Medscape: Treatment of Hepatitis B (May 2002)

liver411

Geoffrey L. Braden, MD http://www.medscape.com/viewarticle/434534 Introduction Hepatitis B remains a major worldwide public health problem. Globally, there are 350 million carriers of the hepatitis B virus (HBV) vs 370 million carriers of the hepatitis C virus (HCV). In the United States, 4.0 million persons are positive for HCV antibodies and 2.7 million of these individuals are chronic carriers, with positive HCV polymerase chain reaction (PCR) assays.[1] In comparison, it is estimated that 1.25 million carriers of hepatitis B are present in the United States. Although hepatitis C may be associated with a higher incidence of chronic hepatitis compared with hepatitis B, and may lead to cirrhosis in 20% to 25% of patients, chronic hepatitis B leads to chronic hepatitis and cirrhosis in 15% to 20% of carriers, and is associated with an even higher incidence of hepatocellular carcinoma (HCC) in asymptomatic carriers than is hepatitis C. The hepatitis B virus is carcinogenic in chronic carriers without objective evidence of liver disease. The yearly risk of HCC in asymptomatic hepatitis B carriers is 0.47%. The incidence of HCC in hepatitis B-related cirrhosis is 2% to 6% per year, similar to the incidence of HCC in HCV-related and other forms of cirrhosis. This tendency for the HBV to induce hepatic carcinogenesis accounts for the fact that HCC is one of the leading forms of cancer in China and Southeast Asia. Asymptomatic carriers of HBV should be screened yearly, using serum alpha feto-protein studies and liver ultrasound to look for HCC. Although definitive studies are lacking, HBV patients with cirrhosis should be screened every 6 months with a serum alpha feto-protein test and an ultrasound of the liver. This screening protocol affords the best opportunity to diagnose small HCCs that can be treated for cure with either a segmental hepatic resection of the involved area or with liver transplantation. Currently, liver transplantation is reserved for patients with HCC who have 3 tumors, all < 3.0 cm in size, or a single tumor 2x normal) are present, along with active liver disease on liver biopsy. Commercial assays for these mutations are available to help define this subset. The prevalence of these mutations ranges from 20% to 90% among patients originating from Europe and the Mediterranean, 10% to 38% among those from Asia and the South Pacific, and is approximately 10% among those in the United States.[4] Use of Genotyping in Hepatitis B The use of genotyping will increase in the future in order to help define different subtypes of patients. The precore mutation is more common with genotype D, which is more prevalent in the Mediterranean, and is rare in patients with genotype A, which is the most common genotype in the Unites States and Western Europe. Chu and colleagues[5] looked at the distribution of genotypes in the US population; all 7 known HBV genotypes were found in this country. The majority of Americans were found to have genotypes A and C (67% combined), but there are regional and ethnic differences in the nationwide breakdown. The precore variant was also found to be more prevalent in genotype D patients. The core promoter variant was more common in genotypes C and D. Genotype D patients showed a higher incidence for developing decompensated cirrhosis. Chien and colleagues[6] looked at variables that affected a sustained response (HBeAg seroconversion) to lamivudine therapy in a group of Taiwanese patients. Using a stepwise regression model that examined many clinical variables, only genotype was found to be the predictor of a sustained response to lamivudine. Sixty-one percent and 14% of patients with genotypes B and C, respectively, had a sustained response. In a related paper, Watanabe and associates[7] looked at the association between genotype and the development of HCC in a group of 100 patients followed for 11 years. Seventy-four percent of their patients were genotype C and 26% were genotype B; HCC developed in 25 patients. Genotype C, along with age, lower platelet counts, and higher gamma-glutamyltranspeptidase (GGTP) levels were associated with a greater risk of HCC. Although the number of patients followed in this study was small, it is possible that genotyping will be used routinely in the future in the setting of hepatitis B to help define subgroups of patients at risk for the development of HCC who will respond to treatment. In contrast to hepatitis C, at present, there are no reliable data on the response of HBV to interferon or lamivudine therapy based on genotype. Treatment of Chronic Hepatitis B The goals of treatment are to decrease or eliminate viral replication and improve histology, by decreasing the amount of inflammation present, and either stabilizing or reversing fibrosis. Other goals are to prevent the development of HCC and to prolong life. Interferon Therapy In the early 1990s, interferon was approved for the treatment of hepatitis B in the United States. The standard dose is 5 million units daily or 10 million units 3 times per week given subcutaneously for a total of 16 weeks. Patients treated should have aminotransferase levels that are > 2x elevated, be HBeAg-positive, and have chronic hepatitis on liver biopsy. The United States Food and Drug Administration (FDA) has approved the use of interferon in patients with serum aminotransferases > 5x normal, but the consensus is that patients with aminotransferases > 2x normal should be evaluated for treatment because they have a significant incidence of chronic hepatitis on liver biopsy and also a significant likelihood of responding to treatment. A treatment response is defined as normalization of liver enzymes, loss of HBV DNA by hybridization assay, and loss of HBeAg with or without conversion to anti-HBe positivity. A sustained viral response is defined as maintaining this improvement for 6 months beyond the end of treatment. Forty percent of patients with aminotransferases between 100 and 200 U/L and 50% with aminotransferases > 200 will normalize serum ALT on treatment. Sixty-seven percent of patients with aminotransferases between 100 and 200 U/L and close to 100% of those with aminotransferases > 200 will develop undetectable HBV DNA on treatment.[4] Thirty-seven percent of patients will develop a sustained loss of HBV DNA, 33% a sustained loss of HBeAg, and 8% will lose HBsAg over time. Liver function tests often flare during treatment because the interferon triggers an immunologic clearance of the virus. This event can cause acute hepatic decompensation in patients with cirrhosis. Patients with advanced cirrhosis should be treated with lamivudine. Pegylated interferon is now being studied for the treatment of chronic hepatitis B. Cooksley and colleagues[8] looked at a 24-week course of pegylated interferon alfa-2a compared with regular interferon alfa-2a. Twelve percent of patients who received short-acting interferon, compared with 27% to 28% of patients who were treated with 90 or 180 mcg per week of pegylated interferon, achieved a sustained response, as defined by loss of HBeAg, undetectable HBV DNA by hybridization assay, and ALT normalization. Pegylated interferon may be one of the treatment approaches of the future. Ribavirin, which is used in hepatitis C regimens, does not have any activity against hepatitis B. Lebensztejn and colleagues[9] looked at the sustained response to short-acting interferon alfa given to 71 children with chronic hepatitis B. Thirty-two of 71 (45%) developed a sustained response to 3 million units of interferon alfa given 3 times per week for 20 weeks. The patients were followed for 36 months and all of the responses were durable. All patients had negative HBV DNA assays and maintained their seroconversion to anti-HBe. Nucleoside Analog Therapy Lamivudine was approved by the FDA for the treatment of chronic hepatitis B in 1999. The approved dose is 100 mg/day given orally for 1 year. Clinical trials[10] have shown response rates at 1 year that include a 32% loss of HBeAg and a 17% seroconversion rate. Almost all patients initially become HBV DNA-negative on treatment. Treatment beyond 1 year is both controversial and problematic. In one study of long-term therapy in Asian patients,[11] the HBeAg conversion rate was 47% after 4 years of continued lamivudine treatment. Improvement in fibrosis occurs in patients with cirrhosis and bridging fibrosis. Asians and whites respond similarly to lamivudine therapy. Patients with aminotransferases > 2x normal are candidates for treatment. Patients with aminotransferases > 5x normal clear HBeAg in 50% to 60% of cases with 1 year of treatment, compared with 25% to 30% of patients with aminotransferases between 2x-5x that of normal. This finding is similar to that observed with interferon, in which case the response is better if the patient has aminotransferases increased > 5x normal. The incidence of lamivudine resistance increases proportionately with the duration of treatment. YMDD-resistant mutations in HBV DNA polymerase develop in 20%, 38%, 49%, and 66% after 1,2,3, and 4 years of continued treatment.[12,13] YMDD resistance is generally associated with lower HBV DNA levels and lower aminotransferase elevations compared with before treatment. However, the long-term natural history of YMDD-resistant mutants is unknown in patients who have been treated with lamivudine. Although generally these mutants do not cause a major reactivation of chronic hepatitis B, fulminant hepatitis has been reported.[14] On the other hand, emergence of YMDD mutants can be associated with continued control of the disease. I am currently treating a patient with HBV-induced polyarteritis nodosa who presented with abdominal pain, peripheral neuropathy, hypertension, and significant renal failure. He has been on lamivudine for 20 months. Fourteen months into treatment, he developed YMDD-resistant mutants, with a rise in his HBV DNA from nondetectable to 14,000,000 copies/mL. He has not developed a recurrence of his disease. Presumably, the lamivudine is still suppressing the wild-type hepatitis virus, which caused the vasculitis initially (Geoffrey L. Braden, 2002; personal observation). Adefovir dipivoxil is currently under review by the FDA for treatment of wild-type and lamivudine-resistant chronic hepatitis B. It has in vitro and in vivo activity against wild-type and YMDD variants. The dose is 10 mg, given once daily. It appears to be effective and no resistance has been reported out to 136 weeks of treatment.[4,15,16] Adefovir can cause renal insufficiency and is contraindicated in patients with chronic renal failure. Entecavir is another nucleoside analog under study for the treatment of chronic hepatitis B. It is a potent inhibitor of HBV DNA polymerase and is also active against wild-type virus and lamivudine-resistant YMDD mutations. Lamivudine can be given to patients with decompensated cirrhosis due to chronic hepatitis B. It has been reported to increase albumin levels, decrease bilirubin levels, decrease Child-Pugh scores, prolong survival, and possibly delay the need for liver transplantation.[4] Future strategies may use adefovir and lamivudine in combination to treat patients in this setting. Trials are currently in progress using short-acting interferon or pegylated interferon in combination with lamivudine. The preliminary results of these studies appear promising. Other nucleoside analogues under study for treatment of chronic hepatitis B include famciclovir, emtricitabine, and tenofovir. Lim and colleagues[17] presented a phase 2 dose-ranging study of Val-LdC, an L-nucleoside agent with activity against hepatitis B. Patients were treated for 28 days and achieved a 3.6-log10 drop in HBV viral loads. Treatment of HBeAg-Negative Chronic Hepatitis B The response to treatment in patients with precore/core promoter mutations is not predicted by baseline ALT or HBV DNA levels. HBV DNA levels are lower in these patients than in patients with wild-type virus, and it may be necessary to use PCR assays to follow the response to treatment. If interferon is used, patients should be treated for at least 12 months. When lamivudine is employed, there is a high rate of relapse in patients who respond to 1 year of therapy. Treatment beyond 1 year may be necessary, but is of unproven value. The natural history of YMDD mutants developing in patients with precore/core promoter variants treated with lamivudine is unknown. Better treatment for this subgroup is a subject of major clinical investigation. Conclusion More effective therapy is needed for the treatment of patients with chronic hepatitis B. Current therapies produce a complete cure (loss of HBsAg) in only 8% to 10% of patients. The current goals of treatment are to produce HBeAg seroconversion, which usually results in a significant improvement in liver histology and may slow or prevent the development of cirrhosis. Currently, candidates for treatment include patients with minotransferases > 2x normal, chronic hepatitis on liver biopsy, HBV DNA levels > 100,000 by hybridization assay, and HBeAg positivity. The future is bright for the development of new nucleoside analogs that will be used alone or in combination with interferon or other nucleoside agents, in a manner similar to that currently employed to treat other chronic viral diseases, such as HIV. References 1.. Alter M, Kruszon-Moran D, Wainan OU, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-562. 2.. Lok SF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225-1241. 3.. Manno M, Grottola A, Ferretti I, et al. Natural history of chronic asymptomatic HBV infection: survival analysis after thirty years. Gastroenterology. 2002;122:A-627. [Abstract #85] 4.. Perrillo R. Hepatitis B: Treatment, AASLD State-of-the-Art Lecture. Program and abstracts of Digestive Disease Week 2002; May 19-22, 2002; San Francisco, California. [Sp419] 5.. Chu CJ, Keefe EB, Han SH, et al. HBV Genotypes in the United States-Results of a nation-wide study. Gastroenterology. 2002;122:A-627. [Abstract #86] 6.. Chien RN, Liaw YF, Tsai SL. HBV genotype is the major factor for durability of HBeAg response to lamivudine therapy. Gastroenterology. 2002;122-216. [Poster #T1359] 7.. Watanabe H, Enomoto N, Ikeda T, et al. Association between HBV genotype and development of hepatocellular carcinoma. Gastroenterology. 2002;122-215. [Poster # T1354] 8.. Cooksley GE, Piratvisuth T, Wang YJ, et al. 40 KDA Peginterferon alpha 2a (Pegasys): Efficacy and safety results from a phase II, randomized, actively controlled, multicenter trial in the treatment of HBeAg positive chronic hepatitis B. Hepatology. 2001;34:349:710A. 9.. Lebensztejn DM, Kaczmarski M, Sinkiewicz J, et al. Long term evaluation of children with chronic hepatitis B after HBeAg/Anti-HBe seroconversion caused by interferon alpha treatment. Gastroenterology. 2002;122:A-303. [Poster #M1448] 10.. Dienstag, JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341:1256-1263. 11.. Chang TT, Lai CL, Liaw YF, et al. Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic HBV (CHB) patients treated with lamivudine for four years. Antivir Ther. 2000;5(suppl 1):44A. 12.. Leung NWY, Lai CL, Chang TT, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology. 2001;33:1527-1532. 13.. Liaw YF, Leung NWY, Chang TT, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology. 2000;119:172-180. 14.. Wang JH, Lu SN, Lee CM, et al. Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis. Scand J Gastroenterol. 2002;37:366-369. 15.. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil (ADV) 10 mg for the treatment of chronic hepatitis B. Gastroenterology. 2002;122-216. [Poster #T1366] 16.. Peters M, Schiff E, Benhamou Y, et al. Adefovir dipivoxil (ADV) demonstrates viral efficacy and clinical benefit in the treatment of lamivudine resistant (LAM-R) chronic HBV: An analysis of four clinical trials. Gastroenterology. 2002;122-216. [Poster # T1367] 17.. Lim, SG, Lai CL, Dan YY, et al. Val-LdC: First evidence of efficacy and safety for a new anti-HBV agent. Gastroenterology. 2002;122:A-628. [Abstract #87]

rachel2000

,   乙肝治疗(2002/5)

    Geoffrey L. Braden,医学博士

   乙肝一直以来都是存在于世界范围内的一个主要的公众健康问题.目前,全球大约有350,000,000乙肝病毒(hbv)携带着和370,000,000丙肝病毒(hcv)携带者.在美国,hcv PCR化验结果有4,000,000人被证实带有hcv(丙肝病毒)抗体,而其中2,700,000人属于慢性丙肝.相较之,美国国内hbv(乙肝病毒)携带者大约估计有1,250,000人.虽然丙型肝炎(hcv)相对于乙型肝炎(hbv)来说是一种影响范围更广的慢性肝炎,并且有20%-25%的丙型肝炎患者会发展成肝硬化,而乙型肝炎患者只有15%-20%的人会发展成肝硬化.但是,乙型肝炎转化成肝癌的机率却高于丙型肝炎.
   
   对于没有明显肝脏病症的病毒携带着来说,体内的乙肝病毒便是致癌物.每年无症状乙肝病毒携带者中有0.47%的人受到肝癌的威胁.每年由于乙肝所引发的肝硬化并最后导致肝癌的机率是2%-6%,而由于丙型肝炎或其他原因转化成肝硬化而最后发展成肝癌的机率也是这个数字.由于乙肝而诱发癌变已成为趋势,事实上目前在中国和东南亚肝癌已成为最主要的癌症之一.无症状的乙肝病毒携带者每年都应该进行血液检查,这样便可以通过化验血清中的蛋白和进行肝脏超音波的检查查找是否存在癌细胞.虽然缺少权威的医学研究,但是肝硬化的乙肝患者每6个月必须进行一次血液过滤以提取血清中的蛋白进行化验,并进行超音波检查.这种检测方案为微小癌细胞的诊断提供了最好的机会.也有助于肝脏坏损部分切除和肝脏移植手术后的治疗.一般来说,肝脏移植适用于有3个3.0cm大小的肿瘤或单个肿瘤的肝癌患者.

   今年,在美国的"消化系统疾病周"中经过几场卓有成效的研讨会使得关于乙肝的诊断和治疗方面的知识更加完善.医学博士Robert Perrillo出席了由"美国肝病研究协会"主办的学术会议,并作了乙肝治疗技术现状的报告."美国肝病研究协会"关于乙肝的学术研究会议于今年的5月19日召开,另一场同样由"美国肝病研究协会"组织的关于乙肝宣传的会议于5月21日举行.医学博士Jenny Heathcote 和  K .Rajender Reddy也在这些公开的学术研讨会上提出了他们的专业见解.这次评论阐述和分析了乙肝病史和乙肝病毒携带者的临床案例.并讨论区别患者基因类型的学术价值和病毒核心变异以及肝癌所带来的危害.同时提到利用干扰素.拉米夫定.阿地福韦来治疗乙肝以及核苷类似物的单独使用和合并使用,包括对代谢失调硬化患者使用拉米夫定.最后,还讨论了对于抗原呈阴性的慢性肝炎患者的治疗方案.
   

   典型乙肝病毒携带者
   在美国,乙型肝炎最常见的情况是成年乙肝病毒携带者表面抗原呈阳性.感染病毒的途径有:输血(这种情况多发生于1976年之前),使用静脉注射毒品,性行为,以及和乙肝病毒携带者一起生活而直接受到感染(感染率3%-6%),HIV(艾滋病病毒)呈阳性的患者,在进行血液透析时也有被感染的危险.当诊断结果出来是有些病人的e抗原呈阴性,e抗体呈阳性,这一类病人通常肝脏酶水平正常,在肝活检时呈现静止炎症.一旦e抗原血清转化,病毒就会从复制状态转变成完整合并状态.不论慢性肝炎程度如何目前都处于不活跃状态，通过杂交化验HBV DNA 为阴性，这种化验对于乙肝患者的诊断和治疗来说是更为精确的。DNA分支化验（bayer），混合交替化验（digene）,液体混合化验(abbott)都可以准确到100，000-1，000，000copies/ml。杂交化验显示HBV DNA 呈阴性说明病毒状态不活跃。当的PCR（一种DNA定量检测方法）化验的精确度变得更告时，所有这些患者的DNA检测结果将为阳性,有些检测工作已精确到100-400copies/ml.一般来说,患者乙肝病毒为1,000,000copies/ml时为不活跃状态.随后的这些结论明显区别于我们以往对大量病毒的处理以及对慢性丙肝患者进行PCR化验的标准.对于e抗原呈阴性的慢性肝炎患者的治疗方法有所区别,所以分开来讨论.

  Manno 和他的同事们跟踪研究了296例来自法国的无症状表面抗原阳性的供血者达30年之久.有32%的人在这段时间里表面抗原自然减弱,大多数患者肝脏酶水平正常.这组被研究的患者有着乙肝患者应有的所有症状和并发症.


   新生儿乙肝
   慢性乙型肝炎在东南亚和南非是一种地域性传染病.有50%甚至更多的乙型肝炎是通过母婴垂直感染的.新生儿和儿童的病毒具有耐药性,e抗原不会什么变化.而在成人阶段会产生e抗原血清转化.许多这样的患者在婴儿阶段HBV DNA 值较高,但肝功能正常.许多这样的患者到了成人阶段会发展成高肝脏酶,e抗原阳性的慢性乙肝.这些人即成为今后发展的肝硬化甚至肝癌群体的主体来源.这些患者中的绝大部分会在成人后自然发生血清转化,e抗原阴性,e抗体阳性.尽管发生了这些转变,大部分肝脏已经受到损害.

   最近我观察研究一位美籍华人患者,他是由于母婴传染感染了乙肝.他的母亲是一位移居到美国的台湾人.这位患者将近30岁,肝脏酶水平正常,表面抗原阳性,e抗原阴性.但是他的肝活检结果却是肝硬化.也就是说,在见到我之前他的肝脏已被感染多年的乙肝病毒损坏了.
有更多乙肝患者从东南亚移居到美国,这一类问题已日趋普遍.

   
   来自非洲撒哈拉,阿拉斯加州和地中海地区的乙肝患者
   在这些国家,乙肝病毒感染通常发生在儿童阶段人与人之间的平行感染.母婴垂直感染的情况不是很普遍.这类孩子中多数人谷丙转安酶(ALT)高.e抗原通常在青春期发生血清转化.

     e抗体阴性慢性乙肝
   这些患者precore and core promoter 变异属于活动炎症的慢性乙肝患者. HBV DNA聚合酶中Precore变量 发生a G1896A 变异,core promoter 变量发生 A1762T and G1764A 变异 .在病毒复制过程中这些变异阻碍e抗原的产生.这些患者表面抗原阳性,e抗原阴性,e抗体阳性.他们的肝脏酶水平高,慢性肝炎,循环的乙肝病毒DNA相对较低.虽然HBV DNA Bayer化验结果为阳性,还需要进行病毒定量PRC化验.这类病人对拉米夫定和干扰素会产生耐药性.记住这一点很重要,虽然不存在e抗原综合体,但这类患者大多e抗体为阳性.这类患者与不活动携带者不同,他们虽然有相似的血清状态但事实上ALT较高.(正常为>2x)
肝活检结果为活动炎症.对这些变异的化验有助于给这个子集下定义.在欧洲和地中海地区的患者中这些变异的发生率已经从20%普及到90%,亚洲和南非为10%-30%,而美国大约是10%.


   乙型肝炎基因类型
   将来基因类型的分类被更多的使用,这有助于区别不同类型的患者.对于更多存在于地中海地区的D基因型患者来说,The precore 变异更常见.而对于大部分生活在美国和西欧的A基因型患者来说这种情况较少发生.
    Chu和同事们研究了美国人口中基因类型的分类.在这个国家一共发现了7种乙型肝炎基因类型.大多数美国患者都属于A和C型(67%为混合型),但是也有地区和人种的不同. precore 变异同样在D基因型里更为经常发生.core promoter 变异更普遍存在于C,D基因型中.D基因型患者显示其代偿失调硬化发生率更高.
    Chien和同事们尝试对一群台湾患者使用拉米夫定治疗,研究e抗原血清转化效果变化.用逐步回归模式试验其临床变化,结果发现只有基因型能预示拉米夫定得持久效果.61%和14%分别属于B和C基因型有持久效果.在一份相关资料中,Watababe个他的助手们用了11年跟踪研究了一组100例患者.基因型和肝癌的发生之间的关联.这些患者中74%的人属于C基因型,26%的人属于B基因型.25人患了肝癌.C基因型患者,随着年龄的增长,血小板降低,GGTP水平升高.的肝癌的几率更高.虽然被研究的病例人数较少,但是将来基因型检测将可能被用于乙肝常规检查中,这样有助于区别那些有可能患肝癌得病患群,以便然他们得到更好的治疗.和丙肝相比,现在还没有资料表明干扰素和拉米夫定对于乙肝的治疗效果与患者的基因型有关.


   乙肝的治疗
   治疗的目的是通过减少验证,稳定或延缓纤维化,而减少或清除病毒复制并改善肝组织结构;
防止癌症的发生.


   干扰素治疗
   上世纪90年代初期,在美国,干扰素就被批准用来治疗乙肝.其使用标准是,在16个星期的时间里,每天皮下用量为5,000,000剂量.病人要求在转安酶高于正常水平,e抗原为阳性,肝活检结果为慢性肝炎的情况下进行治疗.美国食品药品管理局(FDA)已经批准把干扰素对于血清转安酶>5x的患者的治疗.一致认为那些转安酶为>2x正常水平但肝活检为严重慢性肝炎的患者也考虑给与治疗,也会有良好的治疗效果.
依据患者肝脏酶水平的正常情况,HBV DNA减少,以及e抗原减少转化成e抗体阳性来确定治疗效果.如果治疗结束后疗效能保持6个月,说明病毒处于稳定状态.有40%转安酶为100-200u/l和50%转安酶为>200的患者通过治疗,血清ALT会达到正常水平.有67%转安酶在100-200u/l之间和将近100%的转安酶>200的患者,治疗后HBV DNA变为不可查状态.37%的患者HBV DNA将持续减少,33%的人e抗原持续减少,和8%的人表面抗原持续减少.在治疗期间肝功能经常会变得异常,因为干扰素会引发病毒的免疫清除,这种情况会导致肝硬化患者发生急性代偿失调.随着患者肝硬化的发展,将需要开始使用拉米夫定.Pegylated干扰素正被研究用于治疗慢性肝炎.
   Cooksley 和他的同事们进行了一次24星期的研究课程,把Pegylated干扰素alfa-2a和常规干扰素alfa-2a进行对比.12%接受短效干扰素的患者与27%-28%接受每星期90或180mcg  Pegylated干扰素的患者相比, 后者达到了持久效果,表现为e抗原减少,HBV DNA为不可查状态,ALT正常化.
   Ribavirin 用来治疗丙型肝炎,但对乙肝没有任何疗效.
   Lebeztejn 和他的同事们观察研究对71名慢性乙肝儿童使用短效干扰素alfa是否能起到持久效果.32/71(45%)的孩子每星期3次使用3,000,000剂量的干扰素alfa,20个星期后效果稳定.经过36个月的追踪研究,结果显示所有的孩子的治疗效果的持久,所有孩子的HBV DNA化验结果为阴性,并且一直保持转化后的e抗体.


   核甘类似物治疗
   1999年FDA批准使用拉米夫定治疗乙肝.规定一年内每天用量为100mg. 临床试验显示1年内的效果比率.32%的人e抗原减少,17%的人发生血清转化,大多数患者通过治疗 HBV DNA 转为阴性.但治疗达一年以上的效果比率则有所争议和质疑.
   在对亚裔患者的一项长期研究中,坚持拉米夫定治疗4年后e抗原转化率为47%.有肝硬化和桥纤维化的患者纤维化得到改善.亚洲任何白种人使用拉米夫定的治疗,效果相似.转安酶>2x的患者也是适合治疗的人群.转安酶>5x的患者和25-30%转安酶在2x-5x之间的患者相比,经过一年的治疗有50%-60%的人e抗原清晰.转安酶 >5x的患者使用干扰素的效果良好,这一点说明拉米夫定的治疗效果与干扰素一样.拉木夫定的治疗效果好坏与治疗时间长短成正比. HBV DNA 聚合酶中 YMDD-耐药性变异随着持续治疗1,2,3,4年,其改善率分别为20%,38%,49%,60%.和治疗前相比YMDD-耐药性一般和降低的HBV DNA 水平,转安酶水平相联系.已经经过拉米夫定治疗的患者YMDD长期自然史不得而知.虽然据报道,一般来说这些变异不是激活慢性肝炎爆发的主要因素.另一方面,YMDD变异的发生与疾病的持续控制有关.最近我正在治疗以为由于HBV引发了多动脉疾病的患者,伴随腹痛,表皮神经炎,高血压和严重的肾衰竭.他已经使用拉米夫定20个月.期间在经过14个月的治疗后,发展为YMDD-耐药性变异,随之,HBV DNA 由原来的不可查上升到14,000,000copies/ml.他的其他病症也不再发作.拉米夫定还被认为可以作为抑制引发初期血管炎的wild-type病毒.

   阿地弗韦最近被FDA认定作为治疗wild-type乙肝的新药.它可以用来对付wild-type和YMDD-耐药性,每天的用量是10mg.在经过136个星期的治疗后,效果明显且无耐药性.因为阿地弗韦会引发肾脏不适,所以该药被禁止用于肾脏衰竭患者. Entecavia 是另一种研究证明可以用于乙肝治疗的核甘类似物,它对于HBV DNA 聚合酶具有高效的抑制作用,能治疗wild-type病毒和拉米夫定YMDD-耐药性变异.

   拉米夫定可以用于治疗慢性乙肝引起的代偿失调硬化,研究证明它具有提高蛋白质,降低胆红素,降低Child-Pugh值,延长寿命或减少肝脏移植的几率.将来计划将拉米夫定与阿地弗韦相结合用于治疗.初步结果显示这些研究具有可行性.其他用于慢性乙肝治疗研究的核甘类似物有famciclovir ,emtricitabine,and tenofovir.  Lim和同事们进行Val-Ldc和2阶段配置研究,并试验了L-核甘类似物对乙肝的治疗作用,患者进行了28天的治疗,HBV病毒下降3.6-log10.


    e抗原阴性慢性乙肝的治疗
  precore/core promoter 变异患者的治疗效果在ALT和HBV DNA 中无法体现.这些患者的HBV DNA 水平比wild-type病毒患者低.在治疗有所效果后应该随之进行PCR化验.如果使用干扰素至少需要12个月的疗程.患者在使用拉米夫定治疗达一年之后,很少发生反弹.治疗时间只要在一年以上,这一点尚未得到证实. precore/core promoter 变异患者在使用拉米夫定治疗后YMDD自然变异是否会得到发展,还不得而知.


   结论
   慢性乙肝患者需要得到更多更有效的治疗,只有8%-10%的患者在现阶段的治疗中痊愈(表面抗原减少).现阶段的治疗目标是能够产生e抗原血清转化,表现在肝组织明显改善,肝硬化得到延缓或防止.目前适合治疗的人群有:转安酶>2,肝活检为慢性肝炎,HBV DNA 水平>100,000,e抗原阳性.核甘类似物的发展前景是光明的,它将单独使用,或与干扰素或者其他核甘药物合并用于治疗.现阶段,同样的方法已用于治疗其他慢性病毒,如艾滋病病毒.


   附注(reference )部分省略[em03][em03]

[此贴子已经被作者于2003-1-19 19:17:53编辑过]

可可

呵呵..加油!

rachel2000

可可,我的任务完成了!!

内二科第十床

这么长啊，我真佩服你！

liverbj

我也很佩服。不愧是北外的啊！

内二科第十床

不愧是我的老乡啊……

liverbj

竟然是内二的老乡，我很同情你啊。

rachel2000

以下引用作者：liverbj 于2003-1-21 17:45:00的发言

竟然是内二的老乡，我很同情你啊。

身为他的老乡,能被你赏识,提拔...就是不幸中的万幸啊!!

内二科第十床

以下是引用rachel2000在2003-1-29 20:14:00的发言：

身为他的老乡,能被你赏识,提拔...就是不幸中的万幸啊!!

这一枪果然捅得颇有功力啊