核苷类似物的及妊娠安全性及临床应用

1、核苷类似物的及妊娠安全性及临床应用核苷（酸）类似物的生殖安全性核苷（酸）类似物的生殖相关临床研究核苷（酸）类似物生殖相关应用的推荐意见主 要 内 容 FDA的妊娠安全药物分级标准FDA Classification of Drug Safety During Pregnancy FDA. Available at: /fdac/features/2001/301_preg.html. Accessed October 20, 2008.FDA批准的治疗慢性乙型肝炎妊娠安全分级药物Pregnancy Category of FDA-Approved Treatments for Chronic

2、HBVDrugs package insert. 【生殖毒性】 大鼠经口给予拉米夫定4000 mg/kg/天(血药浓度为人临床血药浓度的80-120倍)，其生育力和断奶后仔代的存活、生长、发育未受明显影响。大鼠和家兔分别经口给予拉米夫定4000和1000 mg/kg/天(血药浓度约为人临床推荐剂量血药浓度的60倍)，均未表现出明显的致畸作用。当家兔血药浓度与人临床推荐剂量的血药浓度相近时，出现早期胚胎死亡率升高。但大鼠血药浓度达到相当于人临床推荐剂量血药浓度的60倍时，未见此类现象发生。对妊娠大鼠和家兔的研究结果显示，拉米夫定可以穿过胎盘进入胎仔体内。尚无拉米夫定用于妊娠妇女的充分和严格对照的

3、临床研究资料。哺乳期大鼠乳汁中拉米夫定浓度和其血浆浓度相近。 见贺普丁说明书拉米夫定的生殖安全性 1989年1月至2008年7月间共有超过4600名孕妇在妊娠期的中三月或末三月使用拉米夫定，并向美国抗逆转录病毒药物妊娠登记处（Antiretroviral Pregnancy Registry，APR)登记。这些有限的资料显示，使用拉米夫定母亲的新生儿出生时缺陷并不增多。在妊娠头三月使用拉米夫定母亲的新生儿出生时缺陷为2.7%、中三月或末三月使用拉米夫定母亲的新生儿出生时缺陷为2.5%，均与未使用药物者相当。这些资料初步证实了拉米夫定的生殖安全性。因此2006年美国NIH关于慢性乙型肝炎的专题研

4、讨会中将拉米夫定重新分级为妊娠安全性B级，或参照B级药物处理。 Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989 through 31 July 2008. Wilmington, NC: Registry Coordinating Center; 2008. Antiretroviral Pregnancy Registry Web site. Hoofnagle JH，

5、Doo E， Liang TJ， et al. Management of hepatitis B: Summary of a clinical research workshop . Hepatology，2007;45:1056 -1075拉米夫定的生殖安全性HIV阳性孕妇接受抗病毒治疗死产(Stillbirth)Mandelbort L, et al JAMA 2001,285:2083-2093The Petra study team Lancet.2002,359:1178-1186Moodley D, et al.JID.2003,187:725-735拉米夫定与妊娠安全性（MAT

6、A分析）Major birth defects (cardiac malformation polydactylytalipes)Mandelbort L, et al JAMA 2001,285:2083-2093The Petra study team Lancet.2002,359:1178-1186Moodley D, et al.JID.2003,187:725-735拉米夫定与妊娠安全性（MATA分析） 【生殖毒性】当暴露量大约为人治疗剂量的暴露量19倍时，未见对大鼠生育力的影响。大鼠和家兔经口给予阿德福韦酯（暴露量分别约为人治疗剂量10mg/天下的23和40倍），未见胚胎毒性和致

7、畸作用。妊娠大鼠静脉注射给予阿德福韦，在能产生明显母体毒性剂量时（相当于人体暴露量的38倍），胚胎毒性和胎仔畸形（全身性水肿，眼泡凹陷，脐疝和尾巴扭结）的发生率增加。在静脉注射剂量相等于人暴露量12倍时未见不良影响。 见贺维力说明书阿德福韦酯的生殖安全性 【生殖毒性】生殖毒性研究中，连续4周给予恩替卡韦，剂量最高30mg/kg，即给药剂量超过人体最高推荐剂量天的90倍时，没发现雄性和雌性大鼠生育力受影响。恩替卡韦毒理学研究中，当剂量至人体剂量35倍或以上时，发现啮齿类动物与狗出现输精管的退行性变。猴实验中未发现睾丸改变。 在大鼠和家兔生殖毒性研究中，口服博路定剂量达200和13mg/kg/天，

8、即相当于人体最高剂量天的28倍（对于大鼠）和212倍（对于家兔）时，没有发现胚胎和母体毒性。在大鼠实验中，当母鼠用药量相当于人体剂量3100倍时，观察到恩替卡韦对胚胎-胎鼠的毒性作用（重吸收）、体重降低、尾巴和脊椎形态异常和骨化水平降低（脊椎、趾骨和指骨）并观察到额外的腰椎和肋骨。在家兔实验中，对雌兔用量为人体日剂量的883倍时，观察到对胚胎-胎兔的毒性作用（吸收）、骨化水平降低（舌骨），并且第13根肋骨的发生率增加。在对出生前和出生后大鼠口服恩替卡韦的研究中发现用药量大于人的日剂量的94倍未对后代产生影响。 见博路定说明书恩替卡韦的生殖安全性 【生殖毒性】生殖毒性研究中，雌雄大鼠的全身暴露剂

9、量约为人治疗剂量的14倍时，未观察到有损害生育力的证据。 临床前研究中替比夫定无致畸性，且显示其对胚胎和胎仔发育无不良作用。对妊娠大鼠和家兔的研究显示替比夫定可以通过胎盘。对大鼠和家兔的发育毒理学研究表明，在剂量达每天1,000 mg/kg，暴露量分别高出人体治疗剂量（600mg/日）的6倍和37倍时，未观察到对胎仔有损害的证据。 见替比夫定说明书替比夫定的生殖安全性核苷（酸）类似物的生殖安全性核苷（酸）类似物的生殖相关临床研究核苷（酸）类似物生殖相关应用的推荐意见主 要 内 容 慢性HBV感染者妊娠期间的变化Changes in Chronic HBV Infection During Pr

10、egnancy?多数肝炎不加重 No worsening of liver disease in the majority of women during pregnancy; liver enzymes frequently normalize1有发生暴发性肝炎的病例报告 However, case reports of hepatic exacerbations/fulminant hepatic failures in HBsAg-positive pregnant women2-4 1. Terrault NA, et al. Semin Liver Dis. 2007;(suppl

11、1):18-24.2. Mahtab MA, et al. Hepatobiliary Pancreat Dis Int. 2008;7:161-164.3. Yang YB, et al. World J Gastroenterol. 2004;10:2305-2306.4. Rawal BK, et al. Lancet. 1991;337:364.妊娠期间肝炎发作治疗抗病毒治疗阻止病情加重，降低肝衰竭的风险抗病毒治疗降低病毒载量，阻止母婴垂直传播抗病毒治疗已经形成共识，使用妊娠安全药物抗病毒治疗期间意外妊娠的安全性42例育龄女性患者在接受拉米夫定治疗时意外受孕。其中38例选择继续拉米夫定

12、治疗同时继续妊娠。至1年时血清HBV DNA阴转率92.1%（35/38），HBeAg血清转换率26.3%（10/38），ALT复常率73.2%（28/38），耐药突变率11.4%（4/35）。无1例患者发生流产、早产、胎儿窒息、死胎、胎儿畸形。无1例新生儿发育不良及相关健康受损等状况。新生儿中有12例动态检测HBV标志物，12个月时无1例HBsAg或HBV DNA阳性。研究提示，病情活动的慢性乙型肝炎育龄妇女接受拉米夫定治疗后病情能得到有效控制，病毒复制水平下降。未发现母婴安全性和胎儿致畸性等问题，而且母婴垂直传播减少。 苏关关，赵年丰，方素华，等. 慢性乙型肝炎患者妊娠期服用拉米夫定的安全

13、性和抗病毒效果观察.肝脏 2002：7：84 Su GG, Pan KH, Zhao NF, et al. Efficacy and safety of lamivudine treatment for chronic hepatitis B in pregnancy. World J Gastroenterol 2004;10:910-912.剖腹产不影响免疫接种失败的发生率No effect of cesarean section on incidence of immunoprophylaxis failure1对无条件免疫接种者，剖腹产可能减少母婴传播 If immunoprophyl

14、axis cannot be provided, elective cesarean section might reduce mother-to-child-transmission of HBV2 1. Wang J, et al. Chin Med J. 2002;115:1510-1512.2. Yang J, et al. Virol J. 2008;5:100.分娩方式对HBV传播无影响Mode of Delivery Has No Effect on HBV Transmission1. Linnemann CC, et al. Lancet. 1974;2:155.2. Hil

15、l JB, et al. Obstet Gynecol. 2002;99:1049-1052.3. Cornberg M, et al. J Viral Hepat. 2008;15:1-21.4. Johnson MA, et al. Clin Pharmacokinet. 1999;36:41-66.哺乳对HBV传播的风险Breast-feeding and Risk of HBV Transmission母乳中可检出HBV HBV can be detected in breast milk1经正规免疫接种的新生儿可以母乳喂养 Neonates that are correctly im

16、munized may be breast-fed2,3警告Caveat: 母乳中可检出核苷（酸）类似物 nucleos(t)ide analogues can be detected in breast milk4新生儿疫苗接种疫苗可预防HBV传播Prevention of HBV Transmission by Postnatal Vaccination主动免疫加被动免疫有效率高Active plus passive immunization most effective1母亲HBV水平与传播有关Role of maternal HBV DNA on transmision2HBV DNA

17、 150 pg/mL = 32% transmission1. Ranger-Rogez S, et al. Expert Rev Ant Infect Ther. 2004;2:133-145.2. del Canho R, et al. Vaccine. 1997;15:1624-1630.围产期HBV传播： HBV水平的影响Perinatal Transmission of Hepatitis B: Risk Factor HBV DNAHBeAg positive (n = 61) 4 transmissions (6.6%)138 HBsAg positive, HBV DNApos

18、itive womenActive/passive vaccinationHBeAg negative (n = 77)0 transmissions (0%)HBV DNA cutoff: 8 log10 copies/mLWiseman E, et al. AASLD 2008. Abstract 827.抗病毒治疗能否降低HBV传播发生率Can Antiviral Treatment Reduce Vertical HBV Transmission?不能完全阻断No complete prevention of transmission, even in case of successf

19、ul LAM treatment1分娩前拉米夫定治疗1个月可减少传播LAM given 1 month before delivery decreased HBV transmission from 28.0% in untreated historical controls to 12.5% (OR: 2.9; 95% CI: 0.29-28.0)2All received standard prophylaxisHigh maternal viremia associated with vaccination failureNo adverse events noted with LAM

20、1. Kazim SN, et al. Lancet. 2002;359;1488-1489.2. van Zonneveld M, et al. J Viral Hepat. 2003;10:294-297.妊娠期抗病毒治疗阻断母婴HBV传播HBV Treatment During PregnancyAll infants received HBV vaccine (10 g/0.5mL) and HBIG (200 IU, single dose)Primary endpoint: HBsAg- positive infant at 1 yearSecondary endpoint: HB

21、sAb+, HBV DNA+Xu WM, et al. Hepatology. 2004;40:272A. Abstract 246.Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat 2009;16:94-103.LAM 100 mg/d

22、ay (n = 56)Placebo (n= 58)From 32 2 weeks of gestationTo 4 weeks postpartumHBsAg-positive pregnant women, HBV DNA 1000 mEq/mL(N = 114)Improved outcomes for the infants receiving LAM1.妊娠期间使用替比夫定对于母婴是安全的；2.免疫耐受的高病毒载量母亲使用替比夫定是有效的，平均3个月时HBV DNA低于检测值约21%；3.替比夫定治疗母亲的婴儿1个月时的感染率为0，对照组为10%4.病毒携带母亲和慢性肝炎应当分别统计

23、；5.本文中使用的检测方法有待改进，HBV DNA和血清学检查方法均为上海科华公司生产，HBV DNA 5*102 - 1*108 copies/ml，血清学指标为ELISA.点 评Editorial In summary, treatment of HBV infection during pregnancy remains a challenge, the risks and benefits must be weighed carefully and there are still numerous gaps in our knowledge. The benefits of treat

24、ment appear to be most pronounced in cases with high maternal viremia to prevent transmission and in mothers with advanced fibrosis to prevent flares. Viable treatment choices are limited to lamivudine, tenofovir, and telbivudine. Of these, lamivudine and tenofovir appear to be the therapeutic optio

25、ns with reasonable human exposure and safety data in pregnancy and we do see now an increasing number of data for the safety of telbivudine, too.核苷（酸）类似物的生殖安全性核苷（酸）类似物的生殖相关临床研究核苷（酸）类似物生殖相关应用的推荐意见主 要 内 容 NIH对妊娠抗病毒治疗的推荐意见抗病毒治疗期间妊娠的慢性乙型肝炎患者建议改用拉米夫定治疗。Currently,lamivudine and zidovudine are recommended

26、for HIV-1infected women during pregnancy. Thus, in women beingtreated for hepatitis B who become pregnant, switching to lamivudine for the duration of pregnancy is a reasonable recommendation.Jay H. Hoofnagle, Edward Doo, T. Jake Liang, et al. Management of hepatitis B: Summary of a clinical researc

27、h workshop. Hepatology 2007;45:1056-1075 Keeffe对妊娠抗病毒治疗的推荐意见The use of lamivudine in the last month of pregnancy might prevent mother-to-infant transmission of HBV in women with high HBV DNA levels; However, lamivudine might not prevent the perinatal transmission of precore mutant HBV. Because of th

28、is experience, lamivudine is the most commonly used antiviral agent for the treatment of pregnant women with CHB. For these individuals, antiviral therapy with lamivudine, telbivudine, or tenofovir during the third trimester is recommended.Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorith

29、m for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008;6:13151341.EASL对妊娠抗病毒治疗的推荐意见4.13.7. Pregnant women Lamivudine, adefovir and entecavir are listed by the FDA as pregnancy category C drugs, and telbivudine and tenofovir as c

30、ategory B drugs. These classifications are based on the risk of teratogenicity in preclinical evaluation. There is a considerable body of safety data in pregnant HIV-positive women who have received tenofovir and/or lamivudine or emtricitabine. Recent reports suggest that lamivudine therapy during t

31、he last trimester of pregnancy in pregnant HBsAg-positive women with high levels of viremia reduces the risk of intra-uterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIg and HBV vaccination. Tenofovir or tenofovir with emtricitabineor entecavir co

32、uld be considered. Although apparently safe, these protocols require further confirmation. (B2) HBVinfected women should be monitored closely after delivery as exacerbations of chronic hepatitis B may occur.European Association for the Study of the Liver. EASL clinical practice guidelines: managemen

33、t of chronic hepatitis B . J Hepatol，2009，50:227-242van Zonneveld M, van Nunen AB, Niesters HG, de Man RA, Schalm SW, Janssen HL. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat 2003;10:294297.ter Borg MJ, Leemans WF, de Man RA, J

34、anssen HL. Exacerbation of chronic hepatitis B infection after delivery. J Viral Hepat 2008; 15:3741.APASL对特殊患者的治疗推荐意见育龄期妇女建议10：对于育龄期妇女，非妊娠患者优先选择干扰素治疗，治疗期间采用避孕措施。对于口服抗病毒药物治疗期间妊娠患者，可以继续使用B类药物治疗(VI)。Recommendation 10: For female patients of childbearing age, IFN-based therapy is preferred for nonpregn

35、ant women and pregnancy is discouraged during IFN therapy. Women who become pregnant while on oral antiviral drug(s) can continue treatment with category B drug(s)(VI).Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2008 update. Yun-Fan Liaw, et al. Hepatol int(2008)2:26

36、3-283慢性乙型肝炎防治指南(2010更新版）特殊情况的处理9.妊娠相关情况处理 育龄女性患者，若有治疗适应症，未妊娠者可应用干扰素或核苷（酸）类似物，且在治疗期间应采取可靠措施避孕（I）。口服抗病毒药物治疗过程中发生妊娠患者，若是拉米夫定或其它妊娠B级药物，在充分告知风险、权衡利弊、患者知情同意情况下，可继续治疗。妊娠中出现肝炎发作者，视程度决定是否给予抗病毒治疗，在充分告知风险、权衡利弊，患者知情同意情况下，可用拉米夫定，替比夫定或替诺福韦治疗（III）。中华医学会肝病学分会，中华医学会感染病学分会. 慢性乙型肝炎防治指南(2010年版) .中国病毒病杂志, 2011, 1(1):9-23.妊娠相关情况处理 育龄期妇女有指征者治疗中妊娠者妊娠中乙肝发作者IFN或NUC LAM/LdT/TDF 充分告知签署知情同意 有效避孕继续治疗 充分告知签署知情同意 慢性乙型肝炎防治指南(2010更