Using real-world evidence for pharmacovigilance and drug safety-related decision making by a resource-limited health authority: 10 years of experience in Taiwan.

PURPOSE: Real-world evidence has become increasingly relevant in regulatory decision making. Compared to large regulatory bodies, the national pharmacovigilance system in Taiwan is still under development, and the aim of this study is to demonstrate how a resource-limited health authority utilizes real-world evidence in decision making. METHODS: We described different sources of real-world data available in Taiwan and illustrated the structural framework that integrates real-world evidence into Taiwan's national pharmacovigilance system. Additionally, we reviewed real-world studies conducted in the past 10 years and provided examples to show how these studies influenced drug safety-related decision making in Taiwan. RESULTS: During the past 10 years, real-world evidence used when making drug safety-related regulatory decisions in Taiwan was mainly generated from nationwide claims databases, but other sources of real-world data, such as national registries and large electronic hospital databases, also became available recently. Different types of real-world evidence, including drug utilization studies, risk evaluation studies, and risk minimization measure evaluation studies, have been used to support regulatory decisions in Taiwan. CONCLUSIONS: Through collaborations between the government and academics, Taiwan has started to integrate real-world evidence into the national pharmacovigilance system. However, future efforts, including linkages between different sources of real-world data and improvements in procedural and methodological practices, are needed to generate more regulatory-quality real-world evidence.

Lessons learned from the reimbursement policy for immune checkpoint inhibitors and real-world data collection in Taiwan.

This paper describes the reimbursement policy for immune checkpoint inhibitors in Taiwan and provides a perspective to improve the quality, consistency, and transparency of decision making. Global trends for cancer treatment have shifted from chemotherapies to targeted therapies and immuno-oncology (IO) medicine, leading to significant increases in treatment costs. To enhance the accessibility of advanced therapy, the Taiwan National Health Insurance Administration announced two pathways for high-cost medicine: the managed entry agreement and a set of general rules of reimbursement submission for high-cost drugs. To further manage the financial burden on Taiwan's national health insurance system, the policy makers introduced novel inhibitory drugs for cancer immune checkpoints, subject to a maximum annual budget of NT$800 million (≈US$26.7 million). In April 2019, a national registry was established for patients undergoing cancer immunotherapy. Clinical characteristics, treatment duration, toxicity, and the outcome of the postcheckpoint inhibitor treatments were recorded. By analyzing real-world data, we assess the therapeutic effect of IO treatment in Taiwanese patients, thereby enabling payers to adjust payment regulations and rules for reimbursement. The Health Technology Assessment Team plays an important role in drawing upon the evidence to support policy making. Under an implemented cost-management mechanism, Taiwan's high-cost drug policy has enabled patients to access new medicines and maximized patient benefits.

Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017.

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. A total of five out of 79 products were found. A single dose PK study was conducted to investigate the underlying drug release mechanisms in four of these products. For these products, the applicants also performed multiple dose PK equivalence studies, but the PK parameters used to support the equivalence were different among studies. Information regarding the exposure-response relationship was available for all selected products, which is fundamental for such cases. Although the difference in PK curve shapes is recognized as being critical for the clinical effectiveness, this evaluation was not performed in all selected cases, as indicated in FDA's assessment reports.

Outcomes and Impacts of 10-Year HTA Implementation in Taiwan.

OBJECTIVES: In 2007, Taiwan began conducting health technology assessments (HTA) to support the National Health Insurance Administration (NHIA) in its reimbursement decisions for drugs, medical devices, and medical services. METHODS: In this study, the development, missions, and procedures of the implementation of HTA in Taiwan are briefly introduced. Moreover, the value of HTA is examined by reviewing the outcomes and impacts of recent HTA-related research projects, which are classified into five categories: (i) pharmaceutical products, (ii) medical procedures, (iii) medical devices, (iv) health policy, and (v) social care. RESULTS: Overall, the 10-year implementation of HTA has not only supported the government's decision making but also enhanced patient care. Furthermore, patient evidence has been highlighted, and patient care pathways have been transformed through patient involvement in HTA. CONCLUSIONS: In conclusion, HTA's value has been determined by both government and social aspects in Taiwan.

Analysis of refuse-to-file policy for generic drug application in Taiwan.

Generic drugs are accounted for majority of medicinal products. To reduce the unnecessary review for incomplete dossiers of generic drugs, Taiwanese government launched a refuse-to-file (RTF) process since 2017. The present study aimed to examine the outcome of RTF process by analyzing application characteristic, RTF rate and deficiencies found in the submitted dossiers. Descriptive analyses of administrative information, chemistry, manufacturing and controls, bioequivalence study, and comparative dissolution testing were presented during the first 6 months after the implementation of RTF policy. The results showed that the source of application was likely a determinant to the RTF outcome, i.e., foreign rather than domestic applications were more liable to be RTF. It is possibly that (i) RTF applications were mainly due to incomplete dossiers regarding bioequivalence study and comparative dissolution testing, and (ii) the studies (bioequivalence and dissolution) of domestic applications conducted locally are exempted from the RTF process because they are allowed to submit for review before generic drug applications. Finally, the dossier integrity appeared not improved during the period of analysis as the number of RTF did not reduce by month. Results of the present study may help pharmaceutical industry to improve the dossiers' quality by fixing the deficiencies of generic drug submission.

Development of the risk-based, phased-in approach for the international harmonization of the regulation of container closure systems for drugs in Taiwan.

The main concern for container closure systems of drugs is to ensure suitability for the intended use which is associated with issues regarding protection, compatibility, safety, and performance. Among various concerns, leachables may pose a safety hazard to patients, while risks might vary depending on the dosage form and the administration route. Stringent regulatory authorities such as the European Medicines Agency and the United States Food and Drug Administration have established risk-based regulatory requirements and published corresponding guidelines to facilitate implementation. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes every effort to harmonize with international regulations and to strengthen protection of public health through regulatory controls. The aim of the present study was to investigate the regulatory framework and policies set by stringent regulatory authorities. The strategy proposed for the development of an eventual guideline was sent to the Taiwan Food and Drug Administration for decision. A risk-based, phased-in approach which was extensively discussed in the expert committee was proposed. The approach proposed herein could also serve as a starting point which is worth considered by other countries in which international harmonization is in process.

Epidemiology, clinical profile and treatment patterns of venous thromboembolism in cancer patients in Taiwan: a population-based study.

BACKGROUND: Venous thromboembolism (VTE) is a clinically significant complication that is well documented among Caucasian cancer patients. However, evidence regarding VTE incidence and treatment among Asian cancer patients is very limited. The objective of this study is to investigate the incidence, risk factors and management of VTE among Taiwanese cancer patients. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 43,855 newly diagnosed cancer patients between 2001 and 2008. Two alternative algorithms for identifying VTE event were explored to better quantify a range of incidence rates of VTE in our cancer patients. Multivariable logistic regression models were used to explore VTE risk factors. RESULTS: The incidence rates of VTE were 9.9 (algorithm 1) and 3.4 (algorithm 2) per 1,000 person-years, respectively. The incidence rates were higher in certain cancers, particularly liver, pancreas, and lung. Significant risk factors for VTE were site of cancer, prior history of VTE, chemotherapy and major surgeries. Long-term anticoagulant therapy was initiated in 64.1% patients with VTE and 72.2% of them received warfarin alone. Approximately two-thirds of patients with VTE received ≤ 3 months of anticoagulant therapy. CONCLUSION: Incidence of cancer-related VTE is lower among Taiwanese compared to Caucasian populations. Nevertheless, risk factors for cancer-related VTE found in our study were consistent with current literature.

The evolution and challenges for the international harmonization of the regulation of pharmaceutical excipients in Taiwan.

Excipients, once considered an inert component, have been shown to greatly influence the characteristics of the drug product, such as quality and safety. Functionality-related characteristics of excipients could affect the performance of the drug product. Moreover, the impact of globalization has complicated the issue and made the supervision of supply chain highly important. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes efforts to harmonize with international regulations and to strengthen the protection of patients through regulatory controls. In order to improve the harmonization and the transparency of regulatory requirements, the aim of the present study was to investigate the regulatory framework and considerations of stringent regulatory authorities and to propose the draft regulatory requirements to the Taiwan Food and Drug Administration for jurisdiction. The proposal which was extensively discussed in the expert committee includes the regulatory considerations to ensure the safety and quality of the excipients and may serve as a platform to facilitate the communication with industries about the current thinking on related issues. Moreover, through the review of the recent guidelines published by the stringent regulatory authorities, the trend of the regulatory considerations was revealed and discussed.

Duration of dual antiplatelet therapy following percutaneous coronary intervention on re-hospitalization for acute coronary syndrome.

BACKGROUND: The optimal duration of dual antiplatelet therapy after percutaneous coronary intervention (PCI) remains uncertain. The objective of this study was to examine the association between duration of dual antiplatelet therapy and re-hospitalization for acute coronary syndrome (ACS) in ACS patients who underwent PCI. METHODS: We identified 975 newly diagnosed ACS patients who underwent PCI between July, 2007 and June, 2009, at a medical center in Taiwan. Cox proportional hazard models were used to examine the association between duration of dual antiplatelet therapy (9 months, 12 months and 15 months) and risks of re-hospitalization for ACS. RESULTS: At a mean follow-up of 2.3 years, we found that use of clopidogrel for ≥ 12 months was associated with a decreased risk of re-hospitalization for ACS (adjusted HR 0.59, 95% CI 0.36-0.95; p = 0.03). However, use of clopidogrel for ≥ 15 months was not associated with a decreased risk of re-hospitalization for ACS (adjusted HR 0.57, 95% CI 0.29-1.13; p = 0.11). Similar results were found in patients who implanted drug-eluting stents (DES), for whom at least 12 months of clopidogrel therapy is especially critical. CONCLUSION: The benefit of ≥ 12 months of clopidogrel use in reducing the risk of re-hospitalization for ACS was significant among ACS patients who underwent PCI and was especially critical for those who implanted DES.

Correction: Valuation of the EQ-5D-5L in Taiwan.

[This corrects the article DOI: 10.1371/journal.pone.0209344.].

Use of antipsychotics and risk of cerebrovascular events in schizophrenic patients: a nested case-control study.

OBJECTIVE: This nested case-control study assessed the association between antipsychotic use and cerebrovascular adverse events among schizophrenic patients. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 9715 newly diagnosed schizophrenic patients during 2001 to 2009. Within the schizophrenic cohort, 386 cases of cerebrovascular events and 772 matched control subjects (1:2 ratio) were further identified. Conditional logistic regression models were used to examine the association between the use of antipsychotics (timing, duration, and type) and risk of cerebrovascular events. RESULTS: Current users of antipsychotics were associated with a 2-fold risk of stroke (adjusted odds ratio [OR], 1.94; 95% confidence interval [CI], 1.11-1.39; P = 0.02) as compared with nonusers. Among current users, patients who used antipsychotics less than 15 days (adjusted OR, 9.41; 95% CI, 3.08-28.71; P < 0.01) and 16 to 30 days (adjusted OR, 6.90; 95% CI, 1.09-43.69; P = 0.04) were associated with an extremely high risk of stroke. The risk of stroke was greater for patients who used first-generation antipsychotics alone or combination of first- and second-generation antipsychotics, with adjusted ORs of 2.75 (95% CI, 1.34-5.64; P < 0.01) and 2.37 (95% CI, 1.20-4.68; P = 0.01), respectively, but not in patients who used second-generation antipsychotic alone. CONCLUSIONS: This population-based study extends previous evidence by documenting the increased cerebrovascular events associated with antipsychotic use in a schizophrenic cohort. A temporal association of such risk was reported in our study. Further studies are needed to assess the risk-benefit profile of first- and second-generation antipsychotics in this patient population.

The Impact of Metabolic Syndrome, Homocysteine, and B Vitamins on Carotid Artery Intima-Media Thickness in Hypertensive Patients.

OBJECTIVES: To examine the correlation between metabolic syndrome (MS), plasma total homocysteine (tHcy) level, and serum B vitamin levels on carotid intima-media thickness (CIMT) in hypertensive patients. METHODS: A total of 73 medically treated hypertensive patients (42 men, mean age 70.7 years), fasted for 10 hours, and provided fasting blood samples for measurement of plasma tHcy, serum folic acid, and serum vitamin B12 levels. Additionally, B-mode ultrasound of the distal right common carotid arteries was performed on all participants. RESULTS: There were 50 patients with and 23 patients without MS. Patients with MS had larger CIMT than patient without (0.81 ± 0.13 vs. 0.74 ± 0.10 mm, p = 0.018). Patients with MS had larger waist circumference (p < 0.001), higher body mass index (p < 0.001), elevated serum triglyceride level (p < 0.001), lower serum high density lipoprotein level (p = 0.016), higher prevalence of diabetes mellitus (p = 0.012), higher prevalence of hyperlipidemia (p = 0.019), and a higher prevalence of fibrate usage (p = 0.025) than patients without MS. In univariate analysis, CIMT correlated significantly with the presence of MS (r = 0.256; p = 0.029), usage of angiotensin receptor blocker (ARB; r = -0.256; p = 0.029), and male gender (r = 0.247; p = 0.035). The relationships between CIMT and serum folic acid level (r = -0.212; p = 0.072) or statin usage (r = 0.207; p = 0.079) were borderline significant. In multivariate regression analysis, after adjusting for age and gender, only usage of ARB (ß value -0.078, 95% CI: -0.140 to -0.015, p = 0.016) and the presence of MS (ß value 0.075, 95% CI: 0.020 to 0.131, p = 0.009) were associated with CIMT. In anothermodel, after adjusting four additional parameters including age, gender, systolic blood pressure and usage of statin, usage of ARB (ß value -0.074, 95% CI: -0.137 to -0.011, p = 0.022) and presence of MS (ß value 0.069, 95% CI: 0.012 to 0.125, p = 0.017) remained significantly correlated with CIMT. CONCLUSION: MS and usage of ARB are associated with CIMT in hypertensive patients. KEY WORDS: Folic acid; Homocysteine, Intima-media thickness, Metabolic syndrome.

Regulatory considerations for generic products of non-biological complex drugs.

The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs.

Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients with acute coronary syndrome in Taiwan.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Conflicting results have been reported regarding the increased risk of adverse outcomes in the concomitant use of clopidogrel and proton pump inhibitors (PPIs) compared with the use of clopidogrel alone. WHAT THIS STUDY ADDS: Our study indicated no statistically significant increase in the risk of rehospitalization for acute coronary syndrome due to concurrent use of clopidogrel and PPIs in an Asian population with higher prevalence of CYP2C19 intermediate and poor metabolizers. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for acute coronary syndrome. AIMS Our study aimed to examine the impact of concomitant use of proton pump inhibitors (PPIs) with clopidogrel on the cardiovascular outcomes of patients with acute coronary syndrome (ACS). Furthermore, we sought to quantify the effects of five individual PPIs when used concomitantly with clopidogrel. METHODS: We conducted a retrospective cohort study of patients who were newly hospitalized for ACS between 1 January 2006 and 31 December 2007 retrieved from the Taiwan National Health Insurance Research Database (NHIRD) and who were prescribed clopidogrel (n= 37 099) during the follow-up period. A propensity score technique was used to establish a matched cohort in 1:1 ratio (n= 5173 for each group). The primary clinical outcome was rehospitalization for ACS, while secondary outcomes were rehospitalization for percutaneous transluminal coronary angioplasty (PTCA) with stent, PTCA without stent and revascularization (PTCA or coronary artery bypass graft surgery) after the discharge date for the index ACS event. RESULTS: The adjusted hazard ratio of rehospitalization for ACS was 1.052 (95% confidence interval, 0.971-1.139; P= 0.214) in the propensity score matched cohort. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for ACS (adjusted hazard ratio, 1.226; 95% confidence interval, 1.066-1.410; P= 0.004). Concomitant use of esomeprazole, pantoprazole, rabeprazole and lansoprazole did not increase the risk. CONCLUSIONS: Our study indicated no statistically significant increase in the risk of rehospitalization for ACS due to concurrent use of clopidogrel and PPIs overall. Among individual PPIs, only omeprazole was found to be statistically significantly associated with increased risk of rehospitalization for ACS.

The challenges and opportunities in using real-world data to drive advances in healthcare in East Asia: expert panel recommendations.

OBJECTIVE: To provide recommendations for overcoming the challenges associated with the generation and use of real-world evidence (RWE) in regulatory approvals, health technology assessments (HTAs), and reimbursement decision-making in East Asia. METHODS: A panel of experts convened at the International Society for Pharmacoeconomics and Outcomes Research Asia Pacific 2020 congress to discuss the challenges limiting the use of RWE in healthcare decision-making and to provide insights into the perspectives of regulators, HTA agencies, the pharmaceutical industry, and physicians in China, Japan, and Taiwan. A nonsystematic literature review was conducted to expand on the themes addressed. RESULTS: The use of RWE in regulatory approvals, HTAs, and reimbursement decision-making remains limited by legal/regulatory, technical, and attitudinal challenges in East Asia. CONCLUSIONS: We recommend approaches and initiatives that aim to drive improvements in the utilization of RWE in healthcare decision-making in East Asia and other regions. We encourage large-scale collaborations that leverage the full range of skills offered by different stakeholders. Government agencies, hospitals, research organizations, patient groups, and the pharmaceutical industry must collaborate to ensure appropriate access to robust and reliable real-world data and seek alignment on how to address prioritized evidence needs. Increasingly, we believe that this work will be conducted by multidisciplinary teams with expertise in healthcare research and delivery, data science, and information technology. We hope this work will encourage further discussion among all stakeholders seeking to shape the RWE landscape in East Asia and other regions and drive next-generation healthcare.

Patient Involvement in the Health Technology Assessment Process in Taiwan.

The COVID-19 pandemic initially had a smaller impact on Taiwan than on most other industrialized countries. However, an outbreak in late April 2021 led to a sharp surge in cases from mid-May 2021. Patient involvement in the health technology assessment (HTA) process, however, was not much affected by this; virtual meetings were implemented. This descriptive paper presents an overview of patient involvement in the HTA process in Taiwan via the National Health Insurance Administration (NHIA) online submission platform, participation in appraisal committees, education programs, and cooperation with patients' organizations, and outlines its progress and challenges. The National Health Insurance Act, amended in 2013, protects patients' rights and invites them to voice their opinions, which are then presented to the relevant authority. Based on this act, various mechanisms have been developed to involve patients, caregivers, and patient organizations in both the HTA and the reimbursement process. Prior to the Pharmaceutical Benefit and Reimbursement Scheme (PBRS) Joint Committee meeting, the NHIA built an online platform that allows patients to submit their opinions, which are then incorporated into the HTA reports. The results are also discussed with patient representatives, following which the related documents are published on the NHIA website. From May 2015 to December 2020, 30 patients' insights were published before the PBRS Joint Committee meetings. Of these, 19 (63%) were related to oncology cases. In Taiwan, approaches to fostering patient engagement include the use of a platform for patients' and patients groups' input, among others. Although patient engagement is important for understanding the needs of the target patient population, challenges in ensuring timely patient engagement and provision of relevant resources remain. In addition, further efforts are needed to implement and improve the visibility of patient input in the HTA process.

The impact of the rare disease and Orphan Drug Act in Taiwan.

The Rare Disease and Orphan Drug Act (the Act) was enacted in 2000 in Taiwan for the facilitation of the research, development, and accessibility of orphan drugs and special nutritional foods; for the prevention and early diagnosis of rare diseases; and for providing intensive care for patients with rare diseases. The aim was to investigate the impact of the Act on the availability and use of orphan drugs in Taiwan in the hope of identifying the remaining challenges and possible solutions to assist future policy making, which may be applicable in other countries as well. The information and statistics for rare diseases and orphan drugs retrieved from the official annual reports and documents were analyzed. There were 225 diseases recognized as rare diseases, and one-third (75/225) of them were congenital metabolic disorders. Among the 110 designated orphan drugs that could apply for listing in the National Health Insurance (NHI) Pharmaceutical Benefits and Reimbursement Scheme, approximately half (62/110) of them were granted marketing authorization. While the NHI program compulsory for all citizens increased patient accessibility to orphan drugs, the rapidly increasing economic burden became an urgent issue for the government. Emerging gene therapies may be the solution to unmet medical needs and also a financial obstacle to tackle. The Act increased the availability of orphan drugs while the NHI system facilitated patient access, which benefited many patients with rare diseases in Taiwan. However, the soaring economic burden was noticed and was anticipated to aggravate. More communication and cooperation between stakeholders is critical in finding solutions for the long-term sustainability of the NHI system.

Association between mood stabilizers and hypothyroidism in patients with bipolar disorders: a nested, matched case-control study.

OBJECTIVES: This study investigated whether lithium, carbamazepine, and valproate increased the risk for hypothyroidism using Taiwan's National Health Insurance Dataset. METHODS: The sample included 557 bipolar disorder patients with incident hypothyroidism first diagnosed between 1998 and 2004, and 2,228 sex-, age-, and index date-matched bipolar disorder patients without hypothyroidism from 1996-2004. We compared the use of lithium, carbamazepine, and valproate before the onset of hypothyroidism between the two groups using a conditional logistical regression model. RESULTS: Compared with patients who had never used any of the three mood stabilizers, patients were more likely to have hypothyroidism if they only used carbamazepine [odds ratio (OR) = 1.68; 95% confidence interval (CI): 1.07-2.65]; or comedication of lithium and valproate (OR = 2.40; 95% CI: 1.70-3.40), lithium and carbamazepine (OR = 1.52; 95% CI: 1.10-2.08), and three mood stabilizers (OR = 2.34; 95% CI: 1.68-3.25). There was a dose-response relationship between the number of mood stabilizers and risk for hypothyroidism (OR = 1.34, 95% CI: 1.21-1.49) and a significant interaction between lithium and valproate on the risk for hypothyroidism (p = 0.020). CONCLUSIONS: Our findings indicate that lithium, carbamazepine, and valproate may increase the risk for hypothyroidism, particularly if combined, and suggest regular monitoring of thyroid function and monotherapy of mood stabilizers for treating patients with bipolar disorders.

A prospective study of hepatitis during antituberculous treatment in Taiwanese patients and a review of the literature.

BACKGROUND/PURPOSE: The present study prospectively investigated the incidence of and factors associated with hepatitis during antituberculous treatment in patients with tuberculosis and various underlying diseases. The results were compared with those of previously published studies. METHODS: Patients treated with antituberculous agents were enrolled from July 1, 2000 to July 31, 2001, in the divisions of chest and infectious diseases at National Taiwan University Hospital and followed until November 30, 2001. Hepatitis was defined as an aminotransferase level>5 times the upper limit of normal (ULN), or >3 times ULN in the presence of symptoms of hepatitis, or total bilirubin level>3 mg/dL. Studies reporting the incidence of hepatitis during antituberculous treatment were reviewed for comparison. RESULTS: Among 261 patients, median age was 58 years (range, 17-90 years), 17.7% had abnormal baseline liver function tests and 18.4% had concurrent hepatotoxic drug use. Fifteen patients (5.7%) had hepatitis B virus infection, 17 (6.5%) had hepatitis C virus infection, 14 (5.4%) had liver cirrhosis, and 15 (5.7%) had human immunodeficiency virus infection. Hepatitis occurred in 42 patients (16.1%), with 60% of the events in the first 2 months of treatment. Such an incidence was comparable to that in other Asian countries (5.3-18.2%) and slightly higher than that in Western countries (2.4-19%). In multivariate analysis, abnormal liver function tests at baseline and liver cirrhosis were independent factors for development of hepatitis. CONCLUSION: Elevation of liver function tests was not uncommon during antituberculous treatment, especially in the first 2 months. Patients with abnormal liver function tests at baseline or liver cirrhosis should be closely monitored.