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研究生： 張惠敏
Chang, Hui-Min
論文名稱： 以真實世界數據探討HIV單錠處方的治療結果與服藥依從性及寬容度
Exploring Treatment Outcomes, Patient Adherence and Drug Forgiveness of Single-Tablet Regimens for HIV using Real World Data
指導教授： 周辰熹
Chou, Chen-His
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床藥學與藥物科技研究所
Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年： 2024
畢業學年度： 112
語文別： 英文
論文頁數： 165
中文關鍵詞： HIV 治療 、雙藥療法 、寬容度 、漏服藥物 、服藥依從性
外文關鍵詞： HIV Treatment, Two-Drug Regimens, Forgiveness, Missed Dose, Adherence
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    • 本研究目的在評估單錠抗反轉錄病毒藥物（STRs）中的第二代嵌合酶鏈轉移抑制劑(INSTI)，特別是含dolutegravir（DTG）的三藥方案（3DRs）和雙藥方案（2DRs）在現實世界中的療效、藥物寬容度及達到病毒抑制的依從性閾值。本研究包含回顧性和前瞻性研究，分析初次接受第二代嵌合酶鏈轉移抑制劑的單錠處方以及因病毒失敗或藥物不良反應更換藥物的病人。結果顯示，BIC/FTC/TAF和ABC/DTG/3TC這兩個單錠處方能在HIV-1感染者中有效達到並維持病毒抑制。在含DTG的處方顯示，72.5%的依從性閾值即可達到良好的病毒抑制，允許每週漏服藥1至2次藥物。這證實了即使存在漏服藥的狀況，含DTG的3DR和2DR仍能提供有效的病毒控制，顯示其藥物寬容度。總體而言，這些發現證明了第二代嵌合酶鏈轉移抑制劑的單錠處方其療效和寬容度，突顯其在現實世界中作為不同依從性患者穩定治療選擇的潛力。

    The treatment of HIV infection requires sustained adherence to antiretroviral therapy (ART) to achieve and maintain viral suppression. Recent advancements have introduced single-tablet regimens (STRs), including three-drug regimens (3DRs) and two-drug regimens (2DRs), to simplify treatment and improve adherence. This thesis analyzes the effectiveness, forgiveness, and adherence of second-generation integrase strand transfer inhibitor (INSTI)-based single-tablet regimens (STRs), particularly focusing on dolutegravir (DTG)-based regimen. The findings reveal that STRs, such as BIC/FTC/TAF, are effective in achieving and maintaining viral suppression in real-world settings. For DTG-based STRs, whether 3DR or 2DR, a population pharmacokinetic analysis was conducted using data from various patient cohorts to evaluate adherence thresholds and the impact of missed doses. An adherence rate of 72.5% for DTG-based regimens is sufficient for viral suppression, even with 1 to 2 missed doses per week. Overall, INSTI based STRs demonstrate good efficacy and forgiveness, highlighting their potential to provide stable treatment for diverse patient profiles in real-world settings.

    Certificate of Approval for Doctoral Dissertation Abstract I 中文摘要 VI Acknowledgments X Table of Contents XI List of Tables XIV List of Figures XV List of Abbreviations XVI Chapter 1. General Introduction 1 1.1. Human Immunodeficiency Virus (HIV) Structure and Function 1 1.2. HIV Treatment 1 1.3. Medication Adherence 7 1.4 Pharmacometrics 13 1.5. Problem Statement 19 1.6. Aims of This Thesis 20 Chapter 2. Outcomes after Switching to BIC/FTC/TAF in Patients with Virological Failure to Protease Inhibitors or Non-Nucleoside Reverse Transcriptase Inhibitors: A Real-World Cohort Study 22 2.1. Abstract 23 2.2. Introduction 24 2.3. Methods 25 2.4. Results 28 2.5. Discussion 31 2.6. Conclusions 34 2.7. References 34 2.8 Tables 39 2.9 Figures 42 Chapter 3. Durability of Single Tablet Regimen for Patients with HIV Infection in Southern Taiwan: Data from a Real-World Setting 44 3.1 Abstract 45 3.2 Background 46 3.3 Methods 47 3.4 Results 50 3.5 Discussion 52 3.6 Conclusion 56 3.7 References 57 3.8 Tables 61 3.9 Figures 65 Chapter 4. Defining Optimal Forgiveness Threshold for Achieving Viral Suppression in Real-World ABC/3TC/DTG Treatment 67 4.1 Abstract 67 4.2 Introduction 68 4.3 Methods 70 4.4 Results 73 4.5 Discussion 76 4.6 Conclusion 79 4.7 References 79 4.8 Tables 83 4.9 Figures. 85 Chapter 5. Evaluating Adherence Cut-off Points for Two-Drug Regimens in HIV Treatment: A Real-World Study of Missed Dose Forgiveness and Viremia 89 5.1 Abstract 89 5.2 Introduction 90 5.3 Methods 91 5.4 Results 95 5.5 Discussion 98 5.6 Conclusion 102 5.7 References 103 5.8 Tables 107 5.9 Figures. 110 Chapter 6. General Conclusion and Future Perspectives 113 6.1. Summary of Studies 113 6.2. Synthesis of findings 114 6.3. Considerations in Pharmacokinetic Modeling 118 6.4. Future work: Genetic Influence 119 6.5. Conclusion 121 References 121 Appendix 1. DTG Population PK Modeling Process in Chapter 4 133 Appendix Figure 1-1. Base Models Tested: Each Sample as a Separate Pharmacokinetic Occasion or Each Subject as a Pharmacokinetic Occasion. 134 Appendix Figure 1-2. Error models tested. 135 Appendix Figure 1-3. Fixed effect parameters and categorical covariates. 136 Appendix Figure 1-4. Fixed effect parameters and continuous covariates. 137 Appendix Figure 1-5. Scatter plots of the relationships between genotypes and DTG AUC0-24 concentrations. 138 Appendix Figure 1-6. Scatter plots of the relationships between genotypes and DTG concentrations at 24 hours. 139 Appendix 2. DTG Population PK Modeling Process in Chapter 5 140 Appendix Figure 2-1. Base Models Tested: Each Sample as a Separate Pharmacokinetic Occasion or Each Subject as a Pharmacokinetic Occasion. 141 Appendix Figure 2-2. Error models tested. 142 Appendix Figure 2-3. Fixed effect parameters and categorical covariates. 143 Appendix Figure 2-4. Fixed effect parameters and continuous covariates. 144 Appendix Figure 2-5. Scatter plots of the relationships between genotypes and DTG AUC0-24 concentrations. 145 Appendix Figure 2-6. Scatter plots of the relationships between genotypes and DTG concentrations at 24 hours. 146

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