Article Text

Safety and tolerability of OP-724 in patients with haemophilia and liver cirrhosis due to HIV/HCV coinfection: an investigator-initiated, open-label, non-randomised, single-centre, phase I study
  1. Kiminori Kimura1,
  2. Junko Tanuma2,
  3. Masamichi Kimura1,
  4. Jun Imamura1,
  5. Mikio Yanase3,
  6. Ichiro Ieiri4,
  7. Masayuki Kurosaki5,
  8. Tsunamasa Watanabe6,
  9. Tomoyuki Endo7,
  10. Hiroshi Yotsuyanagi8,
  11. Hiroyuki Gatanaga2
  1. 1Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
  2. 2AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
  3. 3Department of Gastroenterology, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
  4. 4Department of Clinical Pharmacokinetics, Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
  5. 5Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
  6. 6Division of Gastroenterology and Hepatology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
  7. 7Department of Hematology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
  8. 8Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan
  1. Correspondence to Dr Kiminori Kimura; kiminori_kimura{at}


Objective Patients with haemophilia and HIV who acquire hepatitis C virus (HCV) after receiving contaminated blood products can experience accelerated progression of liver fibrosis and a poor prognosis, making liver disease a prominent cause of mortality among these patients. In the current study, we aimed to evaluate the safety and tolerability of the potential antifibrotic agent OP-724—a CREB-binding protein/β-catenin inhibitor—in this patient subset.

Design In this single-centre, open-label, non-randomised, phase I trial, we sequentially enrolled patients with cirrhosis following HIV/HCV coinfection classified as Child-Pugh (CP) class A or B. Five patients received an intravenous infusion of OP-724 at doses of 140 or 280 mg/m2 for 4 hours two times weekly over 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). Secondary endpoints included the incidence of AEs and improved liver stiffness measure (LSM), as determined by vibration-controlled transient elastography. This study was registered at (NCT04688034).

Results Between 9 February 2021 and 5 July 2022, five patients (median age: 51 years) were enrolled. All five patients completed 12 cycles of treatment. SAEs were not observed. The most common AEs were fever (60%) and gastrointestinal symptoms (diarrhoea: 20%, enterocolitis: 20%). Improvements in LSM and serum albumin levels were also observed.

Conclusion In this preliminary assessment, intravenous administration of 140 or 280 mg/m2/4 hours OP-724 over 12 weeks was well tolerated by patients with haemophilia combined with cirrhosis due to HIV/HCV coinfection. Hence, the antifibrotic effects of OP-724 warrant further assessment in patients with cirrhosis.

Trial registration number NCT04688034.

  • HCV

Data availability statement

Data are available upon reasonable request. The anonymous data displayed in the manuscript will be made available on request from the corresponding author following the publication of this article. Data displayed in the manuscript or acquired during the clinical trial will be made available in a form that does not deviate from what is accepted by local regulatory authorities with respect to the handling of patient data and in adherence to the policies of the Tokyo Metropolitan Komagome Hospital.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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  • Patients with HIV/hepatitis C virus (HCV) coinfection develop liver fibrosis more rapidly and have a higher incidence of cirrhosis and hepatocellular carcinoma than those with HCV monoinfection.


  • In this phase I study, a CREB-binding protein (CBP)/β-catenin inhibitor, OP-724 (280 mg/m2/4 hours), was relatively well tolerated and substantially improved the liver stiffness measure and serum albumin levels in patients with haemophilia and liver cirrhosis caused by HIV/HCV coinfection.


  • Intravenous administration of 140 or 280 mg/m2/4 hours OP-724 two times weekly over 12 weeks may represent an effective therapeutic strategy that exerts an antifibrotic effect in patients with haemophilia combined with liver cirrhosis due to HIV/HCV coinfection.


Prior to 1986, approximately 95% of patients infected with HIV and haemophilia following administration of contaminated blood products were coinfected with hepatitis C virus (HCV).1–3 Approximately 30 years later, Ingiliz et al reported that most patients with HCV infection that persisted despite interferon (IFN) therapy develop cirrhosis or hepatocellular carcinoma.4 Additionally, liver fibrosis progresses faster with a poorer prognosis in patients coinfected with HIV/HCV than in those with HCV monoinfection.4 5 Although the underlying cause for these observations remains largely unknown, HIV-associated immunosuppression and the effects of anti-HIV drugs are likely contributors.6

Despite marked improvements in the prognosis of HIV infection following the development of anti-HIV drugs, the number of deaths among patients with HIV who develop liver disease owing to HCV infection continues to increase.2 Moreover, liver cirrhosis due to HIV/HCV coinfection is frequently accompanied by portal hypertension with bleeding from oesophageal varices.7 Meanwhile, direct-acting antiviral (DAA) drugs achieve HCV elimination (sustained virologic response (SVR)) in HIV/HCV-coinfected patients with cirrhosis and improve liver function, even in cases of decompensated cirrhosis.8 9 A Japanese study examined 44 cirrhotic patients with haemophilia and HIV/HCV coinfection, classifying 87% of these patients were classified as Child-Pugh (CP) A classification.10 However, the importance of monitoring liver function was emphasised in cirrhotic patients with haemophilia and HIV/HCV coinfection. More specifically, based on ARFI and FIB-4 expression—non-invasive indicators of liver fibrosis—faster progression of fibrosis was detected in HIV/HCV-coinfected patients with haemophilia than in those with HCV monoinfection, even with a CP A classification.10 Furthermore, a Dutch group reported that successful HCV treatment does not eliminate the risk of liver-related complications in patients with inherited bleeding disorders, including patients with haemophilia and HCV. In fact, there is a risk of developing liver cancer and complications even after SVR.1 Therefore, several patients with haemophilia and liver cirrhosis associated with HIV/HCV coinfection present with advanced disease despite being classified as CP class A, requiring early treatment initiation for liver cirrhosis. Therefore, although this patient subgroup is small, an effective antifibrotic treatment is currently lacking.

We previously reported that OP-724 is safe and well tolerated for the treatment of cirrhosis caused by hepatitis B virus (HBV) or HCV or primary biliary cirrhosis, and that it improves the liver stiffness measure (LSM) and increases albumin levels.11 12 Hence, OP-724 has potential as an antifibrotic treatment for cirrhosis. Accordingly, in the current study, we conducted an investigator-initiated clinical trial to further assess the safety and tolerability of OP-724, particularly in the context of anti-HIV drug administration.


Study design and patients

This study was a single-centre, open-label, phase I dose-escalation trial. We sequentially enrolled patients with haemophilia and liver cirrhosis due to HIV/HCV coinfection treated at the Cancer and Infectious Diseases Center of Tokyo Metropolitan Komagome Hospital (Tokyo, Japan). This trial was registered at (NCT04688034).

Eligible participants included those aged 20–74 years who were diagnosed with haemophilia and liver cirrhosis caused by concurrent HIV and HCV infections. Infection diagnosis was based on serum HIV-RNA-positive or HIV antibody-positive results and serum HCV-RNA-positive or HCV antibody-positive results. Diagnosis of liver cirrhosis was based on the fulfilment of one of the following criteria: (1) FIB-4 index value ≥3.25,13 (2) an LSM by VCTE (FibroScan) ≥11.8 kPa,14 and (3) abdominal CT scan showing changes in liver shape or portal hypertension. Patients with a CP A or B classification were enrolled. The exclusion criteria included patients with current or previous primary liver cancer (excluding those who underwent curative liver cancer resection or radiofrequency ablation ≥1 year prior).

Drug administration protocol

OP-724 was administered intravenously for 4 hours two times per week in two dose groups (140 mg/m2/4 hours (n=3) and 280 mg/m2/4 hours (n=2)). The dosing period was 12 weeks. Administration of investigational drugs comprised two parts: single administration and cycle administration. The safety of the concomitant use of the investigational drug and anti-HIV drug was determined by a single administration prior to initiating cycle administration.

Regarding the single administration, a dose scheduled in the first cycle was administered once by continuous intravenous administration for 4 hours (acceptable administration time: ±15 min) 14 days before the first cycle administration (acceptable range: −7 days). When an integrase inhibitor was administered as the key anti-HIV drug, it was administered simultaneously with the investigational drug (acceptable range: ±5 min) as a single administration.


The primary endpoint was the incidence of serious adverse events (SAEs) for which a causal relationship could not be excluded, and the secondary endpoints included the incidence of adverse events (AEs), side effects, and OP-724 and C-82 pharmacokinetics (PK). Plasma OP-724 and C-82 concentration-time data were analysed using non-compartmental methods as previously reported,15 including the maximum drug concentration (Cmax), time to Cmax (Tmax), terminal half-life (t1/2), and area under the plasma concentration-time curve (AUC). Additional secondary endpoints were the change from baseline in LSM by VCTE (FibroScan, Echosens, Waltham, Massachusetts, USA) and two-dimensional shear wave elastography (2D-SWE; Aplio 500, Toshiba, Tokyo, Japan), the FIB-4 index, and aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) 12 weeks post-administration. In addition, we assessed the change in the baseline CP score and the Model for End-Stage Liver Disease (MELD) score at 12 weeks. Serum cytokine and chemokine levels were also measured using Bio-Plex Cytokine Assay Kits (Bio-Rad Laboratories), according to the manufacturer’s instructions.

Statistical analyses

Sample size calculation

The sample size (n=6) was not determined based on statistical evidence but on the extremely small number of patients (~50) with haemophilia and liver cirrhosis due to HIV/HCV coinfection in Japan.3 However, given that only five candidate patients were identified during the registration period, we ultimately registered only five patients.

Analyses of primary and secondary endpoints

All patients were included in the safety and tolerability analyses following OP-724 treatment, with each patient subjected to statistical analyses, such as PK, were performed on each treated patient. However, LSM, serum albumin, cytokine, and chemokine data were collected for all patients in the trial. Data were expressed as the mean±SD. PK analyses were conducted in patients with evaluable PK concentrations using non-compartmental methods with Microsoft Office Excel and Phoenix WinNonlin V.6.4 (CERTARA, Princeton, New Jersey, USA).

Changes in the LSM, CP score, and MELD score were evaluated from baseline to 12 weeks post-treatment. The group means were compared using a two-tailed Student’s t-test, and multiple group means were compared by one-way analysis of variance, followed by Bonferroni’s post hoc test with GraphPad Prism V.9.0 (GraphPad Software, Boston, Massachusetts, USA). Statistical significance was set at p<0.05.

Data handling

To guarantee the reliability and correct handling of all study-related data, the Data Management Officer and staff executed all procedures leading up to database locking, including EDC system (Datatrak Enterprise Cloud) construction, creation of case reports, and data inspection, based on the data management plan for this study. On completion of the data management operations, a data management report was generated.


We conducted a phase I clinical trial to evaluate the safety and tolerability of OP-724 in patients with haemophilia and liver cirrhosis caused by HIV/HCV coinfection. Five patients were screened between 9 February 2021 and 5 July 2022. Three patients were administered 140 mg/m2/4 hours OP-724 and two patients were administered 280 mg/m2/4 hours (figure 1). Table 1 summarises the baseline patient characteristics. All five patients were male with an average age of 51 years (range: 46–59 years). Four patients had haemophilia A (80%) and one patient had haemophilia B (20%), all of which were severe. All patients were undergoing antiretroviral therapy and exhibited good HIV control. Regarding HCV, all patients were post-SVR for over 48 months. Four patients had a CP class of A and one patient of B.

Table 1

Patient characteristics

No SAEs were observed. The most common AEs were fever (60%) and gastrointestinal symptoms (diarrhoea: 20%, enterocolitis: 20%) (table 2).

Table 2

Adverse events and laboratory abnormalities

We analysed PK parameters related to the plasma OP-724 concentration after a single administration in cohorts 1 and 2. The Cmax (mean±SD) values for cohorts 1 and 2 were 888±149 and 1950±320 ng/mL, respectively, while the AUC0-24 h (mean±SD) values were 3350±280 and 7260±970 ng·hour/mL, respectively. These parameters increased with increasing OP-724 dose. Furthermore, the Tmax was 0.8±0.3 and 1.0±0.0 hour, respectively, and the t1/2 (mean±SD) was 0.5±0.0 and 0.5±0.1 hour in cohorts 1 and 2, respectively (figure 2, table 3 and online supplemental table 1).

Figure 2

Pharmacokinetics of OP-724 and C-82 after OP-724 intravenous infusion. (A) Individual concentration profiles of OP-724 in the plasma of patients with haemophilia and liver cirrhosis caused by HIV/hepatitis C virus coinfection during continuous intravenous OP-724 infusion. (B) Individual plasma concentration profiles of C-82, a metabolite of OP-724, in the same patients.

Table 3

Pharmacokinetic parameters of OP-724 and C-82 after OP-724 intravenous infusion.

Plasma OP-724 concentrations during the 1st, 5th, 9th, and 12th cycles were generally below the lower limit of quantification (BLQ; <0.100 ng/mL) before administration.

During cycle 5 day 4, slight OP-724 concentrations were detected in the plasma of both cohorts. Before the end of treatment, the plasma concentration (mean±SD) ranged from 760±144 to 952±89 ng/mL in cohort 1 and from 1520±80 to 2300±660 ng/mL in cohort 2, increasing with increasing OP-724 dose.

We also analysed the PK parameters associated with the plasma C-82 concentration after a single administration. The Cmax was 1070±580 and 1360±60 ng/mL, and the AUC0-24 h was 5960±3770 and 7260±1170 ng·h/mL in cohorts 1 and 2, respectively. Although individual differences were observed in one subject from cohort 1, these parameters were primarily influenced by the OP-724 dose, exhibiting a dose-dependent increase. Furthermore, the Tmax (mean±SD) values were was 4.0±0.0 and 3.0±1.4 hours, and the t1/2 was 4.4±0.7 and 3.6±0.3 hours in cohorts 1 and 2, respectively (table 3).

Plasma C-82 concentrations during the 1st, 5th, 9th, and 12th cycles were generally BLQ (<0.100 ng/mL) before initiating drug administration. Before the end of treatment, the range of plasma concentrations (mean±SD) in cohort 1 ranged from 1010±450 to 1310±400 ng/mL, and that in cohort 2 ranged from 1660±360 to 2160±350 ng/mL, thereby appearing to be dose-dependent.

We then analysed the PK of integrase inhibitors (anti-HIV drug) when administered concomitantly. Three patients in cohort 1 and one patient in cohort 2 concomitantly received integrase inhibitors. One patient was administered inhibitor dolutegravir, two patients in cohort 1 were administered bictegravir, and one patient in cohort 2 received bictegravir. Online supplemental table 2 shows the analysis results of plasma dolutegravir and bictegravir concentrations after a single administration of OP-724 (14 days before initiating the first cycle). Plasma bictegravir concentrations showed large individual differences regardless of the cohort.

To determine the preliminary antifibrotic therapeutic effect, liver stiffness was measured using VCTE (FibroScan)16 17 and shear wave elastography was determined. Twelve weeks after the first dose, the change from baseline in LSM by (mean±SD) was −3.93±0.75 kPa in cohort 1 and −7.45±1.06 kPa in cohort 2; the total change (in cohorts 1 and 2) was −5.34±2.07 kPa. Statistical analysis was performed using the results of all treated patients, and a significant decreasing trend was observed (p=0.0045; figure 3A). The values measured before and 12 weeks after initiating OP-724 administration for each patient are shown in table 4. Changes from baseline in LSM by 2D-SWE (mean±SD) were −0.237±0.057 m/s for cohort 1 and −0.675±0.898 m/s for cohort 2; the total change (cohorts 1 and 2) was −0.412±0.511 m/s. Although both cohorts exhibited a reduction from baseline, no statistically significant differences were observed before and after administration.

Figure 3

Effects of OP-724 treatment on LSM, liver function, and serum cytokine levels. (A) LSM from baseline to post-treatment following 12 weeks of OP-724 administration (n=5), (B) serum ALB before, during, and after 12 weeks of OP-724 administration, (C) serum CXCL12 before and 4 weeks after completing OP-724 administration. Statistical analyses were performed using paired Student’s t-tests. LSM, liver stiffness measure; VCTE, vibration-controlled transient elastography; ALB, albumin

Table 4

Fibroscan, share wave elastography, FIB-4 index, APRI, and MELD score after OP-724 treatment. Changes in liver stiffness measurement, FIB-4 index, APRI, and MELD score from baseline to 12 weeks post-treatment initiation of OP-724.

In addition, we assessed changes in the FIB-4 index, APRI, CP score, and MELD score as secondary endpoints to explore whether OP-724 improved non-invasive fibrosis and liver function (table 4). The FIB-4 index and APRI decreased after treatment in three out of five patients, although the difference was not significant (p=0.2409, p=0.2070, respectively). Additionally, no changes were observed in the mean CP or MELD scores 12 weeks after OP-724 administration. However, serum albumin levels were significantly increased 4 and 8 weeks after OP-724 administration (figure 3B and table 4).

Finally, serum levels of inflammatory cytokines and chemokines were measured before and after administration of the study drug. Although several cytokines and chemokines were analysed using the Bio-Plex panel, only the abundance of stromal cell-derived factor-1⍺ (SDF-1α:CXCL12) was significantly reduced (p=0.0201) after administration (figure 3C).


We conducted a phase I trial in patients with haemophilia and liver cirrhosis caused by HIV/HCV coinfection to evaluate the safety and PK parameters of OP-724 administration. Although the number of patients in this study was small, no SAEs were observed throughout the administration period, indicating the safety of OP-724. Moreover, an exploratory efficacy study revealed significant improvements in LSM after treatment and serum albumin levels during treatment.

Regarding the safety evaluation as the primary endpoint, the SAE incidence was 0%. The incidences of AEs and side effects, that is, secondary endpoints, was 60.0% (3/5) and 20.0% (1/5), respectively. Furthermore, there were no differences in the incidence of AEs between cohorts 1 and 2. Owing to the limited number of patients, a definitive conclusion could not be reached.

Overall, the only AE reported was diarrhoea (1/5 patients, 20.0%). Diarrhoea is a side effect that also appeared as a gastrointestinal symptom in the previously conducted PRI-724-2101 study—a study conducted in patients with liver cirrhosis caused by HCV or HBV.12 This AE was manageable by monitoring the progress and administering appropriate symptomatic treatment.

The amount of HIV RNA in the blood and the CD4+ T-lymphocyte count remained relatively constant during the trial period in both cohorts, indicating that HIV infection was well controlled during the study drug administration (online supplemental figure 1). Additionally, OP-724 was recently shown to increase the proliferation of stem cell memory (SCM) and central memory (CM) CD4+ T cells in a rhesus macaque model of simian immunodeficiency virus infection.18 Hence, it is crucial to investigate whether OP-724 affects the number of SCM and CM CD4+ T cells in HIV in future investigations. Neither cohort exhibited haemophilic symptoms, such as bleeding, during the drug administration period, suggesting a good safety profile in this regard.

To measure the plasma concentration of the investigational drug and determine changes in the PK parameters, the PK parameters obtained in this clinical trial were compared with those of a previous study, PRI-724-2101, and population PK parameters.12 The relationship between safety and PK was also assessed. The PK of OP-724 and C-82 in patients with cirrhosis due to HIV/HCV coinfection did not differ significantly from that of patients with cirrhosis due to HCV or HBV. Furthermore, there was no abnormal increase or decrease in integrase inhibitor levels in any patient after a single drug administration. These findings suggest that OP-724 can be safely used in combination with integrase inhibitors.

We assessed LSM using VCTE and 2D-SWE and observed a decrease in the LSM from baseline in both cases at 12 weeks after administration. This result may be influenced by the small number of patients; however, it suggests that OP-724 improves liver fibrosis. LSM is a simple and widely used method, although certain limitations cannot be ignored. In particular, obtaining accurate values may be challenging in cases of hepatitis, cholestasis, or areas with accumulated ascites.16 19 Although the present results require careful interpretation owing to the small number of patients, the observed average decrease of −5.34±2.07 kPa at 12 weeks after OP-724 administration is noteworthy and warrants further evaluation. Indeed, in cases such as our target patients, after 1 year or more has passed from SVR, the annual rate of improvement is typically only ~1 kPa.20 Furthermore, the low FIB-4 index and APRI obtained in our study support improvement in liver fibrosis with OP-724 administration. Consistent with these results, an increase in serum albumin levels was observed after OP-724 administration, which aligns with the findings of the previous clinical trials that showed improved albumin synthesis after OP-724 administration.11 15 The mechanism underlying this phenomenon is likely the increase in hepatic blood flow owing to antifibrotic effects and restoration of mitochondrial function (unpublished data).

Non-clinical studies and previous OP-724 trials have established that CXCL12 expression is decreased in the liver tissue and serum, respectively.11 This suggests that CXCL12 contributes to the mechanism of action of OP-724, which was further demonstrated in a study using the CCI4 fibrosis mode.21 Given the clearly defined role of CXCL12 and its receptor CXCR4 in fibrosis, we plan to investigate the mechanism of action of OP-724 in future studies.22 23 Serum CXCL12 levels may also serve as a surrogate marker for evaluating the therapeutic effects of OP-724 administration.

This study has several limitations. First, the sample size was markedly limited. The number of patients targeted in this study with haemophilia, cirrhosis, and HIV/HCV coinfection is extremely small to perform in-depth statistical analyses. Second, the absence of a placebo control group limited the accuracy of the therapeutic effects. In the next phase of the trial, these limitations will be addressed by increasing the number of study sites, and an investigator-led clinical trial will be planned.

In conclusion, in this clinical trial, the safety of OP-724 was determined by administering two doses—cohort 1 (140 mg/m2/4 hours) and cohort 2 (280 mg/m2/4 hours)—to five patients with haemophilia and cirrhosis caused by coinfection with HIV and HCV. The safety and tolerability of OP-724 were confirmed up to a dose of 280 mg/m2/4 hours. Based on these results, the next phase of the trial will evaluate the efficacy and safety of OP-724 at a 280 mg/m2/4 hour dose in a larger number of patients.

Data availability statement

Data are available upon reasonable request. The anonymous data displayed in the manuscript will be made available on request from the corresponding author following the publication of this article. Data displayed in the manuscript or acquired during the clinical trial will be made available in a form that does not deviate from what is accepted by local regulatory authorities with respect to the handling of patient data and in adherence to the policies of the Tokyo Metropolitan Komagome Hospital.

Ethics statements

Patient consent for publication

Ethics approval

This study was approved by the Institutional Review Board of Komagome Hospital (approval number: 20-014 and 3071). Participants gave informed consent to participate in the study before taking part.


We thank all the research and clinical staff at Tokyo Metropolitan Komagome Hospital, especially Akemi Ikoma, Kozue Kobayashi, Yasuo Azuma, Noriyo Okamoto, and Naoko Horikawa, for their hard work in contributing to the study. We thank Editage ( for the English language editing.


Supplementary materials

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  • Contributors KK was article guarantor, the coordinating principal investigator and led the clinical conduct at the Komagome Hospital. MK and JI were the sub-investigators of the study at Komagome Hospital. KK contributed to the conception of the clinical trial, acquired funding, interpreted the clinical data, and wrote the original draft of the manuscript. JT, MY, and HG collected, analysed, and interpreted the data. JT, HY, and HG reviewed and edited the manuscript. MK, TW, and TE interpreted the clinical data and organised the safety committee. II contributed to PK analysis. All the authors have read and approved the final version of the manuscript.

  • Funding This investigator-initiated study was supported by grants from the Research Program on HIV/AIDS (21fk0410030h0003 and 22fk0410049h0001) and the Japan Agency for Medical Research and Development (AMED) (KK).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.