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HIV/HBV 또는 HIV/HCV 이중감염환자의치료 HIV and Liver 서울대학교의과대학내과학교실 오명돈 HIV/HBV 이중감염 HIV환자가운데 5-10% 는만성 B형바이러스감염환자이다. 이런 HIV/HBV이중감염환자들은 HBV 단독만성 B형간염환자들에견주어서간경변, 말기간질환, 간암으로진행하는속도가더빠르다 [1].

1 HIV/HBV 또는 HIV/HCV 이중감염환자의치료 HIV and Liver 서울대학교의과대학내과학교실 오명돈 HIV/HBV 이중감염 HIV환자가운데 5-10% 는만성 B형바이러스감염환자이다. 이런 HIV/HBV이중감염환자들은 HBV 단독만성 B형간염환자들에견주어서간경변, 말기간질환, 간암으로진행하는속도가더빠르다 [1]. 한편, HBV 만성간염은 HIV질병경과에그다지큰영향을끼치지않으며, HIV치료에도영향을주지않는다 [2-3]. 그러나, 다음과같은상황에서간과관련된심각한합병증이발생할수있다 [4-6]. HIV치료제가운데 FTC, 3TC, TDF는 HBV에대한항바이러스제이기도하다. 이들약제를중단하면 HBV재활성화가시작되면서심각한간세포손상이발생할수있다 [7]. HBV치료제 Entecavir는 HIV에대한억제효과가있다. HIV/HBV 이중감염환자에게 HBV치료목적으로 entecavir만사용하면 HIV가 M184V내성을획득하여 lamivudine과 FTC에내성을나타내게된다. 그러므로 HIV/HBV 이중감염환자에게 HBV치료목적으로 entecavir를사용하는경우에는 HIV도완전히억제하도록다른항 HIV를병합해서사용한다 [8]. Lamivudine은단독으로사용하면 2년후 40%, 4년후 90% 에서 lamivudine내성hbv가나타난다. 그러므로 HIV/HBV 이중감염환자에게 HIV치료목적으로 lamivudine ( 또는 FTC) 를사용하는경우에는다른 HBV치료제를병합해서사용한다 [9]. HIV에대한치료를시작하면면역재건축증후군 (Immune reconstitution syndrome) 이나타나면서간효소치가상승할수있다 [10]. 어떤항 HIV약제를투여하면간효소치가올라간다. 이때상승의속도와높이는 HIV/HBV 이중감염된환자에서훨씬더심하다 [11-12]. 이런현상에대한병인론은잘알려져있지못하지만, 약제를계속투여하더라도문제가해결될수도있다. 그러나 ALT가정상범위보다 5-10배이상으로올라가면문제가된약제를끊는전문가들이많다. 효소치상승은위에서기술한면역재건축증후군으로나타날수있으며, 그결과 HBeAg이사라질수있다. 이런이유로효소치가상승하면그원인에대한감별진단을찾아보아야하며, HBeAg, HBeAb, HBV DNA를측정해서 HBeAg의혈청전환이일어나고있는지평가해야한다. 73

2 2012 년대한간학회추계 Single Topic Symposium 1. HIV/HBV이중감염환자의치료 만성 HBV 감염환자는모두 (1) 금주권고, (2) HAV면역능검사 ( 항체음성이면예방접종 ), (3) HBV전파예방교육, (4) HBV의중증도평가를실시한다 항 HIV치료를시작하기전에모든 HBsAg양성인환자는모두 HBV DNA역가를측정하여 HBV증식정도를평가한다. 만일에이미항 HIV치료를받고있으면서그처방에 HBV억제효과가있는약제가포함되어있으면, 그약제의 HBV억제효과를평가하기위해서 6-12개월마다 HBV DNA역가를측정한다. 만일에아직 HIV 또는 HBV에대한치료를시작할필요가없는환자라면, HIV감염이없는환자에서 HBV의치료제로서 TDF와 entecavir가추천된다. 그런데, TDF는 HIV에대한억제효과가충분하지만, entecavir는 HIV에대한억제효과가있지만충분하지못하다. 또한 TDF는 lamivudin내성 HBV에효과가있지만, entecavir는효과가없다. 따라서내성HBV가출현하는것을막기위해서, 항 HIV처방에이들약제를단독으로사용하지않도록주의한다. 2. 어떤처방을추천하나? 먼저추천하는처방 : TDF + FTC 또는 TDF + 3TC [13-15]. 다른대체처방 : TDF를사용할수없는상황 entecavir + (fully suppressive ART) peginterferon alfa 단독요법 adefovir + 3TC 또는 FTC 또는 telbivudine + (fully suppressive ARV) HIV약제를중단하는경우 : 약제부작용이나 HIV내성으로사용하던 TDF, FTC, lamivudine을중단하는경우에는 HBV가급격히튀어오르면서간부전에빠질수있다. 이를예방하기위해서 adefovir dipivoxil, entecavir, 또는 telbivudine을추가한다. 만일에 HBV에대한억제는성공하였으나 HIV내성이발생하여약을바꾸려고하는경우에는 HBV에효과를발휘한약은그대로계속사용할수있다. 대신에 HIV를억제하기위해서새로운항 HIV약제를처방해야한다. HIV/HCV 이중감염 HCV 환자는 20년이지나면약 1/3에서간경변이발생한다. 간경변으로진행하는속도는 HIV/HCV 이중감염환자에서더빠른데, HCV 단독감염환자에견주어간경변 / 간부전의위험도가 3배더높다 [16]. 진행속도는 CD4림프구수가낮을수록더빠르다. 항 HIV치료를하면그진행속도가느려지긴하지만, 그래도 HCV 단독감염환자에견주면빠르다 [17,18]. 74

3 오명돈 HIV and Liver HCV가 HIV감염의진행을더악화시키는지는분명치않다 [9]. 만성 HCV 감염환자에서는항 HIV약제와관련된간독성이더흔하며, 이것때문에 HIV치료가더어렵다. HCV감염에대한치료는 peginterferon+ribavirin (PegIFN/RBV) 이사용되어왔다. 최근에는 HCV NS3/4A 단백분해효소억제제인 boceprevir와 telaprevir가개발되었다. 이들단백분해효소억제제를 PegIFN/RBV에병합하여치료하면바이러스억제성적이훨씬좋아진다 [19,20]. Boceprevir와 telaprevir는모두 cytochrome P (CYP) 3A4/5와 p-glycoprotein (p-gp) 에의해대사되며, boceprevir는 aldo-keto reductase에의해서대사된다. 그러므로이러한대사과정을거치는항 HIV약제와약물상호작용이나타날수있다. 1. 항 HIV치료를시작하기전평가 HIV환자는모두다 HCV선별검사를받아야한다. HCV가음성이라도 HCV에감염될위험인자를가지고있는환자는매년 HCV선별검사를받아야한다. HCV항체가양성인환자는활동성감염증이있는지확인하기위해서 HCV RNA검사를받아야한다 [21]. HIV/HCV 이중감염환자는 (1) 금주권고, (2) HIV/HCV 바이러스전파예방교육, (3) HAV, HBV 감염에대한예방조치 ( 예방접종 ) 를받아야한다. HIV/HCV 이중감염환자는모두 HCV 치료에대한평가를받아야한다. CD4림프구수가낮으면 (< 200 cells/mm 3 ), 먼저항 HIV치료를시작하고 CD4림프구수가상승한다음에 HCV치료를시작하는것이바람직하다 [21,22-24]. 2. HIV/HCV 이중감염환자에서항 HIV치료 항레트로바이러스치료를언제부터시작할까? HIV/HCV 이중감염환자는 HCV 감염의진행 ( 간섬유화 ) 속도가빠르며, 특히 CD4림프구수가낮으면 (<350/mm 3 ) 더빠르다. 항레트로바이러스치료는면역능을유지하거나회복시키고, HIV관련된면역활성화와염증을줄임으로써간염의진행을늦출수있다 [25-27]. 그러므로 HIV/HCV 이중감염환자는 CD4림프구수에상관없이대부분항레트로바이러스치료를시작해야한다 (BII). 그러나, 어떤전문가들은 CD4림프구수 > 500 cells/mm 3 이면치료를연기하기도한다. 어떤약제를선택할까? HCV 이중감염이없는환자에서선택할때와마찬가지다. 다음과같은사항을고려한다. - HIV와 HCV를동시에치료해야할때 : 먼저 HCV치료제를선택하고, 약물상화작용과독성이겹치는지를고려해서항레트로바이러스요법을선택한다. - 간경변환자 : 간에서대사되는약물에대한용량조절이필요하므로간부전에대해주의깊게평가한다. 간독성 : HIV/HCV 이중감염환자에서항레트로바이러스치료를시작한후간독성발생이더흔하다. 75

4 2012 년대한간학회추계 Single Topic Symposium 진행된 HCV감염환자이면이런위험성이더높고, HCV를치료하고난다음에항레트로바이러스치료를시작하면그위험성이더낮아진다 [28,29]. - 간효소치상승 : stavudine (d4t), didanosine (ddi), nevirapine (NVP), ritonavir (RTV) (600 mg twice daily) [30]. - 지방간 : d4t, ddi, or zidovudine (ZDV) [31], - 간문맥고혈압 : ddi [32], - 간독성 : tipranavir/rit [33]. - ALT/AST 수치가상승하면간부전에대한평가를하고, 그원인을찾아보아야한다. 감별진단으로급성 HAV 또는 HBV감염, 간담도계질환, 알코올등을고려한다. 3. HIV/HCV 동시치료 HIV와 HCV를동시에치료할수있다. 그러나, 약의개수가많아지고, 약물-약물상호작용, 약제독성의겹침등이치료를복잡하게만든다. 이런문제때문에 HCV의진행정도를평가하여반드시필요한경우에만 HIV/HCV 동시치료를고려한다. 어떤전문가들은간섬유화가없으면 HCV치료를연기하기도한다. 만일에동시치료를시작하면약물상호작용이나겹치는독성을피하기위해서항레트로바이러스치료제를조절해야하는수가있다. ddi: RBV과함께투여하면약물상호작용이나타나서생명을위협하는미토콘트리아독성 ( 간비대 /steatosis, 췌장염, 락트산증 ) 이발생할수있다. AZT: RBV과함께투여하면빈혈이자주발생하여, RBV용량을줄여야한다. 가능하면 AZT+RBV병합을피한다. 최근에나온단백분해효소억제제를추가하면빈혈이더욱문제가되므로이때는 AZT를피한다. Abacavir: 일부후향적연구에서 PegIFN/RBV 효과를낮춘다. 아직근거가부족하다 [37-39]. 참고문헌 1. Thio CL, Seaberg EC, Skolasky R, Jr., et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360(9349): Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS. 2005;19(6): Hoffmann CJ, Seaberg EC, Young S, et al. Hepatitis B and long-term HIV outcomes in coinfected HAART recipients. AIDS. 2009;23(14): Bellini C, Keiser O, Chave JP, et al. Liver enzyme elevation after lamivudine withdrawal in HIV-hepatitis B virus co-infected patients: the Swiss HIV Cohort Study. HIV Med. 2009;10(1):

5 오명돈 HIV and Liver 5. Law WP, Dore GJ, Duncombe CJ, et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, AIDS. 2003;17(15): Wit FW, Weverling GJ, Weel J, et al. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis. 2002;186(1): Dore GJ, Soriano V, Rockstroh J, et al. Frequent hepatitis B virus rebound among HIV-hepatitis B viruscoinfected patients following antiretroviral therapy interruption. AIDS. 2010;24(6): McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir-effects on HIV-1 replication and resistance. N Engl J Med. 2007;356(25): Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology. 1999;30(5): Manegold C, Hannoun C, Wywiol A, et al. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy. Clin Infect Dis. 2001;32(1): Sulkowski MS, Thomas DL, Chaisson RE, et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000; 283(1): den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS. 2000;14(18): Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006;44(5): Matthews GV, Seaberg E, Dore GJ, et al. Combination HBV therapy is linked to greater HBV DNA suppression in a cohort of lamivudine-experienced HIV/HBV coinfected individuals. AIDS. 2009;23(13): de Vries-Sluijs TE, Reijnders JG, Hansen BE, et al. Long-Term Therapy with Tenofovir is Effective for Patients Co-Infected with HIV and HBV. Gastroenterology Graham CS, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33(4): Weber R, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166(15): Kitahata MM, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18): Poordad F, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13): Jacobson IM, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25): Ghany MG, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4): Ghany MG, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(4): Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV/AIDS. Department of Health and Human Services (In Press). 24. Soriano V, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS. 2007;21(9): Tien PC. Management and treatment of hepatitis C virus infection in HIV-infected adults: recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office. Am J 77

6 2012 년대한간학회추계 Single Topic Symposium Gastroenterol. 2005;100(10): Avidan NU, et al. Hepatitis C Viral Kinetics During Treatment With Peg IFN-alpha-2b in HIV/HCV Coinfected Patients as a Function of Baseline CD4+ T-Cell Counts. J Acquir Immune Defic Syndr. 2009;52(4): Sulkowski MS, et al. Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults. AIDS. 2007;21(16): Brau N, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol. 2006;44(1): Macias J, et al. Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus. Hepatology. 2009;50(4): Verma S, Goldin RD, Main J. Hepatic steatosis in patients with HIV-Hepatitis C Virus coinfection: is it associated with antiretroviral therapy and more advanced hepatic fibrosis? BMC Res Notes. 2008;1: Ragni MV, et al. Highly active antiretroviral therapy improves ESLD-free survival in HIV-HCV co-infection. Haemophilia. 2009;15(2): Aranzabal L, et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis. 2005;40(4): Labarga P, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis. 2007;196(5): Nunez M. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. J Hepatol. 2006;44(1 Suppl):S132-S McGovern BH, et al. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin Infect Dis. 2006;43(3): Kovari H, et al. Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: a nested case-control study. Clin Infect Dis. 2009;49(4): Food and Drug Administration. Aptivus (package insert). label/2011/021814s011lbl.pdf. Accessed March 26, Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected patient. Clin Liver Dis. 2003;7(1): Fleischer R, Boxwell D, Sherman KE. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis. 2004;38(8):e79-e80. 78

Microsoft PowerPoint - Young Seok Kim.pptx

Microsoft PowerPoint - Young Seok Kim.pptx 만성 B 형간염치료 Gastroenterology and Hepatology Unit Department of Internal Medicine Soon Chun Hyang University it School of Medicine, i Soon Chun Hyang University Bucheon Hospital, Bucheon, Korea Young Seok