcome: treatment completion The primary outcome was the proportion completing Methods treatment in each arm of the study assessed using self- Trial design and inclusion criteria report. Treatment completion was defined as taking Individuals were recruited from two TB clinics in more than 90% of the prescribed doses of treatment. London, UK, between March 2015 and January 2017. In- This proportion equates to at least 11 doses for patients clusion criteria included age (between 16 and 65 years); taking the weekly intervention regimen and at least 81 LTBI diagnosis by means of an Interferon Gamma Re- doses for patients in the daily standard of care arm. If a lease Assay (QuantiFERON®-TB Gold In-Tube or T- patient missed a scheduled appointment, the investiga- SPOT®.TB) or Tuberculin Skin Test (threshold > 5 mm tion team tried to contact them within the following irrespective of BCG vaccine status); agreeing to accept week and so total completion had to occur within 16 Surey et al. BMC Infectious Diseases (2021) 21:90 Page 3 of 8 weeks. Additionally, if participants failed to attend two was stopped; following other AEs, trial medication could consecutive appointments, they were considered non- be continued at the discretion of the trial physician. For adherent and to have reached one of the endpoints of full details of AEs and discontinuation rules, see Add- the study. itional File 1, Appendix 4. Adherence data were collected at regular dispensing clinic visits on weeks 2, 4, 8 and at the end of treatment, Data collection and statistical analysis using a standardised questionnaire (see Additional File Pseudonymised data were collected on case report forms 1, Appendix 2). Adherence and treatment completion (CRFs) at study sites. Data were independently double was self-reported and assessed by face-to-face enquiry, entered at the study co-ordinating centre into a pass- wherein patients were asked if they had missed any word protected Microsoft Access database. These data doses of medication since their last clinic visit and the were cross validated and corrections made as required number of tablets reportedly missed was recorded. to ensure data accuracy. Consistency and error checking We asked participants to bring with them, at each was carried out to corroborate the two datasets. An as- visit, their empty pill packages, which were compared to sessment of the distribution of baseline characteristics the number of pills dispensed at the previous visit. At between the two study arms was used to determine if each clinic visit, urine colorimetric testing for detecting adjustment for confounding was required. Treatment isoniazid metabolites and pill count assessment were completion and AEs were described. used to validate the self-reported intake of tablets. The urine tests used a commercially available assay (Iso- Results screen, GFC Diagnostics Ltd., Oxfordshire, UK). For the A total of 126 eligible subjects were screened for eligibil- purpose of ascertaining treatment completion, we ity and 52 enrolled into the study between March 2015 intended to use urinary metabolite and pill count assess- and January 2017. Of these, 27 (51.9%) subjects were ment to validate self-reported intake of tablets with ei- randomly allocated to the intervention treatment arm ther a negative urine test and/or pills still in a pack and 25 (48.1%) to the standard treatment arm (see Fig. 1 taken as evidence of non-compliance. Otherwise, self- for recruitment detail). reports were considered sufficient evidence of outcome. A comparison of the baseline characteristics of the two study arms revealed no evidence of major imbalance Secondary outcomes (See Table 1). Mars There were no important differences between the two A validated medication adherence report scale (MARS™) arms with respect to baseline biochemistry, haematology was used as an assessment of adherence to explore is or clinical signs measurements. utility in TB adherence trials. This uses five dimensions: ‘I alter the dose’, ‘I forget to use it’, ‘I stop taking it for a Primary outcome while’, ‘I decide to miss out on a dose’, and ‘I take less Completion of treatment (defined in the protocol as than instructed’, using a five-point Likert scale of ‘al- more than 90% of doses taken by self-report) was similar ways’, ‘often’, ‘sometimes’, ‘rarely’ and ‘never’, scored one in both arms. In the intervention 3HP arm 21/27 com- to five, respectively. An overall score of 20 points or pleted compared with 19/25 in the standard of care arm higher is considered high adherence [5, 6]. (See Add- of daily 3HR (See Table 2). Considering the lack of evi- itional File 1, Appendix 3 for MARS™ questionnaire.) dence of imbalances between the trial arms, we did not adjust for confounding. Adverse events In both arms there was no clinical appointment where Assessment of AEs for both arms was carried out at individuals who reported full adherence had pills left clinic visits at weeks 2, 4, 8 and at the end of treatment and a negative urine test. There were four individuals, at week 12. A final post treatment telephone call was two in each arm, who reported full adherence and had made 4 weeks after the end of treatment to check that pills remaining, but all had positive urine tests indicating there had been no further AEs following the last dose of they had at least taken some of their prescribed medica- study medication. AEs were assessed from laboratory tion. In the standard of care arm, two individuals re- tests, including regular liver function tests (LFTs) for ported full adherence, had no pills remaining, but had hepatotoxicity, or from a standardised interview to assess negative urine tests. However, there was a marked dis- symptoms. They were recorded and graded (1 to 4) ac- crepancy between the urine test and self-reported full cording to the Division of AIDS (DAIDS) criteria [7]. adherence in the intervention arm. In this group 14 The probability of whether the study regimen was re- (66.7%) individuals had a negative urine test (see Add- lated to any AE was assessed by the prescribing phys- itional File 1, Appendix 5 for detail). We therefore con- ician. Following events scoring 3 or more, medication cluded that the gap between pill intake and testing was Surey et al. BMC Infectious Diseases (2021) 21:90 Page 4 of 8 Fig. 1 Flow diagram of recruitment of individuals to trial, allocation, and outcomes. a: Individuals with latent tuberculosis infection (LTBI) were recruited from TB clinics who agreed to treatment and met the eligibility criteria. b: Subjects randomised to weekly rifapentine/isoniazid (3HP) or daily rifampicin/isoniazid (3HR). c: Follow-up at 2, 4, 8, 12 weeks. d: Treatment completion defined as more than 90% of prescribed doses taken post treatment completion one subject was LFU and another an investigator withdrawal. ** n (%) individuals, per arm, that experienced any AE likely due to drug, as per investigator decision the most likely explanation and this information was not further two which were not attributed a relationship. used to discount self-reported treatment completion. The 25 AEs that were probably the result of the study drugs occurred in nine subjects and are documented by Secondary outcomes study arm in Table 3 and further details can be seen in Adherence using MARS™ tool Additional File 1, Appendix 6. No participant developed There were only two MARS™ ratings of 19, i.e. below the active TB during the trial. score considered to represent high compliance, one in the standard treatment arm at week two, and one in the Blood testing and hepatoxicity intervention treatment arm at week four. Haematological and biochemical tests were performed on subjects throughout the study, with a consideration Adverse events as to whether these are outside of the normal range. A There were 122 AEs reported during the trial. There small number of subjects were observed to fall outside were no serious AEs, as defined by DAIDS criteria as of the normal range for these parameters. Of note are grade 3 or more, recorded during the trial in either study those with raised ALT and AST during the study. There arm. The relationship to the study drugs was considered were seven subjects- three in the experimental treatment probable for 25 (20.5%), possibly for 53 (43.4%), unlikely arm and four in the standard treatment arm that had for 35 (28.7%), not related for seven (5.7%) events and a clinically significant raised ALT results during the trial. Surey et al. BMC Infectious Diseases (2021) 21:90 Page 5 of 8 Table 1 Comparison of intervention and standard of care arms for potentially important confounding variables at baseline Variable Intervention (n = 27) Standard (n = 25) Demographic Male (%) 13 (48.2%) 13 (52%) Age: Mean (range) 38.2 (23–56) 32.5 (17–58) UK Born 2 (7.4%) 3 (12%) Lifestyle Concomitant medication 9 (33.3%) 5 (20%) Alcohol - current 9 (33.3%) 9 (36%) Smoking Current 3 (11.1%) 6 (24.0%) Ex 2 (7.4%) 3 (12.0%) Never 22 (88.5%) 16 (64.0%) Clinical IGRA positive 24 (88.9%) 24 (96%) TST positive 3 (11.1%) 1 (4%) Diabetes 1 (3.7%) 1 (4%) Immunosuppressant medication 1 (3.7%) – In the experimental treatment arm, one subject had daily rifampicin/isoniazid. Furthermore, the frequency raised ALT values throughout the trial; the other two and severity of the AEs of the two regimens was similar. had raised ALTs at one and two measurement points. In Previous research has demonstrated that self- the standard treatment arm, two subjects had raised administered 3HP is non-inferior to directly observed ALTs at two measurement points, the other two having 3HP [8]. Treatment completion rates of 3HP are high raised ALTs at just one point. These subjects had similar when administered using DOT and non-inferior when results for ASTs. compared with longer duration regimens such as isonia- As a result, one participant in the standard treatment zid monotherapy over nine months [4, 9, 10]. In this arm was withdrawn by the investigator as they had LFTs pilot study, we have shown that a fully powered trial effi- > 3 times ULN (upper limit of normal) and were symp- cacy trial comparing these two self-administered regi- tomatic. The remaining participants we able to continue mens is possible, allowing a determination of whether as their results were within acceptable parameters. the 12 weekly 3HP is superior/non-inferior the UK Lessons learned and the data generated are sum- standard of care. marised to inform future trials (see Table 4, p.12). This pilot used self report as the primary measure of adherence with an adherence tool, MARS™, as a second- ary measure. We had hypothesised based on evidence Discussion that it works in asthma and other chronic conditions This is the first UK based RCT comparing the adherence and that if shown to be a good measure of outcomes in of weekly 12-dose 3HP regimen to the UK standard of TB, it can provide an alternative outcome measure in fu- care of daily rifampicin/isoniazid for three months ture trials. Unfortunately, it was not very discriminating (3HR). Within our open label, randomised, multi-site as almost everyone had a high score in the pilot study. pilot study of the two regimens for LTBI, we found that However, we also feel, despite the absence of effect in treatment completion, defined as taking more than 90% our relatively small study, that this merits further explor- of prescribed doses, was comparable between self- ation in the full trial. administered weekly rifapentine/isoniazid regimen and Lessons learned and the data generated in this trial the UK standard of care regimen of self-administered have contributed to the design of the RID-TB trial [11] Table 2 Counts of self-reported adherence and end of trial completion for intervention and standard drug regimen Metric Intervention 3HP n (proportion) [CI*] Standard 3HR n (proportion) [CI*] Allocated to group 27 25 Received at least 90% of prescribed doses 21 (0.78) [0.58–0.91] 19 (0.76) [0.55–0.91] *CI 95% confidence interval Surey et al. BMC Infectious Diseases (2021) 21:90 Page 6 of 8 Table 3 Subjects experiencing at least one adverse event likely it could make treating these patient groups more feasible due to study treatment, by study arm as ensuring adherence once a week is less resource in- Experienced Randomised Group tensive than every day. an adverse Finally, treatment completion was defined as complet- Intervention Standard Total event ing 90% of doses taken within 125% of the timeframe of No 23 20 43 a normal course of treatment. The simplistic nature of a Yes 4 (14.8%) 5 (20.0%) 9 percentage threshold may mask substantial heterogen- Total 27 25 52 eity that could lead to different therapeutic coverages in different patients. There is little good data regards how adherence patterns - which can be highly complex [12] - which will be fully powered to estimate the likelihood of relate to outcomes and exactly what level of adherence treatment completion of the two regimens and the rela- is optimal for any given regimen is unclear [13–15]. tive safety and efficacy of daily 3HR as compared with In considering the fully powered trial, other short regi- weekly 3HP. Subject to cost-effectiveness analyses, mens that have been shown to be effective since the start weekly 3HP regimens could be a useful option in pre- of the HALT trial should be considered. For example, a ventative therapy, especially to improve coverage of pop- large trial amongst HIV infected individuals, in an area ulations who may require adherence support. People with high TB prevalence, showed that a one-month daily living with HIV are eligible to take part in the full trial. rifapentine plus isoniazid (1HP) daily regimen was non- However, concurrent medication will be carefully inferior to 9 months of isoniazid alone in preventing ac- reviewed to ensure that individuals in need for treatment tive TB and had fewer AEs. Whilst patients self- that cannot be safely taken together with study drugs administered treatment under trial conditions, 97% of will be excluded. those who started 1HP treatment completed it, accord- However, caution is needed in interpreting these re- ing to self-reported data [16]. This large trial also had a sults as this was a pilot study which was not powered to major limitation due to the potential enrolment of indi- test equivalence or non-inferiority for any outcome. The viduals who may not have LTBI [17] suggesting that fur- size of the trial means that we were unable to assess the ther trial efficacy data may be needed prior to an efficacy of the intervention. In this study we excluded adherence study of 1HP, especially in the light of the people with risk factors for potential poor treatment ad- recommendation of expanding 1HP regimens [18]. herence, such as homelessness, problematic drug use, mental health concerns or history of incarceration. Conclusion Therefore, our results will not be generalised to these In the first RCT of its kind in the UK, we demonstrate populations. One advantage of a weekly regimen is that similar treatment completion rates between a weekly Table 4 Lessons learned and recommendations of future trials Issue Description Recommendation Maximising Out of individuals who were eligible (126) many (23) declined to take Simplified patient information sheet (PIS) with a plain English subject part in the study. Anecdotally, this was often because they wanted to summary Minimise additional follow-up appointments, so recruitment receive treatment ‘as normal’. Much of this may be out of the desire care is as close to the standard of care as possible to reduce the number of times to attend clinic or perceptions that Making sure that all recruiting clinicians are well trained and they were getting something less efficacious or safe. motivated to recruit and there are dedicated recruitment Individuals were required to attend at weeks 0/2/4/8/12 and have a nurses in clinics telephone consult at week 16 Qualitative interviews of perceptions of LTBI treatment and of taking part in clinical trials Flexible times to attend clinics outside of normal working hours Loss to follow- 6 people were LFU and did not complete the trial. Several were at Larger incentive at end of treatment up (LFU) the end of treatment and so may well have completed treatment Qualitative interviews for those LFU but did not want to attend their last appointment. Adherence The isoniazid metabolite urine test frequently came back as negative Electronic measures of adherence may be more useful, checks because participants in the weekly dosing arm had taken the tablets especially when using a weekly regimen e.g. MEMS cap. more than 24/48 h before being tested. Participants often took the medication at a time convenient for them e.g. when they were not working or at weekends. Inclusion Initially, inclusion criteria specified a positive IGRA test and did not As broad as possible to include anyone eligible to have LTBI criteria include TST. The protocol was subsequently amended to include treatment in usual clinical practice. both. Include under-served populations to generate adherence Individuals under-served populations with social risk factors for poor data regarding their adherence. adherence were excluded Surey et al. BMC Infectious Diseases (2021) 21:90 Page 7 of 8 3HP regimen and the daily 3HR standard of care. We LM could participate in this project thanks to FI10–00443 Predoctoral have also demonstrated the feasibility of undertaking a Government Grant [Ministerio de Economía y Competitividad] from 2010 to 2014. randomised controlled trial of the two regimens, pow- Whilst working on this study, TAY was funded by a Medical Research Council ered to estimate the relative efficacy of the two Doctoral Training Grant. TAY is currently funded via an NIHR Academic regimens. Clinical Fellowship and supported, in part, by the BRC of Imperial College NHS Trust. Supplementary Information Availability of data and materials The online version contains supplementary material available at https://doi. The datasets used and/or analysed during the current study are available org/10.1186/s12879-021-05766-9. from the corresponding author on reasonable request. The protocol can also be provided on request. Additional file 1: Appendix 1: Dosing schedule. Appendix 2: Standardised questionnaire. Appendix 3: MARS™ Adherence Ethics approval and consent to participate Questionnaire. Appendix 4: Adverse events and discontinuation rules. Ethical approval was obtained from the UK NHS Research Ethics Committee Appendix 5: Comparison of self-reported adherence and isoniazid urine (Reference Number: 13/LO/1666). Written informed consent was obtained test. Appendix 6: Adverse events from all study participants prior to any study interventions being carried out. Additional file 2:. CONSORT 2010 checklist of information to include when reporting a randomised trial Consent for publication Not applicable. Abbreviations Competing interests AE: Adverse events; BCG: Bacillus Calmette–Guérin; CI: Confidence interval; The authors declare that they have no competing interests. CRF: Case Report Form; DAIDS: Division of AIDS; DOT: Directly observed therapy; HALT: Hepatitis and Latent Tuberculosis study; HP: Isoniazid Author details Rifapentine; HR: Isoniazid Rifampicin; IGRA: Interferon Gamma; LFTs: Liver 1 Institute for Global Health, University College London, London, UK. 2Faculty function tests; LFU: Lost to follow-up; LTBI: Latent tuberculosis infection; of Medicine, Universidad Autónoma Madrid, Madrid, Spain. 3Usher Institute, MARS: Medication adherence report scale; NHS: National Health Service; University of Edinburgh, Edinburgh, UK. 4Department of Infectious Disease, PIS: Patient Information Sheet; RCT: Randomised controlled trial; Faculty of Medicine, Imperial College London, London W2 1NY, UK. 5UCL-TB TB: Tuberculosis and UCL Respiratory, UCL, London, Royal Free London National Health Service Foundation Trust, London, UK. 6National Infection Service, Public Acknowledgements Health, England, UK. 7Department of Infectious Disease Epidemiology, The views expressed in this publication are those of the author(s) and not Imperial College School of Public Health, MRC Centre for Global Infectious necessarily those of the NHS, the National Institute for Health Research or Disease Analysis and NIHR Health Protection Research Unit in Modelling the Department of Health and Social Care, MRC, NHS, NIHR, or Public Health Methodology, London, UK. 8Clinical Sciences Department. School of England. Medicine, University of Barcelona and Internal Medicine Department, Parc Permission to use the MARS™ adherence tool was kindly given by Prof R Sanitari Sant Joan de Déu. Sant Boi, Barcelona, Spain. 9Blizard Institute, Horne. Queen Mary University of London, London, UK. 10Department of Respiratory Rifapentine (Priftin) 150 mg was supplied by Sanofi-Aventis Groupe for the Medicine, Barts Health NHS Trust, London, UK. conduct of study at no cost. Sanofi-Aventis reviewed the protocol but were not involved in the design, conduct or analysis of the trial. Received: 15 October 2020 Accepted: 5 January 2021 Authors’ contributions JS, HRS, TAY, ML, PJW, LM, LG, MF, MXR, VH, HK and IA made substantial References contributions to the conception or design of the work and have drafted the 1. WHO. World Health Organisation: Global tuberculosis report 2018. Geneva: work or substantively revised it. 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