臺灣博碩士論文加值系統

第一部 高效能抗反轉錄病毒療法相關之代謝併發症
背景
過去五年中，對於愛滋病毒感染之治療有很大突破。目前主要的治療準則為多種藥物共同治療，即所謂「高效能抗反轉錄病毒療法」，可以明顯減少愛滋病患的死亡率。但這樣的治療卻衍生出一些副作用，如型態改變及代謝異常的情形，這些表現又可稱為「人類免疫不全病毒相關的脂肪分布改變症候群」，病人主要有體脂肪分布改變的情形，並伴隨著高總膽固醇血症、高三酸甘油脂血症、或是葡萄糖耐受性不良的代謝異常情形。雖然目前有許多研究認為，蛋白酶抑制劑是主要引起這些不正常表現的原因，但在沒有接受蛋白酶抑制劑的病患，服用核苷反轉錄酶抑制劑或非核苷反轉錄酶抑制劑，也會有這些型態及代謝異常的表現。
研究目的
了解愛滋病患服用高效能抗反轉錄病毒療法後，病患血中總膽固醇值、三酸甘油脂值、尿酸值、血糖的變化情形。
研究對象
愛滋病患者使用固定的高效能抗反轉錄病毒療法達6個月。
研究方法
回溯性的研究，從西元1997年8月1日至西元2002年12月31日，於成大醫院感染科門診就診之愛滋病患。由病歷收集病患之用藥史及臨床檢驗數據。主要測量結果為高膽固醇血症、高三酸甘油脂血症、高尿酸血症及高血糖之發生率，以及比較病患用藥前與用藥後第3, 6, 12, 18, 24, 30個月時，平均總膽固醇值、三酸甘油脂值、尿酸值及血糖值增加的情形。
結果
本實驗收入100位病患，其中有85位為男性。使用含有蛋白酶抑制劑的病患有61位。在追蹤病患用藥後，血中總膽固醇值、三酸甘油脂值、尿酸值，皆有明顯增加的情形；總膽固醇值在服藥後第30個月，平均增加37 mg/dL (P = 0.018)，三酸甘油脂值在服藥後第18, 30個月，平均增加57 mg/dL, 70 mg/dL (P = 0.001, 0.003)，尿酸值在服藥後第24個月，平均增加2.87 mg/dL。而服藥後血糖值的改變較不明顯；但仍可看出在使用含有蛋白酶抑制劑的病患，其血糖值與尿酸值較沒有使用蛋白酶抑制劑的病患高。
結論
我們發現在愛滋病患者使用高效能抗反轉錄病毒療法後，血中總膽固醇值、三酸甘油脂值及尿酸值皆增加。而回顧過去文獻中，並無提及使用蛋白酶抑制劑的病患會增加血中高尿酸值的表現，因此，需要更進一步的前瞻性實驗，確定這樣表現的臨床顯著性及危險因子為何。此外，對於服用高效能抗反轉錄病毒療法的愛滋病患，應小心監測其血中代謝參數異常情形，並小心追蹤其長時間可能導致的心血管疾病。
第二部 臨床服務-愛滋病患者對於抗反轉錄病毒治療的順服性
背景
愛滋病患者若對高效能抗反轉錄病毒療法有較差的順服性，則會導致嚴重的結果，如無法抑制病毒複製，增加病毒產生抗藥性的風險。評估對於抗反轉錄病毒治療的順服性，平均比例從50%到70%。當病患的藥物順服性小於80%時，大部分的病患即可偵測到血中病毒量。治療順服性可由各種方式測量，每個方法在臨床使用上，都有其優缺點。
服務目的
提供愛滋病患藥事服務，並設計出一套對者藥物順服性的衛教與諮詢模式。
服務對象
在成大醫院感染科門診就診並願意接受藥師諮詢的愛滋病患。
服務方法
從西元2002年1月12日至2002年4月30日，70位愛滋病患接受諮詢。我們使用數藥粒及病患自我評估表，評估病患的藥物順服性。介入增加病患順服性的方法為提供：1.藥物資訊（吃藥時間、如何服用藥物、可能副作用、可能的藥物與藥物或藥物與食物之交互作用； 2. 藥盒； 3. 定期會談; 4. 疾病與藥物的衛教。
服務結果
我們發現有82%的病患藥物順服性達到95%以上，但只有34.3%的病患有準時服用藥物，並有17.1%的病患有用藥錯誤的情形，如頻次錯誤或顆粒數錯誤。大部分藥物順服性差的原因，為病患忘記了或太忙了沒有吃藥。針對病患對於愛滋病及高效能抗反轉錄病毒療法的知識測驗，病患主要不了解的是藥物交互作用及藥物治療目標，並仍有30.9%的病患不了解愛滋病的傳染途徑為何。
經由藥師的介入，明顯增加病患遵守藥物注意事項的比例（P <0.001），並減少病患忘記吃藥的情形（P = 0.008），以及改善病患對疾病與藥物的知識（P = 0.024）。
結論
當我們愈來愈了解藥物順服性不佳原因的同時，應在病患尚未開始使用高效能抗反轉錄病毒療法治療前，提供其教育與支持性的諮詢；在病患的疾病病程尚未急需治療時，高效能抗反轉錄病毒療法必須在病患已有充足準備時，再開始治療。而藥師在門診的愛滋病患中扮演很重要的角色，因為藉由藥師臨床藥事服務，增加病患對於複雜度極高的高效能抗反轉錄病毒療法之順服性。

Part 1. Highly active-retroviral therapy related metabolic complications
Background
Treatment of human immunodeficiency virus (HIV) infection has evolved dramatically during the past 5 years. Standard care with potent multidrug regimens has resulted in reduced morbidity and mortality among persons with HIV infection. Such advances, however, have been tempered by a body of reports of adverse events associated with highly active antiretroviral therapy (HAART). Of particular concern is the emergence of morphologic and metabolic abnormalities, often referred as HIV-related lipodystrophy syndrome. The HIV-related lipodystrophy syndrome is characterized by sustained changes in body fat distribution, often accompanied by metabolic disturbances such as hypercholesterolemia, hypertriglyceridemia and impaired blood glucose tolerance. Although many researches clearly suggest a role of protease inhibitors in the etiology of the HIV-related lipodystrophy syndrome, it can be observed in PI-naïve patients taking nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors.
Objective
To examine the temporal trends in serum total cholesterol, triglyceride, uric acid and glucose levels after initiation of HAART in HIV-infected patients.
Subjects
HIV-infected patients with a fixed HAART regimen for a minimum of 6 months.
Methods
We investigated retrospectively, among of HIV-infected patients followed in the outpatient clinic of Infectious Diseases, in National Cheng Kung University Hospital, from August 1 1997 through December 31 2002. Medical history, clinical and laboratory data were retrieved from medical records. The main outcome measure was the prevalence of hypercholesterolemia, hypertriglyceridemia, hyperuricemia, and hyperglycemia and the changes in serum total cholesterol, triglyceride, uric acid, and glucose levels from baseline levels at month 3, 6, 12, 18, 24, and 30 after the initiation of HAART.
Results
The study consisted of 100 patients, of whom 85 were male. A total of 61 patients received PIs containing regimen. Serum levels of total cholesterol, triglyceride and uric acid increased markedly during follow-up period. Total cholesterol increased by 37 mg/dL (P = 0.018) at month 30; Triglyceride increased by 57 mg/dL and 70 mg/dL (P = 0.001, 0.003) at month 18 and 30. Uric acid increased by 2.87 mg/dL at month 24 after the initiation of HAART. However, the changes of serum glucose levels were insignificant. The upsurges of serum uric acid and glucose in PI-treated patients were greater than those in PI-naïve patients.
Conclusion
We found there were increased levels of total cholesterol, triglyceride and uric acid in HIV-infected patients after using HAART. The patients who treated with PIs have a greater increase in serum uric acid levels, which is not mentioned in published articles. It deserves more prospective studies to reveal its clinical significance and associated risk factors. Patient with HIV infection on HAART should be monitored for metabolic disarrangements and carefully followed for possible long-term cardiovascular risk.
Part 2. Clinical service: Adherence to antiretroviral therapy in
HIV-infected patients
Background
Poor adherence to highly active antiretroviral therapy (HAART) has serious consequences for HIV-infected patients, including failure to prevent viral replication and an increased risk of developing viral resistance. Estimates of average rates of nonadherence to antiretroviral therapy range from 50% to 70%. Adherence rates of <80% are associated with a detectable viremia in a majority of patients. Treatment adherence can be measured by use of a variety of methods and these measures of adherence have different strengths and weaknesses in regard to practical application and identifying deficient adherence.
Objective
To provide pharmaceutical care and develop a medication adherence program providing education and counseling for HIV-infected patients.
Subjects
HIV-1 infected patients who agree to receive pharmacist’s counseling in the Infectious Diseases clinic, NCKUH.
Methods
From January 12, 2002 to April 30, 2002. Seventy HIV-infected patients were consulted. We estimated adherence by pill count and self-report form. The interventions contain medication information (organized medication administration schedules, how to take the drug, possible adverse effects, possible drug-drug interaction or drug-food interaction), drug boxes, appointment, education and counseling on HAART.
Results
We found 82% of patients reported >95% adherence. However, only 34.3% of patients followed the dosing schedule. Incorrect medication use in dosing frequency or pill numbers were found in 17.1% of patients. The most common reasons for nonadherence were that they forgot or were busy. As for the relevant knowledge of HIV disease and HAART, the majority of patients did not understand the drug interactions and the goal of HAART. There were 30.9% of patients had no idea about the transmission routes of HIV.
The pharmacist-led intervention significantly increase numbers of patients that followed prescribing order (P <0.001) and decrease numbers of patients skipped taking pills (P = 0.008) and improve patients’ knowledge of HIV disease and HAART (P = 0.024).
Conclusion
With the knowledge of the causes of nonadherence, it is vital to educate and offer supportive counseling, preferably before the initiation of HAART. “Start when the patient is ready” is the first consideration when patients’ disease progression is not emergent. Pharmacists play an important role in the outpatient care of HIV-infected patients by providing pharmaceutical care to ensure the patient adherence to complex treatment regimens.

中文摘要 I
英文摘要 V
縮寫表 X
目錄 XI
表目錄 XVI
圖目錄 XIX
第一部高效能抗反轉錄病毒療法相關之代謝併發症
第一章研究背景.. 1
第二章文獻回顧.. 4
第一節研究方法.. 4
第二節愛滋病患之高血脂症或血脂異常..5
2.1 高血脂症之特性、預測因子和盛行率..5
2.1.1 高血脂症和HIV 感染的相關性..5
2.1.2 高血脂症和HAART的相關性..5
2.1.2.1 蛋白酶抑制劑 ... 6
2.1.2.2 核酶反轉錄酶抑制劑... 7
2.1.2.3 非核酶反轉錄酶抑制劑... 8
2.1.3 高血脂症和其他影響因子.. 9
2.1.4 高血脂症的盛行率與發生率..9
2.2 高血脂症發生機轉.. 11
2.3 高血脂症之處理
2.3.1 評估病人風險與治療目標.. 15
2.3.1.1 風險評估.. 15
2.3.1.2 治療目標與時機.. 16
2.3.2 高血脂症之治療.. 17
2.3.2.1 非藥物治療.. 17
2.3.2.2 其他藥物取代治療... 17
2.3.2.2.1 持續病毒抑制的安全性..18
2.3.2.2.2 藥物順服性及副作用..19
2.3.2.2.3 血脂異常..19
2.3.2.3 藥物治療 .. 20
2.3.2.3.1 高膽固醇血症及高三酸甘油脂血症..20
2.3.2.4 結論.. 22
第三節葡萄糖代謝疾病.. 23
3.1 糖尿病、胰島素抗性或葡萄糖耐受不良的發生率.. 23
3.1.1 糖尿病發生率.. 23
3.1.2 胰島素抗性或葡萄糖耐受不良之發生率.. 24
3.1.3 b-細胞功能和HIV..25
3.1.4 使用PIs 和葡萄糖不正常代謝之相關性.. 26
3.1.5 不同的PIs 影響葡萄糖代謝的差異性..27
3.2 PIs 相關的胰島素抗性及糖尿病發生機轉.. 29
3.3 胰島素抗性之處理..31
3.3.1 評估病人.. 31
3.3.2 治療.. 31
3.3.2.1 生活型態改變..31
3.3.2.2 取代藥物治療.. 32
3.3.2.3 藥物治療.. 32
第四節脂肪分布改變症候群之各症狀的相關性.. 34
第五節HIV 治療與冠狀動脈心臟疾病（coronary heart disease)..36
5.1 冠狀動脈心臟疾病..36
5.2 動脈粥狀硬化（atherosclerosis).. 38
5.3 結論..39
第三章研究目的.. 40
第四章研究方法.. 41
第一節研究對象.. 41
第二節數據收集.. 41
第三節統計分析.. 41
3.1 結果之定義.. 41
3.2 分析方法.. 42
3.2.1 統計學模式設定.. 42
3.2.2 資料分析.. 42
3.3 統計軟體.. 43
第五章結果.. 44
第一節病患特性.. 44
第二節血中總膽固醇的變化.. 45
2.1 用藥後發生高膽固醇血症的比例.. 45
2.2 病患服藥前後總膽固醇變化.. 45
2.3 使用PIs 與沒有使用PIs 的病患用藥後總膽固醇值之差異..46
第三節血中三酸甘油脂的變化.. 46
XIV
3.1 用藥後發生高三酸甘油脂血症的比例.. 46
3.2 病患服藥前後三酸甘油脂變化.. 46
3.3 使用PIs 與沒有使用PIs 的病患用藥後三酸甘油脂值之差異..47
第四節血中尿酸的變化.. 47
4.1 用藥後發生高尿酸血症的比例.. 47
4.2 病患服藥前後尿酸變化.. 47
4.3 使用PIs 與沒有使用PIs 的病患用藥後尿酸值之差異.. 48
第五節血糖的變化.. 48
5.1 用藥後發生高血糖的比例.. 48
5.2 病患服藥前後血糖變化.. 48
5.3 使用PIs 與沒有使用PIs 的病患用藥後血糖值之差異..49
第六章討論.. 50
第一節總膽固醇變化.. 50
第二節三酸甘油脂變化.. 50
第三節尿酸變化.. 51
第四節血糖變化.. 52
第五節研究限制與未來研究.. 53
第七章結論.. 54
第一部參考文獻..103
第二部臨床實習-愛滋病患者對於抗反轉錄病毒治療的順服性
第一章背景.. 118
第一節藥物順服性的測量方式.. 119
第二節藥物順服性與病毒量及臨床治療結果的相關性.. 121
第三節臨床上愛滋病患者之藥物順服性.. 122
第四節加強病患藥物順服性的方法.. 123
4.1 藥物順服性的影響因子.. 123
4.1.1 病人特性及藥物順服性.. 123
4.1.2 藥物療程的特性和藥物順服性.. 123
4.1.3 臨床照顧系統.. 124
第五節結論.. 125
第二章服務目的.. 126
第三章服務方法.. 127
第四章結果.. 129
第五章討論.. 132
第六章結論.. 140
第二部參考文獻..157
附錄..161
<表1-1 > 抗反轉錄病毒藥物種類.. 55
<表1-2 > 愛滋病感染者的血脂變化..56
<表1-3 > 蛋白? 抑制劑和血脂異常之相關的longitudinal研究.. 57
<表1-4 > 愛滋病患處理血脂異常和心血管疾病風險之考量.. 58
<表1-5 > 冠狀動脈心臟疾病的其他危險因子.. 59
<表1-6 > Framingham point scores 評估10 年心血管疾病（男性).. 60
<表1-7 > Framingham point scores 評估10 年心血管疾病（女性).. 61
<表1-8 > NCEP ATP III中脂質高低的分類.. 62
<表1-9 > 不同程度的危險因子之治療目標.. 63
<表1-10 > 診斷代謝症狀的標準.. 64
<表1-11 > 高血脂治療時機與目標.. 65
<表1-12 > 取代藥物- Abacavir..66
<表1-13 > 取代藥物-Efavirenz..67
<表1-14 > 取代藥物-Nevirapine.. 68
<表1-15 > statins 藥品與HAART 的交互作用..69
<表1-16 > 愛滋病患使用降血脂藥物..70
<表1-17 > 愛滋病患者服用降血脂藥物的選擇..72
<表1-18 > 處理愛滋病患高血脂之考量..73
<表1-19 > 除PIs 外使用於愛滋病患可能引起葡萄糖代謝異常的藥品.. 74
<表1-20 > 第二型糖尿病主要危險因子.. 75
<表1-21 > 糖尿病的診斷標準.. 76
<表1-22 > 降血糖藥品與抗反轉錄病毒藥物之交互作用.. 77
<表1-23 > HIV 感染者使用HAART可能導致心血管疾病的危險因子..78
<表1-24 > 所有病人特性之基礎值.. 79
<表1-25 > 比較使用PIs 和沒有使用PIs 的病人特性之基礎值.. 80
<表1-26 > 使用抗反轉錄病毒藥物的分佈情形.. 81
<表1-27 > 比較使用PIs 和沒有使用PIs 病人用藥後發生高膽固醇血症..82
<表1-28 > 所有病人用藥前後血中總膽固醇值的比較.. 83
<表1-29 > 使用PIs 的病患用藥前後血中血中總膽固醇值的比較.. 83
<表1-30 > 沒有使用PIs 的病患用藥前後血中血中總膽固醇值的比較.. 83
<表1-31 > 比較使用PIs 與沒有使用PIs 病人的血中總膽固醇值..84
<表1-32 > 比較使用PIs 和沒有使用PIs 病人用藥後發生高三酸甘油脂血症
的比例.. 85
<表1-33 > 所有病人用藥前後血中高三酸甘油脂值的比較.. 86
<表1-34 > 使用PIs 的病患用藥前後血中高三酸甘油脂值的比較.. 86
<表1-35 > 沒有使用PIs 的病患用藥前後血中高三酸甘油脂值的比較.. 86
<表1-36 > 比較使用PIs 與沒有使用PIs 病人的血中三酸甘油脂值..87
<表1-37 > 比較使用PIs 和沒有使用PIs 病人用藥後發生高尿酸血症的比例..88
<表1-38 > 所有病人用藥前後血中尿酸值的比較.. 89
<表1-39 > 使用PIs 的病患用藥前後血中尿酸值的比較.. 89
<表1-40 > 沒有使用PIs 的病患用藥前後血中尿酸值的比較.. 89
<表1-41 > 比較使用PIs 與沒有使用PIs 病人的血中尿酸值..90
<表1-42 > 比較使用PIs 和沒有使用PIs 病人用藥後發生高血糖的比例.. 91
<表1-43 > 所有病人用藥前後血糖值的比較.. 92
<表1-44 > 使用PIs 的病患用藥前後血糖值的比較.. 92
<表1-45 > 沒有使用PIs 的病患用藥前後血糖值的比較.. 92
<表1-46 > 比較使用PIs 與沒有使用PIs 病人的血糖值.. 93
<表1-47 > 病患服藥後病毒量的變化.. 94
<表2-1 > 測量病患服藥順從性方法之優缺點.. 142
<表2-2 > 愛滋病患藥物順服性不佳的主要因素.. 143
<表2-3 > 藥師臨床服務內容.. 144
<表2-4 > 病患特性.. 145
<表2-5 > 病患用藥特性.. 146
<表2-6 > 病患使用抗反轉錄病毒藥物之分佈情形..147
<表2-7 > 病患使用抗反轉錄病毒療程分布情形..148
<表2-8 > 衛教前後病患用藥情形..149
<表2-9 > 衛教前後病患藥物順服性之情形..150
<表2-10 > 造成病患沒有按時吃藥的原因.. 151
<表2-11 > 病患服藥後最常發生的症狀.. 152
<表2-12 > 衛教前後病患疾病與用藥知識測驗答對題數... 153
<表2-13 > 衛教前病患疾病與用藥知識測驗之分析.. 153
圖目錄
<圖1-1 > 影響愛滋病患血脂異常的可能原因.. 95
<圖1-2 > PIs 引起脂肪分布改變及血脂異常的可能機轉.. 96
<圖1-3 > PIs 在HepG2細胞中對apoprotein B的影響..97
<圖1-4 > PIs 引起脂質異常的可能機轉.. 98
<圖1-5 > SREBP-1C 在體內可能影響的代謝路徑.. 99
<圖1-6 > 胰島素抗性產生之可能機轉.. 100
<圖1-7 > 嘌呤核? 酸的降解過程... 101
<圖1-8 > Didanosine 的結構式與體內尿酸形成過程.. 102
<圖2-1 > 病患自我評估藥物順服性與愛滋病毒量抑制情形.. 154
<圖2-2 > 藥歷回顧評估藥物順服性與愛滋病毒抑制情形..154
<圖2-3 > 電子監測藥瓶MEMS 評估藥物順服性與愛滋病毒量抑制情形.. 154
<圖2-4 > 忘記吃藥的原因.. 155
<圖2-5 > 病患自我評估與電子監測藥瓶兩種藥物順服性的評估方式與愛
滋病毒量抑制情形..156

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