中国常用抗逆转录病毒药物临床药效学研究
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摘要
研究背景
高效抗逆转录病毒疗法(Highly Active Antiretroviral Therapy,HAART)被认为是现今治疗HIV/AIDS行之有效的办法。包括个体间药代动力学差异在内的诸多因素影响药物在体内发挥作用。为了提高药物的治疗效果,使得药物在有效浓度水平发挥效能,并且减小毒性,国外已经开展了治疗药物监测(therapeutic drugmonitoring,TDM)以帮助个体化用药剂量。针对国内一线的抗逆转录病毒药物,目前尚无大样本量的以中国人为研究对象的有效血药浓度数据。
研究目的
探讨奈韦拉平(NVP)、齐多夫定(AZT)和司他夫定(d4T)血药浓度与疗效、耐药和不良反应的相关性。
对象与方法
随机选取HIV/AIDS门诊规律随诊,服用固定HARRT方案,自愿签署知情同意书的患者共计244人(男123人,女121人),在服药前或服药后2-4小时抽取EDTA抗凝静脉血2ml,用高效液相色谱法方法检测药物血浆浓度。详细记录患者治疗前及每次随诊的一般情况及实验室检查结果。
结果
1.血浆NVP谷浓度在病毒学失败组(3.81μg/ml)显著低于病毒抑制组(5.40μg/ml,P=0.018),在对NVP耐药组(3.23μg/ml)显著低于未发生耐药组(5.92μg/ml,P=0.004)。
2.与国外通用的3μg/ml相比,3μg/ml是更适合中国人群的治疗浓度下限。NVP血浆谷浓度低于3.9时,发生病毒学失败和耐药的几率是NVP血浆谷浓度高于3.9μg/ml时的5.4倍和6.3倍。
3.男性人群中,发生严重肝损的患者的NVP血浆谷浓度中位值(8.20μg/ml)显著高于未发生严重肝损的患者(5.48μg/ml, P=0.015)。NVP血浆谷浓度超过8μg/ml时,发生严重肝损的几率是NVP血浆谷浓度低于8μg/ml时的2.4倍。
4.皮疹的发生与NVP血浆峰谷浓度均无显著相关性。
5.服用AZT后出现骨髓抑制的患者其AZT血浆峰浓度中位值(0.68)显著高于未发生骨髓抑制的患者(0.25μg/ml, P=0.001)。
6.d4T血药浓度与血脂异常、周围神经病、脂肪异常分布无显著相关性。
结论
1.NVP早期病毒学应答和病毒耐药的发生与奈韦拉平血浆谷浓度有显著的相关性。NVP血浆谷浓度低于治疗浓度下限将增加病毒学失败和耐药的风险。
2.NVP血浆谷浓度高于治疗浓度上限将增加严重肝毒性的发生。
3.适合中国人的NVP谷浓度的治疗浓度范围是3.9-8.0μg/ml。
4.AZT血浆峰浓度与骨髓抑制有显著相关性。
5.d4T血浆峰浓度与其常见不良反应的发生无显著相关性。
Background
Highly active antiretroviral therapy is considered to be the only effective therapy of HIV/AIDS. Pharmocokinetics is different from person to person. In order to improve outcomes, reduce toxicity, and increase efficacy, therapeutic drug monitoring is used to adjust the individual dose. However, we don't have the data of effective drug plasma concentration in Chinese population.
Objective
To evaluate the relationship between NVP/AZT/d4T concentrations and viralogical response, drug resistance and adiverse events in Chinese population.
Materials and Methods
244outpatients (male123, femal121) of HIV/AIDS clinic were enrolled randomly, all of whom were treated with HAART (NVP/AZT/d4T) and follow-up regularly. Blood samples were taken before administration, or2to4hours thereafter. Drug concentreation were detected by HPLC. Clinical informations and lab data were collected at the same time. The relationships between the concentration and clinic outcomes were analyzed.
Results
1. NVP-Ctrough (Trough concentration of NVP) in viralogical failure group (3.81μg/ml) or resistant group (3.23μg/ml) was lower than viralogical response group (5.40μg/ml, P=0.018).
2.3.9μg/ml was a better low limit of NVP-Ctrough in Chinese population. The risk of viralogical failure and NVP resistance increased5.4times and6.3times when NVP-Ctrough was below3.9μg/ml.
3. NVP-Ctrough in the severe hepatotoxicity group (8.20μg/ml) was higher than control group and mild hepatotoxicity group (5.48μg/ml, P=0.015) in male. The risk of severe hepatotoxicity increased2.4times when NVP-Ctrough is above8μg/ml.
4. NVP-Ctrough and Cpeak showed no correlation with rash.
5. Peak concentration of AZT (AZT-Cpeak) in the hematotoxicity group (0.68μg/ml) was higher than the control group (0.25μg/ml, P=0.001).
6. d4T Cpeak showed no correlation with hyperlipidemia, peripheral neuropathy or lipodystrophy.
Conclusions
1. NVP Ctrough showed significant correlation with viralogical response and resistant. Reduction of NVP Ctrough showed significant correlation with efficacy and resistant mutation.
2. Elevation of NVP Ctrough showed significant correlation with severe hepatotoxicity, especially in male.
3.3.9-8.0μg/ml were an appropriate effective drug plasma concentration in Chinese population.
4. AZT Cpeak showed significant correlation with hematotoxicity.
5. d4T Cpeak showed no correlation with hyperlipidemia, peripheral neuropathy or lipodystrophy.
高效抗逆转录病毒疗法(Highly Active Antiretroviral Therapy,HAART)被认为是现今治疗HIV/AIDS行之有效的办法。包括个体间药代动力学差异在内的诸多因素影响药物在体内发挥作用。为了提高药物的治疗效果,使得药物在有效浓度水平发挥效能,并且减小毒性,国外已经开展了治疗药物监测(therapeutic drugmonitoring,TDM)以帮助个体化用药剂量。针对国内一线的抗逆转录病毒药物,目前尚无大样本量的以中国人为研究对象的有效血药浓度数据。
研究目的
探讨奈韦拉平(NVP)、齐多夫定(AZT)和司他夫定(d4T)血药浓度与疗效、耐药和不良反应的相关性。
对象与方法
随机选取HIV/AIDS门诊规律随诊,服用固定HARRT方案,自愿签署知情同意书的患者共计244人(男123人,女121人),在服药前或服药后2-4小时抽取EDTA抗凝静脉血2ml,用高效液相色谱法方法检测药物血浆浓度。详细记录患者治疗前及每次随诊的一般情况及实验室检查结果。
结果
1.血浆NVP谷浓度在病毒学失败组(3.81μg/ml)显著低于病毒抑制组(5.40μg/ml,P=0.018),在对NVP耐药组(3.23μg/ml)显著低于未发生耐药组(5.92μg/ml,P=0.004)。
2.与国外通用的3μg/ml相比,3μg/ml是更适合中国人群的治疗浓度下限。NVP血浆谷浓度低于3.9时,发生病毒学失败和耐药的几率是NVP血浆谷浓度高于3.9μg/ml时的5.4倍和6.3倍。
3.男性人群中,发生严重肝损的患者的NVP血浆谷浓度中位值(8.20μg/ml)显著高于未发生严重肝损的患者(5.48μg/ml, P=0.015)。NVP血浆谷浓度超过8μg/ml时,发生严重肝损的几率是NVP血浆谷浓度低于8μg/ml时的2.4倍。
4.皮疹的发生与NVP血浆峰谷浓度均无显著相关性。
5.服用AZT后出现骨髓抑制的患者其AZT血浆峰浓度中位值(0.68)显著高于未发生骨髓抑制的患者(0.25μg/ml, P=0.001)。
6.d4T血药浓度与血脂异常、周围神经病、脂肪异常分布无显著相关性。
结论
1.NVP早期病毒学应答和病毒耐药的发生与奈韦拉平血浆谷浓度有显著的相关性。NVP血浆谷浓度低于治疗浓度下限将增加病毒学失败和耐药的风险。
2.NVP血浆谷浓度高于治疗浓度上限将增加严重肝毒性的发生。
3.适合中国人的NVP谷浓度的治疗浓度范围是3.9-8.0μg/ml。
4.AZT血浆峰浓度与骨髓抑制有显著相关性。
5.d4T血浆峰浓度与其常见不良反应的发生无显著相关性。
Background
Highly active antiretroviral therapy is considered to be the only effective therapy of HIV/AIDS. Pharmocokinetics is different from person to person. In order to improve outcomes, reduce toxicity, and increase efficacy, therapeutic drug monitoring is used to adjust the individual dose. However, we don't have the data of effective drug plasma concentration in Chinese population.
Objective
To evaluate the relationship between NVP/AZT/d4T concentrations and viralogical response, drug resistance and adiverse events in Chinese population.
Materials and Methods
244outpatients (male123, femal121) of HIV/AIDS clinic were enrolled randomly, all of whom were treated with HAART (NVP/AZT/d4T) and follow-up regularly. Blood samples were taken before administration, or2to4hours thereafter. Drug concentreation were detected by HPLC. Clinical informations and lab data were collected at the same time. The relationships between the concentration and clinic outcomes were analyzed.
Results
1. NVP-Ctrough (Trough concentration of NVP) in viralogical failure group (3.81μg/ml) or resistant group (3.23μg/ml) was lower than viralogical response group (5.40μg/ml, P=0.018).
2.3.9μg/ml was a better low limit of NVP-Ctrough in Chinese population. The risk of viralogical failure and NVP resistance increased5.4times and6.3times when NVP-Ctrough was below3.9μg/ml.
3. NVP-Ctrough in the severe hepatotoxicity group (8.20μg/ml) was higher than control group and mild hepatotoxicity group (5.48μg/ml, P=0.015) in male. The risk of severe hepatotoxicity increased2.4times when NVP-Ctrough is above8μg/ml.
4. NVP-Ctrough and Cpeak showed no correlation with rash.
5. Peak concentration of AZT (AZT-Cpeak) in the hematotoxicity group (0.68μg/ml) was higher than the control group (0.25μg/ml, P=0.001).
6. d4T Cpeak showed no correlation with hyperlipidemia, peripheral neuropathy or lipodystrophy.
Conclusions
1. NVP Ctrough showed significant correlation with viralogical response and resistant. Reduction of NVP Ctrough showed significant correlation with efficacy and resistant mutation.
2. Elevation of NVP Ctrough showed significant correlation with severe hepatotoxicity, especially in male.
3.3.9-8.0μg/ml were an appropriate effective drug plasma concentration in Chinese population.
4. AZT Cpeak showed significant correlation with hematotoxicity.
5. d4T Cpeak showed no correlation with hyperlipidemia, peripheral neuropathy or lipodystrophy.
引文
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[7].F van Leth, P Phanuphak, K Ruxrungtham, E Baraldi, S Miller, B Gazzard et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine:a randomised open-label trial, the 2NN Study. THE LANCET·Vol 363·April 17,2004
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[11]. Almond LM, Boffito M, Hoggard PG, Bonora S, Raiteri R, Reynolds HE, Garazzino S, Sinicco A, Khoo SH, Back DJ, Di Perri G. The relationship between nevirapine plasma concentrations and abnormal liver function tests. AIDS Res Hum Retroviruses.2004 Jul;20(7):716-22.
[12]. Dailly E, Billaud E, Reliquet V, Breurec S, Perre P, Leautez S, Jolliet P, Bourin M, Raffi F. No relationship between high nevirapine plasma concentration and hepatotoxicity in HIV-1-infected patients naive of antiretroviral treatment or switched from protease inhibitors. Eur J Clin Pharmacol.2004 Jul;60(5):343-8. Epub 2004 May 20.
[13]. Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J AIDS 2004; 35:538-539
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[15]. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD.Hepatology. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy:role of hepatitis C and B infections.2002 Jan;35(1):182-9.
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[1].de Vries-Sluijs TE, Dieleman JP, Arts D, Huitema AD, Beijnen JH, Schutten M, van der Ende ME. Low nevirapine plasma concentrations predict virological failure in an unselected HIV-1-infected population. Clin Pharmacokinet.2003;42(6):599-605.
[2].Duong M, Buisson M, Peytavin G, Kohli E, Piroth L, Martha B, Grappin M, Chavanet P, Portier H. Low trough plasma concentrations of nevirapine associated with virologic rebounds in HIV-infected patients who switched from protease inhibitors. Ann Pharmacother 2005;39(4):603-9
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[5].谢静,李太生。HIV-1耐药性产生机制及检测方法。中国艾滋病性病2005年4月第11卷第2期。
[6].Gonzalez de Requena D, Bonora S, Garazzino S, Sciandra M, D'Avolio A, Raiteri R, Marrone R, Boffito M, De Rosa FG, Sinicco A, Di Perri G Nevirapine plasma exposure affects both durability of viral suppression and selection of nevirapine primary resistance mutations in a clinical setting. Antimicrob Agents Chemother. 2005 Sep;49(9):3966-9.
[7].F van Leth, P Phanuphak, K Ruxrungtham, E Baraldi, S Miller, B Gazzard et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine:a randomised open-label trial, the 2NN Study. THE LANCET·Vol 363·April 17,2004
[8].Gonzalez de Requena D, Nunez M, Jimenez-Nacher I, Soriano V. Liver toxicity caused by nevirapine. AIDS.2005 Mar 24;19(6):621-3.
[9].Podzamczer D, Olmo M, et al. Safety of Switching Nevirapine Twice Daily to Nevirapine Once Daily in Virologically Suppressed Patients. J Acquir Immune Defic Syndr.2009 Apr 1;50(4):390-6.
[10]. Kappelhoff BS, van Leth F, Robinson PA, MacGregor TR, Baraldi E, Montella F, Uip DE, Thompson MA, Russell DB, Lange JM, Beijnen JH, Huitema AD; 2NN Study Group. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther.2005;10(4):489-98.
[11]. Almond LM, Boffito M, Hoggard PG, Bonora S, Raiteri R, Reynolds HE, Garazzino S, Sinicco A, Khoo SH, Back DJ, Di Perri G. The relationship between nevirapine plasma concentrations and abnormal liver function tests. AIDS Res Hum Retroviruses.2004 Jul;20(7):716-22.
[12]. Dailly E, Billaud E, Reliquet V, Breurec S, Perre P, Leautez S, Jolliet P, Bourin M, Raffi F. No relationship between high nevirapine plasma concentration and hepatotoxicity in HIV-1-infected patients naive of antiretroviral treatment or switched from protease inhibitors. Eur J Clin Pharmacol.2004 Jul;60(5):343-8. Epub 2004 May 20.
[13]. Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J AIDS 2004; 35:538-539
[14]. de Maat MM, Huitema AD, Mulder JW, Meenhorst PL, van Gorp EC, Beijnen JH. Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals. Br J Clin Pharmacol 2002;54:378-385
[15]. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD.Hepatology. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy:role of hepatitis C and B infections.2002 Jan;35(1):182-9.
[16]. Labarga P, Soriano V, Vispo ME, Pinilla J, Martin-Carbonero L, Castellares C, Casado R, Maida I, Garcia-Gasco P, Barreiro P. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis.2007 Sep 1;196(5):670-6. Epub 2007 Jul 13.
[17]. Stone S, Lee S, Keane N, Price P, French M. Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26 dipeptidyl peptidase IV enzyme activity with hepatotoxicity after highly active antiretroviral therapy in HIV/HCVcoinfected patients. J Infect Dis 2002,186:1498-1502.
[18]. de Maat MM, ter Heine R, et al. Incidence and risk factors for nevirapine-associated rash. Eur J Clin Pharmacol.2003 Sep;59(5-6):457-62. Epub 2003 Aug12.
[19]. Montaner JS, Cahn P, Zala C, et al. Randomized, controlled study of the effects of a short course of prednisone on the incidence of rash associated with nevirapine in patients infected with HIV-1. J Acquir Immune Defic Syndr.2003 May 1;33(1):41-6.
[20]. G. K. Namayanja, J. M. Nankya, J. K. Byamugisha, F. N. Ssali, C. M. Kityo, S.D. Rwambuya, R. D. Mugerwa, F. A. Mmiro, C. S. Morrison, R.A.Salata. Stevens-Johnson syndrome due to nevirapine African Health Sciences Vol 5 No 4 December 2005
[21]. Kiertiburanakul S, Malathum K, Watcharananan S, Sathapatayavongs B, Sungkanuparph S. Predicting factors for unsuccessful switching from nevirapine to efavirenz in HIV-infected patients who developed nevirapine-associated skin rash. Int J STD AIDS.2009 Mar;20(3):176-9.
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