HIVH合并肝炎.ppt

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1、HIV合并肝炎,提纲,流行病学肝炎的预防HCVHBV,流行病学,具有相同的传播途径慢性感染率高,欧洲和美国,流行病学,在HIV病人中丙肝感染率：在西方世界有近25%的HIV感染者患有慢性丙型肝炎。美国有近10%的慢性丙型肝炎病人同时感染HIV。研究发现HIV感染者中613共同感染HBV。共同感染HIV更常见于来自两种病毒流行地区的人，如撒哈拉以南的非洲。,乙肝慢性HBV感染,在西方，在HIV阳性的患者当中慢性HBV感染是低于，在男性同性恋和吸毒中最高。在亚洲合并感染率在。在西方乙肝感染在青少年和早期成年的性欲活动。尽管在免疫正常的人中自发清除率，但是在HIV病人慢性感染率是。,肝炎的预防,1.

2、既往没有肝炎的病史的患者，予以甲肝和乙肝疫苗2.对病人的教育，减少疾病的传播3.避免酒精和限制使用其他肝脏毒性药物,HCV和HIV相互作用,1.加速了丙肝的进程肝硬化的进程失代偿肝病发生的肝细胞癌的发生死亡,HCV和HIV相互作用,2.影响患者的认知和精神功能3.增加了糖尿病的患病率4.影响HAART 的治疗（）,肝脏损害的分析,肝活检（可以帮助选择治疗、提供预后的重要指标）注：In one study,29%of patients with HIV and HCV coinfection and persistently normal alanine aminotransferase lev

3、els had considerable fibrosis that warranted treatment 目前没有非侵袭性检查可以代替肝活检。对于有肝硬化的病人应当常规检测失代偿肝病和肝癌的证据，以安排肝移植。,丙肝的治疗目标,1.保证持续的病毒学的反应2.停止肝脏损伤，可能逆转肝脏的纤维化。在结束治疗后血清HCV RNA持续6月的阴性，这是目前治疗丙肝的目标。,丙肝治疗药物,聚二乙醇干扰素利巴韦林这种方案对丙肝不是特殊的，但是他们同时具有免疫调节和抗病毒作用。,丙肝治疗药物,1.PEG-IFN：180ug/kg IH QW 2.利巴韦林:基因1或4型（75kg:1200mg QD，75k

4、g:1000mg QD)基因2或3型(800mg QD)基因1或4型:PEG-IFN联合利巴韦林 治疗48周基因2或3型:PEG-IFN联合利巴韦林 治疗24周,丙肝治疗药物,不论基因型所有患者接受了48周治疗，在基因1或4中病毒反应是14-44（HBV单独感染42%到46%），基因2或3型是44（HBV单独感染76%及82）治疗很好地耐受。一个小型的研究在体重基础的利巴韦林在联合感染病人对比丙肝单独感染分别为18和39%反应率。尽管利巴韦林剂量在联合感染更有可能减量。,目前的问题,反应效果在低CD的病人，对不同基因型的疗程。此外，节制饮酒和药物滥用开始对持久的病毒反应的作用不清。对于治疗失败

5、的病人，甚至在缺乏病毒学治愈，长时间使用干扰素是否有利于纤维化的进程。两个重要的药物进展是丝氨酸蛋白酶（非结构蛋白）和依赖于RNA的RNA聚合酶（非结构蛋白）。早期二期研究对蛋白酶抑制剂（-950）显示在治疗中，早期的病毒载量的显著下降。然而进一步研究需要在确定与抗逆转录病毒治疗或其他治疗的相互作用。,HBV与HIV影响,1.增加了肝硬化、终末期肝病和其导致的死亡注：特别在低CD4计数和长期饮酒的人群2.更易发生慢性感染和高的HBV-DNA的复制注：在免疫正常的大于30岁人群，HBV-DNA水平与肝硬化和肝癌相关。但是在合并HIV人群没有这方面的资料。,乙肝血清学,在单独anti-HBc 阳性

6、的病人，有10-40可以检测到HBV-DNA的水平。推荐所有HIV病人应当查HBsAg、anti-HBs、anti-HBc。如果HBsAg和anti-Hbc任一种阳性，应当检测HBV-DNA的水平。如果没有HBV-DNA的水平的病人应当接种疫苗。,HIV中HBV 感染的特点,HBV和HIV共同感染者倾向于HBV DNA水平更高、自发性HBeAg血清转换率更低、肝病更严重且肝脏相关死亡率增加。肝炎的严重发作（flares）会发生于HAART开始后经过免疫重建CD4计数低的HIV共同感染患者。HBV/HIV共同感染患者肝酶升高可由除HBV外的其它因素引起，包括HAART和某些机会感染如巨细胞病毒和

7、鸟分枝杆菌。,治疗目标,1.抑制病毒复制（没有HBV-DNA和HBcAg转阴）2.肝病的改善,治疗的时机？,乙肝治疗（AASLD）,对于符合慢性乙型肝炎诊断标准的患者应当实施治疗（）。一过性或轻微ALT升高（12ULN）的患者应当考虑肝活检（-3）。对于没有进行HAART治疗和近期不需要进行HAART治疗的患者，应当选用无抗HIV活性药物进行抗乙型肝炎病毒治疗，例如聚乙二醇化干扰素、阿德福韦酯或恩替卡韦。尽管替比夫定无抗HIV活性，但在这种情况下不应当选用（-3）。对于正在接受有效HARRT治疗的患者，若HARRT方案中无抗乙型肝炎病毒药物，则可选用聚乙二醇化干扰素、阿德福韦酯或恩替卡韦治疗（

8、-3）。对于拉米夫定耐药患者，应当加用替诺福韦或阿德福韦酯治疗（）。当需要改变HAART方案时，不应当在无有效药物替代前就中断抗乙型肝炎病毒的有效药物，除非患者已经获得HBeAg血清转换，并完成了足够的巩固治疗时间（-3）。,乙肝治疗（AASLD）,对于将要同时进行抗HBV和抗HIV治疗的患者，应当选用对这两种病毒均有效的药物。优先选用拉米夫定加替诺福韦或恩曲他滨加替诺福韦（-3）。其对核苷酸耐药可能性和初期病毒抑制的程度呈反比。,HBV的核苷类药物治疗,干扰素,在HBV病人的治疗反应较好，尤其在高转氨酶和低病毒复制目前没有研究在HBV和HIV合并感染的随机对照实验,目前的问题,治疗的疗程抗乙

9、肝病毒和HAART治疗的相互关系CD4细胞数和病毒应答率的关系,谢谢,影响HAART 的治疗,Results：Eight trials involving 6216 patients were analyzed.Patients with HIV-HCV coinfection had a mean increase in the CD4 cell count that was 33.4 cells/mm3(95%CI,23.5 43.3 cells/mm3)less than that for HIV-infected patients without HCV infection.Concl

10、usions：This meta-analysis shows that patients with HIV-HCV coinfection do,in fact,have less immune reconstitution,as determined by CD4 cell count after 48 weeks of HAART,than do patients with HCV infection alone.Impact of Hepatitis C Virus on Immune Restoration in HIV-Infected Patients Who Start Hig

11、hly Active Antiretroviral Therapy:A Meta-analysis Results:A total of 10 481 HIV-infected individuals were followed for a median of 1.9 years;19%had HCV.HCV infection was not associated with progression to AIDSOI or death after controlling for important confounding conditions.Factors significantly co

12、nfounding the risk of both death and diagnosis of an AIDSOI were alcoholism,drug-induced hepatitis,and the type of ART prescribed.Acute and chronic hepatitis B infection confounded the risk of AIDSOI diagnosis.During the 12 months after starting HAART,proportional increases in CD4 cell counts did no

13、t differ between HCV-infected and HCV-uninfected individuals.Likewise,the short-term change in viral load did not differ.Conclusion:In our cohort,HCV did not increase the risk of death or AIDSOI,and did not affect the early immunological or virological response to initial HAART.Clinicians should eva

14、luate patients with HCV for other,manageable problems,including alcoholism and other viral hepatitis.Effect of hepatitis C infection on progression of HIV disease and early response to initial antiretroviral therapy,Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treat

15、ed with tenofovir.,RESULTS:Mean exposure to LAM was 35.3+/-27.5 months and to TDF 11.2+/-6.7 months.Genotypic analyses from 21 of the patients revealed LAM-associated mutations,and a further two patients developed a novel mutation,rtA194T,along with LAM-resistance-associated mutations.Phenotypic ana

16、lyses revealed that constructs harbouring rtA194T combined with rtL180M and rtM204V displayed an over 10-fold increase in the IC50 for TDF compared with the wild type.CONCLUSION:The selection of HBV mutations in HBV/HIV-coinfected patients failing TDF therapy is an unlikely event within the first 12

17、 months of treatment.However,HBV from two of the 43 patients treated with TDF for more than 12 months was found to contain one novel mutation located distal to the catalytic site of the HBV pol.In vitro,rtA194T conferred a reduced susceptibility to TDF in the presence of LAM-associated mutations.,Tr

18、eatment algorithm for chronic hepatitis B in HIV-infected patients,Agents with dual activity(TDF,FTC,LAM)should be included in the anti-retroviral regimen.Combination of a nucleoside and a nucleotide analogue should be the preferred association in order to prevent long-term resistance(TDF+LAM or FTC

19、).ADV may be an alternative if TDF could not be used and ETV an alternative to FTC or LAM.Although not the first choice,mono-therapy remains an option.In this situation,nucleotides(TDF)should be preferred to nucleosides(FTC,LAM)because of a more favourable resistance profile.,Patients who need anti-

20、HIV therapy and no anti-HBV therapy,Patients with persistent controlled HBV replication(serum HBV DNA 45log10copies/mL)and no or mild liver disease.The strategy should be the same as for patients with indication for both viruses in order to prevent hepatitis of immune reconstitution。,Patients with c

21、irrhosis,The sustained control of HBV replication in patients with cirrhosis is critical to prevent liver decompensation,hepatocellular carcinoma and death.Compliance to therapy and prevention of resistance are major.Therefore,patients with cirrhosis should be treated with combination therapy.In add

22、ition,cirrhotic patients with high serum HBV DNA and low CD4 cell count are at risk of severe hepatitis related to immune reconstitution after HAART initiation.In this situation,the use of combination anti-HBV therapy(TDF+LAM or FTC)first to reduce serum HBV before adding the third anti-retroviral d

23、rug may be an option.This strategy need to be confirmed.,Among the subjects with no virologic response at week 24,45 of 57 subjects in the group given interferon and ribavirin(79 percent)underwent liver biopsy,as did 26 of 37 subjects in the group given peginterferon and ribavirin(70 percent).A hist

24、ologic response was observed in 25 of these 71 subjects(35 percent),36 percent of such subjects in the group given interferon and ribavirin and 35 percent of such subjects in the group given peginterferon and ribavirin.The magnitude of the reduction in HCV RNA levels among subjects with a histologic

25、 response did not differ from that among those without a histologic response,indicating that a partial virologic response did not predict histologic improvement.Among the 39 subjects with a virologic response at week 24,27 underwent a biopsy at week 48.Fourteen of these 27 subjects(52 percent)had a

26、histologic improvement,11(41 percent)had no change,and 2(7 percent)had worsening disease,Peginterferon Alfa-2a plus Ribavirin versus Interferon Alfa-2a plus Ribavirin for 目前的问题Chronic Hepatitis C in HIV-Coinfected Persons,治疗影响的变量,Unfortunately,there is no noninvasive test that accurately predicts ei

27、ther the degree of injury seen on liver biopsy or subsequent clinical events,although elastography,a measure of liver stiffness,in combination with serum markers shows promise in the evaluation of fibrosis,1对所有HIV感染者均应进行抗-HCV的检测;2对HIV感染而且抗-HCV阳性者,应进行HCV RNA检测以肯定HCV感染;3对HIV/HCV共同感染者,并有严重肝病的可能时,应治疗丙肝。

28、对治疗应答、疾病的危害性及治疗药物的副作用,应权衡利弊;4对大多数HIV感染者,治疗其丙肝可用PEG IFN-2a加RBV,疗程48周,对治疗药物的副作用应密切观察;5RBV应用于骨髓造血功能降低,并正在服用齐多夫定(zidovudine)或司他夫定(stavudine)的病人,应当特别细心观察可能出现的副作用。在开始服用RBV之前,病人正在应用地丹诺辛者,应当停用,可换用相当的抗逆转录病毒的药物;6HIV感染者伴有失代偿性肝病,可考虑作原位肝移植的对象。,治疗反应,(一)HCV RNA基因为1型，或(和)HCV RNA定量2106拷贝/ml者，可选用下列方案之一：1PEG-IFN联合利巴韦林

29、治疗方案：PEG-IFN-2a 180g，每周1次皮下注射，联合口服利巴韦林1 000mg/d，至12周时检测HCV RNA：(1)如HCV RNA下降幅度2个对数级，则考虑停药；(2)如HCV RNA定性检测为阴转，或低于定量法的最低检测限，继续治疗至48周；(3)如HCV RNA未转阴，但下降2个对数级，则继续治疗到24周。如24周时HCVRNA转阴，可继续治疗到48周；如果24周时仍未转阴，则停药观察。2普通IFN联合利巴韦林治疗方案：IFN 3MU5MU，隔日1次肌肉或皮下注射，联合口服利巴韦林1000mg/d，建议治疗48周。3不能耐受利巴韦林不良反应者治疗方案：可单用普通IFN、复合IFN或PEG-IFN，方法同上。(二)HCV RNA基因为非1型，或(和)HCV RNA定量2106拷贝/ml者，可采用以下治疗方案之一：1PEG-IFN联合利巴韦林治疗方案：PEG-IFN-2a 180g，每周1次皮下注射，联合应用利巴韦林800mg/d，治疗24周。2普通IFN联合利巴韦林治疗方案：IFN 3MU每周3次肌肉或皮下注射，联合应用利巴韦林8001000mg/d，治疗2448周。3不能耐受利巴韦林不良反应者治疗方案：可单用普通IFN或PEG-IFN。,