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.

1. Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men-New York
City and California. MMWR Weekly 1981; 30:305-308.
2. Hymes KB, Cheung T, Greene JB, et al. Kaposi's sarcoma in homosexual men-a
report of eight cases. Lancet 1981; 2:598-600.
3. Current trends update on acquired immune deficiency syndrome (AIDS)- United
States. MMWR 1982; 31:507-508, 513-514.
4. Coffin J HA, Levy JA, Montagnier L, Oroszlan S and Teich N, et. al. What to call the AIDS virus. Nature 1986; 321:10.
5. Palella FJ, Jr., Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853-60.
6. Heath KV, Hogg RS, Singer J, Chan KJ, O'Shaughnessy MV, Montaner JS.
Antiretroviral treatment patterns and incident HIV-associated morphologic and
lipid abnormalities in a population-based chort. J Acquir Immune Defic Syndr 2002;30:440-7.
7. Mooser V, Carr A. Antiretroviral therapy-associated hyperlipidaemia in HIV
disease. Curr Opin Lipidol 2001; 12:313-9.
8. Stein JH. Dyslipidemia in the era of HIV protease inhibitors. Prog Cardiovasc Dis 2003; 45:293-304.
9. Constans J, Pellegrin JL, Peuchant E, et al. Plasma lipids in HIV-infected patients: a prospective study in 95 patients. Eur J Clin Invest 1994; 24:416-20.
10. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Lipids,lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992; 74:1045-52.
11. Thiebaut R, Dequae-Merchadou L, Ekouevi DK, et al. Incidence and risk factors of severe hypertriglyceridaemia in the era of highly active antiretroviral therapy: the Aquitaine Cohort, France, 1996-99. HIV Med 2001; 2:84-8.
12. Fellay J, Boubaker K, Ledergerber B, et al. Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study. Lancet 2001; 358:1322-7.
13. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy,
hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.AIDS 1998; 12:F51-8.
14. Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell
function and lipid metabolism in HIV patients under treatment with protease
104 inhibitors. AIDS 1999; 13:F63-70.
15. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA.
Diagnosis, prediction, and natural course of HIV-1 protease- inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999;353:2093-9.
16. Churchill DR, Pym AS, Babiker AG, Back DJ, Weber JN. Hyperlipidaemia
following treatment with protease inhibitors in patients with HIV-1 infection. Br J Clin Pharmacol 1998; 46:518-9.
17. Danner SA, Carr A, Leonard JM, et al. A short-term study of the safety,
pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease.
European-Australian Collaborative Ritonavir Study Group. N Engl J Med 1995;
333:1528-33.
18. Roberts AD, Muesing RA, Parenti DM, Hsia J, Wasserman AG, Simon GL.
Alterations in serum levels of lipids and lipoproteins with indinavir therapy for human immunodeficiency virus-infected patients. Clin Infect Dis 1999; 29:441-3.
19. Berthold HK, Parhofer KG, Ritter MM, et al. Influence of protease inhibitor therapy on lipoprotein metabolism. J Intern Med 1999; 246:567-75.
20. Segerer S, Bogner JR, Walli R, Loch O, Goebel FD. Hyperlipidemia under
treatment with proteinase inhibitors. Infection 1999; 27:77-81.
21. Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV- infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation 1999; 100:700-5.
22. Purnell JQ, Zambon A, Knopp RH, et al. Effect of ritonavir on lipids and
post-heparin lipase activities in normal subjects. AIDS 2000; 14:51-7.
23. Noor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001; 15:F11-8.
24. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5- year cohort study. Arch Intern Med 2000; 160:2050-6.
25. Thiebaut R, Dabis F, Malvy D, Jacqmin-Gadda H, Mercie P, ValentinVd. Serum
triglycerides, HIV infection, and highly active antiretroviral therapy, Aquitaine Cohort, France, 1996 to 1998. Groupe d'Epidemiologie Clinique du Sida en Aquitaine (GECSA). J Acquir Immune Defic Syndr 2000; 23:261-5.
26. Vergis EN, Paterson DL, Wagener MM, Swindells S, Singh N. Dyslipidaemia in
HIV- infected patients: association with adherence to potent antiretroviral therapy. Int J STD AIDS 2001; 12:463-8.
27. Saint-Marc T, Partisani M, Poizot-Martin I, et al. Fat distribution evaluated by 105 computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS 2000;14:37-49.
28. Walli R, Herfort O, Michl GM, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients. AIDS 1998; 12:F167-73.
29. Rojas C CP, Rhodes T, Robertson MN, DiNubile MJ and Cuess HA. Indinavir did
not further increase mean triglyceride levels in HIV-infected patients treated with nucleoside reverse transcriptase inhibitors: an analysis of three randomized clinical trials. Pharmacoepidemiology and drug safety (in press) 2003.
30. Haubrich R, Thompson M, Schooley R, et al. A phase II safety and efficacy study of amprenavir in combination with zidovudine and lamivudine in HIV- infected patients with limited antiretroviral experience. Amprenavir PROAB2002 Study Team. AIDS 1999; 13:2411-20.
31. Murphy RL, Gulick RM, DeGruttola V, et al. Treatment with amprenavir alone or amprenavir with zidovudine and lamivudine in adults with human
immunodeficiency virus infection. AIDS Clinical Trials Group 347 Study Team. J
Infect Dis 1999; 179:808-16.
32. Scott T, Garris C, Rogers M, Graham N, Garrett L, Pedneault L. Safety profile and tolerability of amprenavir in patients enrolled in an early access program. Clin Ther 2001; 23:252-9.
33. Saint-Marc T, Partisani M, Poizot-Martin I, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999; 13:1659-67.
34. Galli M, Ridolfo AL, Adorni F, et al. Body habitus changes and metabolic
alterations in protease inhibitor-naive HIV-1-infected patients treated with two nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr 2002; 29:21-31.
35. Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1- infected patients: results of a substudy from a comparative trial. AIDS 2002; 16:2447-54.
36. Rakotoambinina B, Medioni J, Rabian C, Jubault V, Jais JP, Viard JP.
Lipodystrophic syndromes and hyperlipidemia in a cohort of HIV-1-infected
patients receiving triple combination antiretroviral therapy with a protease inhibitor. J Acquir Immune Defic Syndr 2001; 27:443-9.
37. Bonnet F, Bonarek M, De Witte S, Beylot J, Morlat P. Efavirenz-associated severe hyperlipidemia. Clin Infect Dis 2002; 35:776-7.
106
38. Garcia-Benayas T, Blanco F, de la Cruz JJ, et al. Role of nonnucleosides in the development of HAART-related lipid disturbances. J Acquir Immune Defic Syndr 2001; 28:496-8.
39. Doser N, Sudre P, Telenti A, et al. Persistent dyslipidemia in HIV- infected individuals switched from a protease inhibitor-containing to an
efavirenz-containing regimen. J Acquir Immune Defic Syndr 2001; 26:389-90.
40. van der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing
antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS 2001; 15:2407-14.
41. Roberts AD, Liappis AP, Chinn C, et al. Effect of delavirdine on plasma lipids and lipoproteins in patients receiving antiretroviral therapy. AIDS 2002; 16:1829-30.
42. Gervasoni C, Ridolfo AL, Trifiro G, et al. Redistribution of body fat in
HIV-infected women undergoing combined antiretroviral therapy. AIDS 1999;
13:465-71.
43. Dong KL, Bausserman LL, Flynn MM, et al. Changes in body habitus and serum
lipid abnormalities in HIV-positive women on highly active antiretroviral therapy (HAART). J Acquir Immune Defic Syndr 1999; 21:107-13.
44. Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1-protease
inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin
resistance. Lancet 1998; 351:1881-3.
45. Carr A. HIV protease inhibitor-related lipodystrophy syndrome. Clin Infect Dis 2000; 30 Suppl 2:S135-42.
46. Distler O, Cooper DA, Deckelbaum RJ, Sturley SL. Hyperlipidemia and inhibitors of HIV protease. Curr Opin Clin Nutr Metab Care 2001; 4:99-103.
47. Miserez AR, Muller PY, Spaniol V. Indinavir inhibits sterol-regulatory
element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase
gene activations. AIDS 2002; 16:1587-94.
48. Dube MP, Sprecher D, Henry WK, et al. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin Infect Dis 2000; 31:1216-24.
49. Currier JS. Cardiovascular risk associated with HIV therapy. J Acquir Immune Defic Syndr 2002; 31 Suppl 1:S16-23; discussion S24-5.
50. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143-421.
51. Jones SP, Doran DA, Leatt PB, Maher B, Pirmohamed M. Short-term exercise
training improves body composition and hyperlipidaemia in HIV-positive
individuals with lipodystrophy. AIDS 2001; 15:2049-51.
52. Barrios A, Blanco F, Garcia-Benayas T, et al. Effect of dietary intervention on highly active antiretroviral therapy-related dyslipemia. AIDS 2002; 16:2079-81.
53. Drechsler H, Powderly WG. Switching effective antiretroviral therapy: a review. Clin Infect Dis 2002; 35:1219-30.
54. Barreiro P, Soriano V, Blanco F, Casimiro C, de la Cruz JJ, Gonzalez- Lahoz J. Risks and benefits of replacing protease inhibitors by nevirapine in HIV- infected subjects under long-term successful triple combination therapy. AIDS 2000;14:807-12.
55. Ruiz L, Negredo E, Do mingo P, et al. Antiretroviral treatment simplification with nevirapine in protease inhibitor-experienced patients with hiv-associated lipodystrophy: 1- year prospective follow-up of a multicenter, randomized, controlled study. J Acquir Immune Defic Syndr 2001; 27:229-36.
56. Clumeck N, Goebel F, Rozenbaum W, et al. Simplification with abacavir-based
triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. AIDS 2001; 15:1517-26.
57. Opravil M, Hirschel B, Lazzarin A, et al. A randomized trial of simplified
maintenance therapy with abacavir, lamivudine, and zidovudine in human
immunodeficiency virus infection. J Infect Dis 2002; 185:1251-60.
58. lafeuillade A MJ, Cheret A, et al. Comparison of the metabolic disorders and clinical lipodystrophy 48 weeks after switching from highly active antiretroviral therapy to Trizizvir versus continued highly acitve antiretroviral therpay. Antiviral Therapy 2001; 6.
59. Knechten H, Sturner KH, Hohn C, Braun P. Switch to efavirenz in a protease
inhibitor-containing regimen. HIV Clin Trials 2001; 2:200-4.
60. Estrada V, De Villar NG, Larrad MT, Lopez AG, Fernandez C, Serrano-Rios M.
Long-term metabolic consequences of switching from protease inhibitors to
efavirenz in therapy for human immunodeficiency virus- infected patients with
lipoatrophy. Clin Infect Dis 2002; 35:69-76.
61. Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long- lasting viral suppression. Clin Infect Dis 2002; 34:504-10.
62. Moyle GJ, Buss NE, Gazzard BG. Pravastatin does not alter protease inhibitor 108 exposure or virologic efficacy during a 24-week period of therapy. J Acquir Immune Defic Syndr 2002; 30:460-2.
63. Doser N, Kubli S, Telenti A, et al. Efficacy and safety of fluvastatin in
hyperlipidemic protease inhibitor-treated HIV- infected patients. AIDS 2002;
16:1982-3.
64. Palacios R, Santos J, Gonzalez M, et al. Efficacy and safety of atorvastatin in the treatment of hypercholesterolemia associated with antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 30:536-7.
65. Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of HMG-CoA reductase
inhibitors for treatment of hyperlipidemia in patients with HIV infection.
Pharmacotherapy 2000; 20:1066-71.
66. Henry K, Melroe H, Huebesch J, Hermundson J, Simpson J. Atorvastatin and
gemfibrozil for protease-inhibitor-related lipid abnormalities. Lancet 1998;
352:1031-2.
67. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation 1992; 85:37-45.
68. Green ML. Evaluation and management of dyslipidemia in patients with HIV
infection. J Gen Intern Med 2002; 17:797-810.
69. Dever LL, Oruwari PA, Figueroa WE, O'Donovan CA, Eng RH. Hyperglycemia
associated with protease inhibitors in an urban HIV- infected minority patient
population. Ann Pharmacother 2000; 34:580-4.
70. Visnegarwala F, Krause KL, Musher DM. Severe diabetes associated with protease inhibitor therapy. Ann Intern Med 1997; 127:947.
71. Dube MP, Johnson DL, Currier JS, Leedom JM. Protease inhibitor-associated
hyperglycaemia. Lancet 1997; 350:713-4.
72. Lumpkin MM. Reports of diabetes and hyperglycemia in patients receiving
protease inhibitors for the treatment of huma n immunodeficiency virus(HIV). FDA Public Health Advisory. Waschington, DC: US Food and Drug Administration
1997.
73. Mulligan K, Grunfeld C, Tai VW, et al. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr 2000; 23:35-43.
74. Yarasheski KE, Tebas P, Sigmund C, et al. Insulin resistance in HIV protease inhibitor-associated diabetes. J Acquir Immune Defic Syndr 1999; 21:209-16.
75. Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, Grinspoon S. Fasting
hyperinsulinemia and changes in regional body composition in human
109 immunodeficiency virus-infected women. J Clin Endocrinol Metab 1999;
84:1932-7.
76. Hadigan C, Corcoran C, Stanley T, Piecuch S, Klibanski A, Grinspoon S. Fasting hyperinsulinemia in human immunodeficiency virus- infected men: relationship to body composition, gonadal function, and protease inhibitor use. J Clin Endocrinol Metab 2000; 85:35-41.
77. Shikuma CM, Waslien C, McKeague J, et al. Fasting hyperinsulinemia and
increased waist-to-hip ratios in non-wasting individuals with AIDS. AIDS 1999;
13:1359-65.
78. Dube MP. Disorders of glucose metabolism in patients infected with human
immunodeficiency virus. Clin Infect Dis 2000; 31:1467-75.
79. Kaul DR, Cinti SK, Carver PL, Kazanjian PH. HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications.
Pharmacotherapy 1999; 19:281-98.
80. Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS 1999; 13:805-10.
81. Justman JE, Benning L, Danoff A, et al. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women. J Acquir Immune Defic Syndr 2003; 32:298-302.
82. Akinmokun A SP, Ramaiya K, et al. The short insuoin tolerance test for
determination of insulin sensitivity: a comparison with the euglycemic clamp.
Diabet Med 1992; 9:423-7.
83. Dube MP, Edmondson-Melancon H, Qian D, Aqeel R, Johnson D, Buchanan TA.
Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV- infected patients. J Acquir Immune Defic Syndr 2001; 27:130-4.
84. Dube MP AR, Edmondson-Melancon H, et al. Effect of initiation indinavir therapy on glucose metabolism in HIV patients under treatment with protease inhibitors. Antiviral Therapy 1999; 4:34.
85. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000; 275:20251-4.
86. Uzzan B, Bentata M, Campos J, et al. Effects of aerosolized pentamidine on
glucose homeostasis and insulin secretion in HIV-positive patients: a controlled study. AIDS 1995; 9:901-7.
87. Perronne C, Bricaire F, Leport C, Assan D, Vilde JL, Assan R. Hypoglycaemia and diabetes mellitus following parenteral pentamidine mesylate treatment in AIDS 110 patients. Diabet Med 1990; 7:585-9.
88. Kilby JM, Tabereaux PB. Severe hyperglycemia in an HIV clinic: preexisting
versus drug-associated diabetes mellitus. J Acquir Immune Defic Syndr Hum
Retrovirol 1998; 17:46-50.
89. Chidiac C, Alfandari S, Caron J, Mouton Y. Diabetes mellitus following treatment of AIDS with didanosine. AIDS 1995; 9:215-6.
90. Vittecoq D, Zucman D, Auperin I, Passeron J. Transient insulin-dependent diabetes mellitus in an HIV- infected patient receiving didanosine. AIDS 1994; 8:1351.
91. Munshi MN, Martin RE, Fonseca VA. Hyperosmolar nonketotic diabetic syndrome
following treatment of human immunodeficiency virus infection with didanosine.
Diabetes Care 1994; 17:316-7.
92. Hommes MJ, Romijn JA, Endert E, Eeftinck Schattenkerk JK, Sauerwein HP.
Insulin sensitivity and insulin clearance in human immunodeficiency virus- infected men. Metabolism 1991; 40:651-6.
93. Modest GA, Fuller J. Abacavir and diabetes. N Engl J Med 2001; 344:142-4.
94. Hellerstein MK, Grunfeld C, Wu K, et al. Increased de novo hepatic lipogenesis in human immunodeficiency virus infection. J Clin Endocrinol Metab 1993; 76:559-65.
95. Tanwani LK, Mokshagundam SL. Lipodystrophy, insulin resistance, diabetes
mellitus, dyslipidemia, and cardiovascular disease in human immunodeficiency
virus infection. South Med J 2003; 96:180-8; quiz 189.
96. Kelley DE, Goodpaster BH. Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance. Diabetes Care 2001; 24:933-41.
97. Nolte LA, Yarasheski KE, Kawanaka K, Fisher J, Le N, Holloszy JO. The HIV
protease inhibitor indinavir decreases insulin- and contraction-stimulated glucose transport in skeletal muscle. Diabetes 2001; 50:1397-401.
98. Duong M, Petit JM, Piroth L, et al. Association between insulin resistance and hepatitis C virus chronic infection in HIV- hepatitis C virus-coinfected patients undergoing antiretroviral therapy. J Acquir Immune Defic Syndr 2001; 27:245-50.
99. Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC. Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr 2000; 25:312-21.
100. Koda-Kimble MA CB. Diabetes Mellitus. In: Mary Anne Koda-Kimble LYY, ed.
Applied Therapeutics. Vol. 48. Philadelphis, 2000:48-1.
101. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA.2000; 284:472-7.
102. Saint-Marc T, Touraine JL. Effects of metformin on insulin resistance and centraladiposity in patients receiving effective protease inhibitor therapy. AIDS 1999;13:1000-2.
103. Arioglu E, Duncan-Morin J, Sebring N, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 2000; 133:263-74.
104. Gelato M MD, McNurlan MA. Rosiglitazone mediated restoration of subcutaneous fat and improvement in insulin sensitivity in HIV-associated lipodystrophy. J Invest Med 2002; 50:177A.
105. Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr 2002;31:257-75.
106. Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 2000;14:F25-32.
107. Madge S, Kinloch-de-Loes S, Mercey D, Johnson MA, Weller IV. Lipodystrophy in patients naive to HIV protease inhibitors. AIDS 1999; 13:735-7.
108. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999;354:1112-5.
109. Saint-Marc T, Touraine JL. The effects of discontinuing stavudine therapy on clinical and metabolic abnormalities in patients suffering from lipodystrophy. AIDS 1999; 13:2188-9.
110. Behrens G, Schmidt H, Meyer D, Stoll M, Schmidt RE. Vascular complications
associated with use of HIV protease inhibitors. Lancet 1998; 351:1958.
111. Henry K, Melroe H, Huebsch J, et al. Severe premature coronary artery disease with protease inhibitors. Lancet 1998; 351:1328.
112. Vittecoq D, Escaut L, Monsuez JJ. Vascular complications associated with use of HIV protease inhibitors. Lancet 1998; 351:1959.
113. Eriksson U, Opravil M, Amann FW, Schaffner A. Is treatment with ritonavir a risk factor for myocardial infarctio n in HIV-infected patients? AIDS 1998; 12:2079-80.
114. Flynn TE, Bricker LA. Myocardial infarction in HIV- infected men receiving
protease inhibitors. Ann Intern Med 1999; 131:548.
115. Muise A, Arbess G. The risk of myocardial infarction in HIV-infected patients 112 receiving HAART: a case report. Int J STD AIDS 2001; 12:612-3.
116. Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardiovascular and
cerebrovascular events in patients treated for human immunodeficiency virus
infection. N Engl J Med 2003; 348:702-10.
117. Maggi P, Serio G, Epifani G, et al. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS 2000; 14:F123-8.
118. Depairon M, Chessex S, Sudre P, et al. Premature atherosclerosis in HIV- infected individuals--focus on protease inhibitor therapy. AIDS 2001; 15:329-34.
119. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol
1997; 146:483-94.
120. Chimowitz MI, Weiss DG, Cohen SL, Starling MR, Hobson RW, 2nd. Cardiac
prognosis of patients with carotid stenosis and no history of coronary artery disease. Veterans Affairs Cooperative Study Group 167. Stroke 1994; 25:759-65.
121. Stein JH, Klein MA, Bellehumeur JL, et al. Use of human immunodeficiency
virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 2001; 104:257-62.
122. Fischbach F. Manual of laboratory and diagnostic tests. Philadelphia: Lippincott, 1999:396.
123. Yarchoan R, Mitsuya H, Thomas RV, et al. In vivo activity against HIV and
favorable toxicity profile of 2',3'-dideoxyinosine. Science 1989; 245:412-5.
124. Dolin R, Lambert JS, Morse GD, et al. 2',3'-Dideoxyinosine in patients with AIDS or AIDS-related complex. Rev Infect Dis 1990; 12 Suppl 5:S540-9; discussion S549-51.
125. Connolly KJ, Allan JD, Fitch H, et al. Phase I study of 2'-3'-dideoxyinosine administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine. Am J Med 1991; 91:471-8.
126. Back DJ, Ormesher S, Tjia JF, Macleod R. Metabolism of 2',3'-dideoxyinosine (ddI)in human blood. Br J Clin Pharmacol 1992; 33:319-22.
127. Devlin TM. textbook of biochemistry with clinical correlations. In: G.Cory J, ed.Purine and pyrimidine nucleotide metabolism. Vol. 12. New York: Wiley-Liss,1997:502.
128. Nadler RB, Rubenstein JN, Eggener SE, Loor MM, Smith ND. The etiology of
urolithiasis in HIV infected patients. J Urol 2003; 169:475-7.
129. Currier J, Carpenter C, Daar E, Kotler D, Wanke C. Identifying and managing morphologic complications of HIV and HAART. AIDS Read 2002; 12:114-9,
124-5.
130. Lien WP, Lai LP, Shyu KG, et al. Low-serum, high-density lipoprotein cholesterol concentration is an important coronary risk factor in Chinese patients with low serum levels of total cholesterol and triglyceride. Am J Cardiol 1996; 77:1112-5.