新疆地区70例随访的艾滋病患者高效抗逆转录病毒治疗相关肝毒性研究
摘要
目的：了解HAART治疗期间肝损害发生情况,为临床治疗AIDS避免肝损害而提供科学依据。方法：对随访的70例病例治疗过程中CD4+T淋巴细胞计数、淋巴细胞计数的变化进行分析；对随访不同时间里肝脏酶学指标变化进行比较；分析不同的抗病毒方案对肝脏酶学指标变化影响；合并病毒性肝炎或结核感染的病例肝功能情况,与无合并感染病例进行比较；不同性别、维汉不同民族、不同年龄段患者的肝功损害的比较。结果：1)CD4+T淋巴细胞计数在治疗3月时,均有明显上升。在治疗6月后,CD4+T淋巴细胞的生长趋势逐渐平稳；2)经HAART治疗后不同时间不同程度的出现AST、ALT、GGT、ALP值的升高。与治疗前相比较,AST与ALT值在治疗后的第1个月后和第12个月后显著增高；3)不同抗病毒方案治疗对肝脏酶学指标影响进行比较无明显差异；4)合并病毒性肝炎或结核感染的病例肝功能情况,与非感染病例相比,出现肝脏酶学指标异常的比例明显增加；不同性别对肝脏损害无影响；对维汉两个民族出现肝损害比较,第一个月时有统计学意义；不同年龄段患者肝功能损害没有统计学差异。结论：AIDS经过抗病毒治疗,多数病人出现不同程度的肝损害,以轻、中度肝损害为主；时间上以第1月和第12月两次升高为主；多数病人能耐受HAART治疗,同时抗痨治疗对肝脏损害影响不大。
Objective:To investigate and analyse the correlated hepatotoxicity during the HAART therapy, to avord the liver function injure, provide the scientic evidence. Methods:the CD4+ T lymphocyte counts, lymphocyte count's change of 70 cases who followed up with the HAART; The effection of the liver function by different therapy time were comparead retrospectively; Comparing the different treatment effect to the liver enzyme; Comparing the virus hepatitis or TB infected cases with HIV/AIDS; Comparing the effection of the liver function in different sex; Comparing the effection of the liver function in different age and nationality. Results:CD4+ T lymphocyte counts were increased significantly in the third month.7th month after the treatment, CD4+ T lymphocytes steady grewn in six month; After the HAART the 70 AIDS patients appearanced different extent liver function injure, and the count of AST, ALT, GGT, ALP increased, Comparing with before therapy, the count of AST, ALT have increased; There were statistics significance of hepatic lesion in co-infection with viral hepatitis. There were no statistics significance of hepatic lesion in different sex and age and nationality. Conclusion:It is obviously improved that the CD4+ T lymphocytes were increased evidently than before therapy; After ARV the hepato-enzymology markers have increased at the first month and 12th month; There were hepatic lesion in co-infection with viral hepatitis, and other aspacts. There were no statistics significance of hepatic lesion in different sex.
Objective:To investigate and analyse the correlated hepatotoxicity during the HAART therapy, to avord the liver function injure, provide the scientic evidence. Methods:the CD4+ T lymphocyte counts, lymphocyte count's change of 70 cases who followed up with the HAART; The effection of the liver function by different therapy time were comparead retrospectively; Comparing the different treatment effect to the liver enzyme; Comparing the virus hepatitis or TB infected cases with HIV/AIDS; Comparing the effection of the liver function in different sex; Comparing the effection of the liver function in different age and nationality. Results:CD4+ T lymphocyte counts were increased significantly in the third month.7th month after the treatment, CD4+ T lymphocytes steady grewn in six month; After the HAART the 70 AIDS patients appearanced different extent liver function injure, and the count of AST, ALT, GGT, ALP increased, Comparing with before therapy, the count of AST, ALT have increased; There were statistics significance of hepatic lesion in co-infection with viral hepatitis. There were no statistics significance of hepatic lesion in different sex and age and nationality. Conclusion:It is obviously improved that the CD4+ T lymphocytes were increased evidently than before therapy; After ARV the hepato-enzymology markers have increased at the first month and 12th month; There were hepatic lesion in co-infection with viral hepatitis, and other aspacts. There were no statistics significance of hepatic lesion in different sex.
引文
[1]AIDS Clinical trials Group. Division of AIDS table for grading the severity of adult and pediatrinc adverse events.2004[2004-12-28]. Http://www3.niaid.nih.gov/ LabsAndResources/resources/DAIDSClinRsrch/PDF/DAIDSAEGradingTable. pdf.
[2]Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse tran-scriptase inhibitors. Semin Liver Dis,2003,23:173-182.
[3]谢朝梅曾希鹏,HIV感染者混合感染HBV.HCV的调查研究[J],实用预防医学,2008,15,(5)：1418-1420.
[4]Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis,2001,32 (3):492-497.
[5]Soriano V, Puoti M, Garcia-Gasco P, et al. Antiretroviral drugs and liver injury. AIDS, 2008,22(1):1-13.
[6]Wit FW, Weverling GJ, Weel J, et al. Incidence of and risk factors for severe hepatot-oxicity associated with antiretroviral combination therapy. J Infect Dis,2002,186 (1): 23-31.
[7]Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse transcri-ptase inhibitors. Semin Liver Dis,2003,23:173-182.
[8]Murphy MD, Marousek GI, Chou S. HIV protease mutations associated with ampr-enavir resistance during salvage therapy:Importance of I54M. J Clin Virol 2004,30: 62-67.
[9]Moyle G, Higgs C, et al. An openlabel, randomized comparative pilot study of a sing-le-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy. Antivir Ther 2006,11:73-78.
[10]Molto J, Ruiz L, Valle M, et al. Increased antiretroviral potency by the addition of enfuvirtide to a fourdrug regimen in antiretroviral-naive, HIV-infected patients. Ant-ivir Ther 2006,11:47-51.
[11]Moh R, Danel C, Sorho S, Sauvageot D, Anzian A, et al. Haematological changes in adults receiving a zidovudine-containing HAART regimen in combination with cotrimoxazole in Cote d'Ivoire. Antivir Ther 2005,10:615-624.
[12]Jain R, Clark NM, Diaz-Linares M, Grim SA Limitations of current antiretroviral agents and opportunities for development. Curr Pharm Des 2006,12:1065-1074.
[13]Arribas JR, Pulido F, Delgado R et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression:48-Week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 2005,40:280-287.
[14]Nunez M, Soriano V. Hepatotoxicity of antiretrovirals:incidence. mechanisms and management. Drug Saf,2005,28:53-66.
[15]Kilaru KR, Kumar A, Sippy N, et al. Immunological and virological responses to highly active antiretroviral therapy in a non-clinical trial setting in a developing Caribbean country. HIV Med 2006,7 (2):99-104.
[16]van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study firstline combination therapy with or without a protease inhibitor in HIV-1-infected patients. Aids 2003,17 (7):987-999.
[17]Ananworanich J, Moor Z, Siangphoe U, et al. Incidence and risk factors for rash in Thai patients randomized to regimens with nevirapine, efavirenz or both drugs. Aids 2005,19(2):185-192.
[18]Achaz G, Palmer S, Kearney M, Maldarelli F, Mellors JW, et al. A robust measure of HIV-1 population turnover within chronically infected individuals. Mol Biol Evol 2006,21:1902-1912.
[19]Sulkowski MS, Benhamou Y. Therapeutic issues in HIV/HCV coinfected patients. J Viral Hepat,2007,14:371-386.
[20]Oliva J, Moreno S, Sanz J, et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. Aids 2003,17 (4):637-638.
[21]Stern JO, Robinson PA, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003,34 Suppl 1:S21-33.
[1]Miriam J, Alter. Epidemiology of viral hepatitis and HIV coinfection. Hepatology, 2006,44 (2):56-59.
[2]Margaret JK, Marion G, Peters. Viral Hepatitis in HIV infection. N Engl J Med,2007, 356:1445-1454.
[3]Curtis L, CooPer. An overview of HIV and chronic viral hepatitis coinfection. Dig Dis Sci,2008,53:899-904.
[4]David L. Growing importance of liver disease in HIV-infected persons. Hepatology, 2006,43 (1):221-229.
[5]Jurgen Kurt Rockstroh and Ulrich Spengler.HIV and hepatitis C virus co-infection[J]. Lancet Infect Dis 2004,4, (4):37-44.
[6]Vande LT, vander BA, Prins M, et al. Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission. J Infect Dis,2007,196:230-238.
[7]Danta M, Brown D, Bhagani S, et al. Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours. AIDS,2007,21:983-991.
[8]Sheng WH, Chen MY, Hsieh SM, et al. Impact of chronic hepatitis B virus (HBV) infection on outcomes of patients infected with HIV in an area where HBV infection is hyperendemic. Clin Infect Dis,2004,38:1471-1477.
[9]Lydia M. Petrovic HIV/HCV co-infection:histopathologic endings, natural history, ebrosis, and impacto antiretroviral treatment:a reviewarticle. Liver Internat,2007: 598-606.
[10]Dominguez S, Ghosn J, Valantin MA, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS,2006,20:1157-1161.
[11]姚勤伟,张可.慢性HBV感染合并HIV感染患者治疗研究进展,传染病信息,2006,19(5)：248-251.
[12]Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med,2005,352: 2682-2695.
[13]Matthews GV, Bartholomeusz A, Locarnini S, et al. Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. AIDS,2006,20:863-870.
[14]Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med,2003,348:808-816.
[15]Peters MG, Hann HW, Martin P, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastro-enterology,2004,126:91-101.
[16]Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir dipivoxil in pati-ents infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol,2006,44: 62-67.
[17]Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefo-vir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroe-nterology,2006,131:1743-1751.
[18]De Vries-Sluijs T, Hansen B, van Doornum G, et al. The efficacy of high-dose recombinant hepatitis B vaccination in HIV-infected patients who failed at first series of vaccinations. Program and abstracts of the 14th Conference on Retro viruses and Opportunistic Infections; February 25-28,2007; Los Angeles, California. Abstract 883.
[19]Van BF, Zollner B, Sarrazin C, et al. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology,2006,44:318-325.
[20]Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology,2007,45:507-509.
[21]Kwo P, Lawitz E, McCone J, et al. Interim results from HCV SPRINT-1:RVR/EVR from phase 2 study of boceprevir plus Pegintron (pegint erferon alfa-2b)/ribavirin in treatment-naive subjects with genotype-1 CHC. Program and abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver; 2008; Milan, Italy. Abstract 995.
[22]Reesink H, Verloes R, Farha KA, et al. Safety of the HCV protease inhibitor TMC435350 in healthy volunteers and safety and activity in chronic hepatitis C infected individuals:a phase I study. Program and abstracts of the 43rd Annual Meet-ing of the European Association for the Study of the Liver; 2008; Milan, Italy. Abstr-act 64.
[23]张跃新,买买提艾力·吾布力.新疆地区40例艾滋病患者临床特点分析,中国感染控制杂志,2008,7(6)：389-391.
[24]江雪艳译,卢洪洲审校.HIV与多种病毒感染[J].世界感染杂志,2007,7(2)： 173-174.
[25]Hoffmann CJ, Thio CL, Clinical implications of HIV and hepatitis B coinfection in Asia and Africa[J], Antivir Ther,2007,12 (1):119-220.
[26]周泱,刘艳.HBV重叠HIV感染患者细胞免疫功能及临床特征的研究,中西医结合肝病杂志,2008,18(6)：332-394.
[2]Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse tran-scriptase inhibitors. Semin Liver Dis,2003,23:173-182.
[3]谢朝梅曾希鹏,HIV感染者混合感染HBV.HCV的调查研究[J],实用预防医学,2008,15,(5)：1418-1420.
[4]Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis,2001,32 (3):492-497.
[5]Soriano V, Puoti M, Garcia-Gasco P, et al. Antiretroviral drugs and liver injury. AIDS, 2008,22(1):1-13.
[6]Wit FW, Weverling GJ, Weel J, et al. Incidence of and risk factors for severe hepatot-oxicity associated with antiretroviral combination therapy. J Infect Dis,2002,186 (1): 23-31.
[7]Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse transcri-ptase inhibitors. Semin Liver Dis,2003,23:173-182.
[8]Murphy MD, Marousek GI, Chou S. HIV protease mutations associated with ampr-enavir resistance during salvage therapy:Importance of I54M. J Clin Virol 2004,30: 62-67.
[9]Moyle G, Higgs C, et al. An openlabel, randomized comparative pilot study of a sing-le-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy. Antivir Ther 2006,11:73-78.
[10]Molto J, Ruiz L, Valle M, et al. Increased antiretroviral potency by the addition of enfuvirtide to a fourdrug regimen in antiretroviral-naive, HIV-infected patients. Ant-ivir Ther 2006,11:47-51.
[11]Moh R, Danel C, Sorho S, Sauvageot D, Anzian A, et al. Haematological changes in adults receiving a zidovudine-containing HAART regimen in combination with cotrimoxazole in Cote d'Ivoire. Antivir Ther 2005,10:615-624.
[12]Jain R, Clark NM, Diaz-Linares M, Grim SA Limitations of current antiretroviral agents and opportunities for development. Curr Pharm Des 2006,12:1065-1074.
[13]Arribas JR, Pulido F, Delgado R et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression:48-Week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 2005,40:280-287.
[14]Nunez M, Soriano V. Hepatotoxicity of antiretrovirals:incidence. mechanisms and management. Drug Saf,2005,28:53-66.
[15]Kilaru KR, Kumar A, Sippy N, et al. Immunological and virological responses to highly active antiretroviral therapy in a non-clinical trial setting in a developing Caribbean country. HIV Med 2006,7 (2):99-104.
[16]van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study firstline combination therapy with or without a protease inhibitor in HIV-1-infected patients. Aids 2003,17 (7):987-999.
[17]Ananworanich J, Moor Z, Siangphoe U, et al. Incidence and risk factors for rash in Thai patients randomized to regimens with nevirapine, efavirenz or both drugs. Aids 2005,19(2):185-192.
[18]Achaz G, Palmer S, Kearney M, Maldarelli F, Mellors JW, et al. A robust measure of HIV-1 population turnover within chronically infected individuals. Mol Biol Evol 2006,21:1902-1912.
[19]Sulkowski MS, Benhamou Y. Therapeutic issues in HIV/HCV coinfected patients. J Viral Hepat,2007,14:371-386.
[20]Oliva J, Moreno S, Sanz J, et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. Aids 2003,17 (4):637-638.
[21]Stern JO, Robinson PA, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003,34 Suppl 1:S21-33.
[1]Miriam J, Alter. Epidemiology of viral hepatitis and HIV coinfection. Hepatology, 2006,44 (2):56-59.
[2]Margaret JK, Marion G, Peters. Viral Hepatitis in HIV infection. N Engl J Med,2007, 356:1445-1454.
[3]Curtis L, CooPer. An overview of HIV and chronic viral hepatitis coinfection. Dig Dis Sci,2008,53:899-904.
[4]David L. Growing importance of liver disease in HIV-infected persons. Hepatology, 2006,43 (1):221-229.
[5]Jurgen Kurt Rockstroh and Ulrich Spengler.HIV and hepatitis C virus co-infection[J]. Lancet Infect Dis 2004,4, (4):37-44.
[6]Vande LT, vander BA, Prins M, et al. Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission. J Infect Dis,2007,196:230-238.
[7]Danta M, Brown D, Bhagani S, et al. Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours. AIDS,2007,21:983-991.
[8]Sheng WH, Chen MY, Hsieh SM, et al. Impact of chronic hepatitis B virus (HBV) infection on outcomes of patients infected with HIV in an area where HBV infection is hyperendemic. Clin Infect Dis,2004,38:1471-1477.
[9]Lydia M. Petrovic HIV/HCV co-infection:histopathologic endings, natural history, ebrosis, and impacto antiretroviral treatment:a reviewarticle. Liver Internat,2007: 598-606.
[10]Dominguez S, Ghosn J, Valantin MA, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS,2006,20:1157-1161.
[11]姚勤伟,张可.慢性HBV感染合并HIV感染患者治疗研究进展,传染病信息,2006,19(5)：248-251.
[12]Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med,2005,352: 2682-2695.
[13]Matthews GV, Bartholomeusz A, Locarnini S, et al. Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. AIDS,2006,20:863-870.
[14]Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med,2003,348:808-816.
[15]Peters MG, Hann HW, Martin P, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastro-enterology,2004,126:91-101.
[16]Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir dipivoxil in pati-ents infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol,2006,44: 62-67.
[17]Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefo-vir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroe-nterology,2006,131:1743-1751.
[18]De Vries-Sluijs T, Hansen B, van Doornum G, et al. The efficacy of high-dose recombinant hepatitis B vaccination in HIV-infected patients who failed at first series of vaccinations. Program and abstracts of the 14th Conference on Retro viruses and Opportunistic Infections; February 25-28,2007; Los Angeles, California. Abstract 883.
[19]Van BF, Zollner B, Sarrazin C, et al. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology,2006,44:318-325.
[20]Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology,2007,45:507-509.
[21]Kwo P, Lawitz E, McCone J, et al. Interim results from HCV SPRINT-1:RVR/EVR from phase 2 study of boceprevir plus Pegintron (pegint erferon alfa-2b)/ribavirin in treatment-naive subjects with genotype-1 CHC. Program and abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver; 2008; Milan, Italy. Abstract 995.
[22]Reesink H, Verloes R, Farha KA, et al. Safety of the HCV protease inhibitor TMC435350 in healthy volunteers and safety and activity in chronic hepatitis C infected individuals:a phase I study. Program and abstracts of the 43rd Annual Meet-ing of the European Association for the Study of the Liver; 2008; Milan, Italy. Abstr-act 64.
[23]张跃新,买买提艾力·吾布力.新疆地区40例艾滋病患者临床特点分析,中国感染控制杂志,2008,7(6)：389-391.
[24]江雪艳译,卢洪洲审校.HIV与多种病毒感染[J].世界感染杂志,2007,7(2)： 173-174.
[25]Hoffmann CJ, Thio CL, Clinical implications of HIV and hepatitis B coinfection in Asia and Africa[J], Antivir Ther,2007,12 (1):119-220.
[26]周泱,刘艳.HBV重叠HIV感染患者细胞免疫功能及临床特征的研究,中西医结合肝病杂志,2008,18(6)：332-394.