中文摘要

研究背景
相當少的研究探討抗反轉錄病毒療法的潛在交互作用。台灣全民健保自1997年開始給付愛滋病患抗反轉錄病毒藥品，而截至2002年全民健康保險納保率高達97%，且全民健保特約醫療機構，占全國醫療機構總數之93%，使得台灣的愛滋病感染有完善的資料，可用來進行Highly Active Antiretroviral Therapy的藥品使用研究。

研究目的
探討接受抗反轉錄病毒藥品的愛滋門診病患所處方藥品當中，抗反轉錄病毒藥品之間以及抗反轉錄病毒藥品與合併用藥的潛在交互作用盛行率，並歸納常見交互作用之用藥組合。

研究設計與方法
此研究為回溯性橫斷面之研究。研究材料為2002年1月1日至3月31日的全民健康保險申報檔案。納入分析條件為西醫門診處方及治療明細檔以及相對應之西醫門診處方醫令明細檔：案件分類為愛滋病（Case type 91）或 International Classification of Disease, Ninth Revision, code為：042- 044（人類免疫不全病毒感染併特定狀況及所致其他特定狀況）以及與上述條件有相同身分證號碼之病患資料。排除條件：研究期間沒有使用抗反轉錄病毒藥品的患者。交互作用參考文獻為Drug Interaction Facts 2004，偵測交互作用為第一級與第二級交互作用且藥品併用時間須重疊達三天以上。此外，進一步分析交互作用是否來自同一處方醫師與醫療機構。

結果
在三個月的西醫門診申報檔案中，共有1,662人接受抗反轉錄病毒藥品，總計8,926筆就醫人次，發生585個交互作用事件。因此，接受抗反轉錄病毒藥品的愛滋病病患發生潛在交互作用的盛行率為6.6%（585/8,926）；第一級交互作用佔所有交互作用事件的6.3%，其中64.9%是由於不同次就醫所產生之交互作用。最常發生的潛在交互作用為Indinavir/Terfenadine、Indinavir/Simvastatin、Ritonavir/Terfenadine。第二級交互作用佔所有交互作用事件的93.7%，其中86.9%是由於同次就醫產生之交互作用；最常發生的潛在交互作用為Indinavir/Ritonavir、Indinavir/Didanosine、Efavirenz/Alprazolam。

結論
我們發現接受抗反轉錄病毒藥品的門診愛滋病患，曾被處方具有嚴重、跨處方不易避免之交互作用，且比率不低。此外，相當高比例的交互作用是發生於同一位處方醫師及醫療處所，因此，建議須加強醫師的在職訓練、強調藥師於調劑過程至交付藥品過程，能有效介入與提供用藥教育、而且醫療機構應研擬策略解決這些可避免之交互作用。

Abstract

Background:
Little information exists about the potential drug interactions（PDIs）related to antiretroviral therapy within large numbers of people. In Taiwan, the National Health Insurance（NHI）has started to provide free antiretroviral drugs to HIV-infected patients since 1997. According to the statistic data in 2002, the coverage of NHI is more than 97% of Taiwan’s population, and health-care contracted providers under this plan is about 93% of all health facilities. Therefore, the claim data of the plan become a valuable resource for drug utilization study about the antiretroviral therapy.

Objectives:
We aimed to examine the prevalence of PDIs of antiretroviral agents and concurrent medications in outpatient settings. In addition, we also analyzed and identified patterns of the common PDIs.

Methods:
A retrospective cross-sectional study was conducted to analyze claims of the Ambulatory Care Expenditures by Visits and the Details of Ambulatory Care Orders from 1 January, to 31 March, 2002. The inclusion criteria were the prescriptions with Case-Claim Classification human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) or International Classification of Disease, Ninth Revision, code 042-044, while claims without antiretroviral agents given during the study period were excluded. We only surveyed the PDIs including antiretroviral agents available in Taiwan with co-administrations continued for 3 days or more. PDIs were screened based on the Drug Interaction Facts 2004 and we only identified levels 1 and 2 drug interactions. Furthermore, we also analyzed the PDIs related to the same physicians or health care organizations.

Results:
Among claims of the first quarter in 2002, a total of 1,662 patients prescribed antiretroviral agents accounted for 8,926 patient visits, and 585 PDIs were identified. The prevalence of PDIs pertinent to antiretroviral therapy was 6.6%，and 6.3% of these PDIs were classified as the level 1. Among these prescriptions with PDIs, 64.9% came from different visits and the top three interactions were Indinavir/Terfenadine, Indinavir/Simvastatin, and Ritonavir/Terfenadine.
The remaining 93.7% of PDIs belonged to the level 2, and 86.9% were from the same visits. The most common ones were Indinavir/Ritonavir, Indinavir/Didanosine, and Efavirenz/Alprazolam.

Conclusions:
We found that there were some severe and even unpreventable PDIs among patients receiving antiretroviral therapy in outpatient settings. Drug safety facilities should have a better evaluation of these drugs. Moreover, a great proportion of PDIs were prescribed by the same physicians or health facilities. Therefore, we suggest that there should be better on-going training sessions and interventions offered by pharmacists to provide more information, and health care providers should also develop appropriate strategies to prevent these PDIs.

1. Hamilton RA, Briceland LL, Andritz MH. Frequency of hospitalization after exposure to known drug-drug interactions in a Medicaid population. Pharmacotherapy 1998;18(5):1112-20.
2. McDonnell PJ, Jacobs MR. Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother 2002;36(9):1331-6.
3. Halkin H, Katzir I, Kurman I, Jan J, Malkin BB. Preventing drug interactions by online prescription screening in community pharmacies and medical practices. Clin Pharmacol Ther 2001;69(4):260-5.
4. Seymour RM, Routledge PA. Important drug-drug interactions in the elderly. Drugs Aging 1998;12(6):485-94.
5. de Maat MM, Ekhart GC, Huitema AD, Koks CH, Mulder JW, Beijnen JH. Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet 2003;42(3):223-82.
6. 台灣年鑑. http://www.gov.tw/EBOOKS/TWANNUAL/.
7. 中央健康保險局. http://www.nhi.gov.tw/.
8. Center for Disease Control Taiwan ROC. http://www.cdc.gov.tw/index1024.htm.
9. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949-56.
10. Weideman RA, Bernstein IH, McKinney WP. Pharmacist recognition of potential drug interactions. Am J Health Syst Pharm 1999;56(15):1524-9.
11. Langdorf MI, Fox JC, Marwah RS, Montague BJ, Hart MM. Physician versus computer knowledge of potential drug interactions in the emergency department. Acad Emerg Med 2000;7(11):1321-9.
12. Tomika DK, Kennedy DL, Baum C, Knapp DE, Anello C. Drug utilization in the united states: 1988. Rockville, Md: Food and Drug Administration; November 1989.
13. Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR, Jr. Torsades de pointes occurring in association with terfenadine use. JAMA 1990;264(21):2788-90.
14. Pratt CM, Hertz RP, Ellis BE, Crowell SP, Louv W, Moye L. Risk of developing life-threatening ventricular arrhythmia associated with tefenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine. Am J Cardiol 1994;73(5):346-52.
15. DeVault KR, Castell DO. Guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Practice Parameters Committee of the American College of Gastroenterology. Arch Intern Med 1995;155(20):2165-73.
16. Vandenplas Y, Belli DC, Benatar A, et al. The role of cisapride in the treatment of pediatric gastroesophageal reflux. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 1999;28(5):518-28.
17. Janssen Pharmaceutica Inc. Limited-acess program announced in United States to ensure appropriate use of Propulsid (cisapride): product no longer to be promoted in United States. http://www.us.janssen.com/news/current/propuls_lim_acc.html.
18. Food and Drug Administration. Janssen Pharmaceutica stops marketing cisapride in the US. http://www.fda.gov/bbs/topics/ANSWERS/ANS01007.html.
19. Michalets EL, Williams CR. Drug interactions with cisapride: clinical implications. Clin Pharmacokinet 2000;39(1):49-75.
20. Jones JK, Fife D, Curkendall S, Goehring E, Jr., Guo JJ, Shannon M. Coprescribing and codispensing of cisapride and contraindicated drugs. JAMA 2001;286(13):1607-9.
21. Carter BL, Lund BC, Hayase N, Chrischilles E. A longitudinal analysis of antihypertensive drug interactions in a Medicaid population. Am J Hypertens 2004;17(5 Pt 1):421-7.
22. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 1987;317(4):185-91.
23. 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(13):853-60.
24. U.S. Food and Drug Administration http://www.fda.gov/.
25. 藥物食品檢驗局許可證查詢作業 http://203.65.100.151/DO8180.asp.
26. Tatro DS (Ed). Drug Interactions Fatcs. United States: Facts & Comparisons; 2004.
27. Aronson JK, Grahame-Smith DG. Clinical pharmacology. Adverse drug interactions. Br Med J (Clin Res Ed) 1981;282(6260):288-91.
28. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med 2001;344(13):984-96.
29. Sahai J, Gallicano K, Oliveras L, Khaliq S, Hawley-Foss N, Garber G. Cations in the didanosine tablet reduce ciprofloxacin bioavailability. Clin Pharmacol Ther 1993;53(3):292-7.
30. Sahai J. Avoiding the ciprofloxacin-didanosine interaction. Ann Intern Med 1995;123(5):394-5.
31. Zimmermann T, Yeates RA, Laufen H, Pfaff G, Wildfeuer A. Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole. Eur J Clin Pharmacol 1994;46(2):147-50.
32. Nelson DR, Kamataki T, Waxman DJ, et al. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 1993;12(1):1-51.
33. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 2002;41(14):1195-211.
34. Wolf CR, Smith G. Pharmacogenetics. Br Med Bull 1999;55(2):366-86.
35. Infection: PoCPfToH. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescedts, the Department of Health and Human Services and Human Services. April 7, 2005.
36. Kolars JC, Lown KS, Schmiedlin-Ren P, et al. CYP3A gene expression in human gut epithelium. Pharmacogenetics 1994;4(5):247-59.
37. Moore KH, Yuen GJ, Raasch RH, et al. Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole. Clin Pharmacol Ther 1996;59(5):550-8.
38. Hochster H, Dieterich D, Bozzette S, et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group Study. Ann Intern Med 1990;113(2):111-7.
39. Merrill DP, Manion DJ, Chou TC, Hirsch MS. Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in vitro. J Infect Dis 1997;176(1):265-8.
40. Jankel CA, Speedie SM. Detecting drug interactions: a review of the literature. DICP 1990;24(10):982-9.
41. Dry TJ, Butt HR, Schiefley CH. The effect of oral administration of para-aminobenzoic on the concentration of salicylates in the blood: preliminary report. Proc Mayo Clin 1946;21:497-504.
42. Khan SA. Descriptions of adverse drug events should be standardised. BMJ 1999;318(7176):127.
43. Micromedex Healthcare Series. 2005;124.
44. Sheehan NL, Kelly DV, Tseng AL, van Heeswijk RP, Beique LC, Hughes CA. Evaluation of HIV drug interaction web sites. Ann Pharmacother 2003;37(11):1577-86.
45. Roberts JS, Watrous ML, Schulz RM, Mauch RP, Nightengale BS. Quantifying the clinical significance of drug-drug interactions: scaling pharmacists' perceptions of a common interaction classification scheme. Ann Pharmacother 1996;30(9):926-34.
46. Panels on Clinical Practices for Treatment of HIV Infection: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescedts, the Department of Health and Human Services and Human Services. April 7, 2005.
47. Dambro MR, Kallgren MA. Drug interactions in a clinic using costar. Comput Biol Med 1988;31(1):31-8.
48. Shinn AF, Shrewsbury PR, Anderson KW. Development of a computerized drug interaction database (MEDICOM) use in a patient specific enveronment. Drug Inf J 1983;17:205.
49. Preston SL, Postelnick M, Purdy BD, Petrolati J, Aasi H, Stein DS. Drug interactions in HIV-positive patients initiated on protease inhibitor therapy. AIDS 1998;12(2):228-30.
50. de Maat MM, de Boer A, Koks CH, et al. Evaluation of clinical pharmacist interventions on drug interactions in outpatient pharmaceutical HIV-care. J Clin Pharm Ther 2004;29(2):121-30.
51. 高雅慧. 健保給付藥品ATC編碼對照系統2003年版. 2003.
52. 行政院衛生署統計資訊網. http://www.doh.gov.tw/statistic/index.htm.
53. Damle BD, Mummaneni V, Kaul S, Knupp C. Lack of effect of simultaneously administered didanosine encapsulated enteric bead formulation (Videx EC) on oral absorption of indinavir, ketoconazole, or ciprofloxacin. Antimicrob Agents Chemother 2002;46(2):385-91.
54. Guedon-Moreau L, Ducrocq D, Duc MF, et al. Absolute contraindications in relation to potential drug interactions in outpatient prescriptions: analysis of the first five million prescriptions in 1999. Eur J Clin Pharmacol 2003;59(8-9):689-95.
55. Product Information: Norvir(R), ritonavir. Abbott Laboratories, North Chicago, IL, 12/2000.
56. Product Information: Crixivan(R), indinavir sulfate. Merck & Co., Inc., West Point, PA, 1998.
57. Product Information. Efavirenz (Sustiva). DuPont Pharmaceuticals. Semptember 1998.
58. Simons FE. H1-receptor antagonists. Comparative tolerability and safety. Drug Saf 1994;10(5):350-80.
59. Scott JD. Simplifying the treatment of HIV infection with ritonavir-boosted protease inhibitors in antiretroviral-experienced patients. Am J Health Syst Pharm 2005;62(8):809-15.
60. Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med 2003;348(16):1556-64.
61. Borowitz SM, Wyatt JC. The origin, content, and workload of e-mail consultations. JAMA 1998;280(15):1321-4.
62. US Food and Drug Administration. Withdrawal of toglitazone and cisapride. JAMA 2000;283(17):2228.
63. Estelle F, Simons R. H1-receptor antagonists: safety issues. Ann Allergy Asthma Immunol 1999;83(5):481-8.
64. Morera T, Gervasini G, Carrillo JA, Benitez J. Using a computerized drug prescription screening system to trace drug interactions in an outpatient setting. Ann Pharmacother 2004;38(7-8):1301-6.
65. Tamblyn R, Huang A, Perreault R, et al. The medical office of the 21st century (MOXXI): effectiveness of computerized decision-making support in reducing inappropriate prescribing in primary care. CMAJ 2003;169(6):549-56.
66. Bates DW, Leape LL, Cullen DJ, et al. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA 1998;280(15):1311-6.
67. Evans RS, Pestotnik SL, Classen DC, et al. A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med 1998;338(4):232-8.
68. Chang HJ. Health care systems in transition. II. Taiwan, Part II. The current status of HIV-AIDS in Taiwan. J Public Health Med 1998;20(1):11-5.
69. Wood E, Hogg RS, Yip B, Harrigan PR, O'Shaughnessy MV, Montaner JS. Is there a baseline CD4 cell count that precludes a survival response to modern antiretroviral therapy? AIDS 2003;17(5):711-20.
70. Sethi AK, Celentano DD, Gange SJ, Moore RD, Gallant JE. Association between adherence to antiretroviral therapy and human immunodeficiency virus drug resistance. Clin Infect Dis 2003;37(8):1112-8.
71. Murphy DA, Wilson CM, Durako SJ, Muenz LR, Belzer M. Antiretroviral medication adherence among the REACH HIV-infected adolescent cohort in the USA. AIDS Care 2001;13(1):27-40.
72. Warnock AC, Rimland D. The provision of pharmaceutical care in a Veterans' Affairs Medical Center outpatient HIV clinic. Hosp Pharm 1994;29(2):114-6, 9-20.
73. Foisy MM, Tseng A, Blaikie N. Pharmacists' provision of continuity of care to patients with human immunodeficiency virus infection. Am J Health Syst Pharm 1996;53(9):1013-7.
74. Colombo J. Establishing pharmaceutical care services in an HIV clinic. J Am Pharm Assoc (Wash) 1997;NS37(5):581-92; quiz 93-4.
75. Fung HB, Pecini RA, Brown ST. HIV pharmacotherapy clinic. Am J Health Syst Pharm 1998;55(9):955-6.
76. 廖敏惠 碩士論文 高效能抗反轉錄病毒療法相關之代謝異常併發症. 2003.
77. Http://www.caps.ucsf.edu/capsweb/progects/adherenceabs.htm.
78. AIDS Info http://www.aidsinfo.nih.gov/.
79. 柯乃熒.成功大學醫學院1700-019計劃：「觸控互動式用藥教育電腦軟體之研發:應用使用雞尾酒療法之愛滋感染者」.2004.
80. ASHP statement on the pharmacist's role in the care of patients with HIV infection. Am J Health Syst Pharm 2003;60(19):1998-2003.