核苷類似物的及妊娠安全性及臨床應(yīng)用

1、核苷類似物的及妊娠安全性及臨床應(yīng)用核苷（酸）類似物的生殖安全性核苷（酸）類似物的生殖相關(guān)臨床研究核苷（酸）類似物生殖相關(guān)應(yīng)用的推薦意見主 要 內(nèi) 容 FDA的妊娠安全藥物分級標(biāo)準(zhǔn)FDA Classification of Drug Safety During Pregnancy FDA. Available at: /fdac/features/2001/301_preg.html. Accessed October 20, 2008.FDA批準(zhǔn)的治療慢性乙型肝炎妊娠安全分級藥物Pregnancy Category of FDA-Approved Treatments for Chronic

2、HBVDrugs package insert. 【生殖毒性】 大鼠經(jīng)口給予拉米夫定4000 mg/kg/天(血藥濃度為人臨床血藥濃度的80-120倍)，其生育力和斷奶后仔代的存活、生長、發(fā)育未受明顯影響。大鼠和家兔分別經(jīng)口給予拉米夫定4000和1000 mg/kg/天(血藥濃度約為人臨床推薦劑量血藥濃度的60倍)，均未表現(xiàn)出明顯的致畸作用。當(dāng)家兔血藥濃度與人臨床推薦劑量的血藥濃度相近時，出現(xiàn)早期胚胎死亡率升高。但大鼠血藥濃度達(dá)到相當(dāng)于人臨床推薦劑量血藥濃度的60倍時，未見此類現(xiàn)象發(fā)生。對妊娠大鼠和家兔的研究結(jié)果顯示，拉米夫定可以穿過胎盤進(jìn)入胎仔體內(nèi)。尚無拉米夫定用于妊娠婦女的充分和嚴(yán)格對照的

3、臨床研究資料。哺乳期大鼠乳汁中拉米夫定濃度和其血漿濃度相近。 見賀普丁說明書拉米夫定的生殖安全性 1989年1月至2008年7月間共有超過4600名孕婦在妊娠期的中三月或末三月使用拉米夫定，并向美國抗逆轉(zhuǎn)錄病毒藥物妊娠登記處（Antiretroviral Pregnancy Registry，APR)登記。這些有限的資料顯示，使用拉米夫定母親的新生兒出生時缺陷并不增多。在妊娠頭三月使用拉米夫定母親的新生兒出生時缺陷為2.7%、中三月或末三月使用拉米夫定母親的新生兒出生時缺陷為2.5%，均與未使用藥物者相當(dāng)。這些資料初步證實(shí)了拉米夫定的生殖安全性。因此2006年美國NIH關(guān)于慢性乙型肝炎的專題研

4、討會中將拉米夫定重新分級為妊娠安全性B級，或參照B級藥物處理。 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陽性孕婦接受抗病毒治療死產(chǎn)(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拉米夫定與妊娠安全性（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拉米夫定與妊娠安全性（MATA分析） 【生殖毒性】當(dāng)暴露量大約為人治療劑量的暴露量19倍時，未見對大鼠生育力的影響。大鼠和家兔經(jīng)口給予阿德福韋酯（暴露量分別約為人治療劑量10mg/天下的23和40倍），未見胚胎毒性和致

7、畸作用。妊娠大鼠靜脈注射給予阿德福韋，在能產(chǎn)生明顯母體毒性劑量時（相當(dāng)于人體暴露量的38倍），胚胎毒性和胎仔畸形（全身性水腫，眼泡凹陷，臍疝和尾巴扭結(jié)）的發(fā)生率增加。在靜脈注射劑量相等于人暴露量12倍時未見不良影響。 見賀維力說明書阿德福韋酯的生殖安全性 【生殖毒性】生殖毒性研究中，連續(xù)4周給予恩替卡韋，劑量最高30mg/kg，即給藥劑量超過人體最高推薦劑量天的90倍時，沒發(fā)現(xiàn)雄性和雌性大鼠生育力受影響。恩替卡韋毒理學(xué)研究中，當(dāng)劑量至人體劑量35倍或以上時，發(fā)現(xiàn)嚙齒類動物與狗出現(xiàn)輸精管的退行性變。猴實(shí)驗(yàn)中未發(fā)現(xiàn)睪丸改變。 在大鼠和家兔生殖毒性研究中，口服博路定劑量達(dá)200和13mg/kg/天，

8、即相當(dāng)于人體最高劑量天的28倍（對于大鼠）和212倍（對于家兔）時，沒有發(fā)現(xiàn)胚胎和母體毒性。在大鼠實(shí)驗(yàn)中，當(dāng)母鼠用藥量相當(dāng)于人體劑量3100倍時，觀察到恩替卡韋對胚胎-胎鼠的毒性作用（重吸收）、體重降低、尾巴和脊椎形態(tài)異常和骨化水平降低（脊椎、趾骨和指骨）并觀察到額外的腰椎和肋骨。在家兔實(shí)驗(yàn)中，對雌兔用量為人體日劑量的883倍時，觀察到對胚胎-胎兔的毒性作用（吸收）、骨化水平降低（舌骨），并且第13根肋骨的發(fā)生率增加。在對出生前和出生后大鼠口服恩替卡韋的研究中發(fā)現(xiàn)用藥量大于人的日劑量的94倍未對后代產(chǎn)生影響。 見博路定說明書恩替卡韋的生殖安全性 【生殖毒性】生殖毒性研究中，雌雄大鼠的全身暴露劑

9、量約為人治療劑量的14倍時，未觀察到有損害生育力的證據(jù)。 臨床前研究中替比夫定無致畸性，且顯示其對胚胎和胎仔發(fā)育無不良作用。對妊娠大鼠和家兔的研究顯示替比夫定可以通過胎盤。對大鼠和家兔的發(fā)育毒理學(xué)研究表明，在劑量達(dá)每天1,000 mg/kg，暴露量分別高出人體治療劑量（600mg/日）的6倍和37倍時，未觀察到對胎仔有損害的證據(jù)。 見替比夫定說明書替比夫定的生殖安全性核苷（酸）類似物的生殖安全性核苷（酸）類似物的生殖相關(guān)臨床研究核苷（酸）類似物生殖相關(guān)應(yīng)用的推薦意見主 要 內(nèi) 容 慢性HBV感染者妊娠期間的變化Changes in Chronic HBV Infection During Pr

10、egnancy?多數(shù)肝炎不加重 No worsening of liver disease in the majority of women during pregnancy; liver enzymes frequently normalize1有發(fā)生暴發(fā)性肝炎的病例報告 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.妊娠期間肝炎發(fā)作治療抗病毒治療阻止病情加重，降低肝衰竭的風(fēng)險抗病毒治療降低病毒載量，阻止母嬰垂直傳播抗病毒治療已經(jīng)形成共識，使用妊娠安全藥物抗病毒治療期間意外妊娠的安全性42例育齡女性患者在接受拉米夫定治療時意外受孕。其中38例選擇繼續(xù)拉米夫定

12、治療同時繼續(xù)妊娠。至1年時血清HBV DNA陰轉(zhuǎn)率92.1%（35/38），HBeAg血清轉(zhuǎn)換率26.3%（10/38），ALT復(fù)常率73.2%（28/38），耐藥突變率11.4%（4/35）。無1例患者發(fā)生流產(chǎn)、早產(chǎn)、胎兒窒息、死胎、胎兒畸形。無1例新生兒發(fā)育不良及相關(guān)健康受損等狀況。新生兒中有12例動態(tài)檢測HBV標(biāo)志物，12個月時無1例HBsAg或HBV DNA陽性。研究提示，病情活動的慢性乙型肝炎育齡婦女接受拉米夫定治療后病情能得到有效控制，病毒復(fù)制水平下降。未發(fā)現(xiàn)母嬰安全性和胎兒致畸性等問題，而且母嬰垂直傳播減少。 蘇關(guān)關(guān)，趙年豐，方素華，等. 慢性乙型肝炎患者妊娠期服用拉米夫定的安全

13、性和抗病毒效果觀察.肝臟 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.剖腹產(chǎn)不影響免疫接種失敗的發(fā)生率No effect of cesarean section on incidence of immunoprophylaxis failure1對無條件免疫接種者，剖腹產(chǎn)可能減少母嬰傳播 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.分娩方式對HBV傳播無影響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.哺乳對HBV傳播的風(fēng)險Breast-feeding and Risk of HBV Transmission母乳中可檢出HBV HBV can be detected in breast milk1經(jīng)正規(guī)免疫接種的新生兒可以母乳喂養(yǎng) Neonates that are correctly im

16、munized may be breast-fed2,3警告Caveat: 母乳中可檢出核苷（酸）類似物 nucleos(t)ide analogues can be detected in breast milk4新生兒疫苗接種疫苗可預(yù)防HBV傳播Prevention of HBV Transmission by Postnatal Vaccination主動免疫加被動免疫有效率高Active plus passive immunization most effective1母親HBV水平與傳播有關(guān)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.圍產(chǎn)期HBV傳播： HBV水平的影響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.抗病毒治療能否降低HBV傳播發(fā)生率Can Antiviral Treatment Reduce Vertical HBV Transmission?不能完全阻斷No complete prevention of transmission, even in case of successf

19、ul LAM treatment1分娩前拉米夫定治療1個月可減少傳播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.妊娠期抗病毒治療阻斷母嬰HBV傳播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.妊娠期間使用替比夫定對于母嬰是安全的；2.免疫耐受的高病毒載量母親使用替比夫定是有效的，平均3個月時HBV DNA低于檢測值約21%；3.替比夫定治療母親的嬰兒1個月時的感染率為0，對照組為10%4.病毒攜帶母親和慢性肝炎應(yīng)當(dāng)分別統(tǒng)計

23、；5.本文中使用的檢測方法有待改進(jìn)，HBV DNA和血清學(xué)檢查方法均為上?？迫A公司生產(chǎn)，HBV DNA 5*102 - 1*108 copies/ml，血清學(xué)指標(biāo)為ELISA.點(diǎn) 評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）類似物的生殖安全性核苷（酸）類似物的生殖相關(guān)臨床研究核苷（酸）類似物生殖相關(guān)應(yīng)用的推薦意見主 要 內(nèi) 容 NIH對妊娠抗病毒治療的推薦意見抗病毒治療期間妊娠的慢性乙型肝炎患者建議改用拉米夫定治療。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對妊娠抗病毒治療的推薦意見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對妊娠抗病毒治療的推薦意見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對特殊患者的治療推薦意見育齡期婦女建議10：對于育齡期婦女，非妊娠患者優(yōu)先選擇干擾素治療，治療期間采用避孕措施。對于口服抗病毒藥物治療期間妊娠患者，可以繼續(xù)使用B類藥物治療(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）特殊情況的處理9.妊娠相關(guān)情況處理 育齡女性患者，若有治療適應(yīng)癥，未妊娠者可應(yīng)用干擾素或核苷（酸）類似物，且在治療期間應(yīng)采取可靠措施避孕（I）?？诜共《舅幬镏委熯^程中發(fā)生妊娠患者，若是拉米夫定或其它妊娠B級藥物，在充分告知風(fēng)險、權(quán)衡利弊、患者知情同意情況下，可繼續(xù)治療。妊娠中出現(xiàn)肝炎發(fā)作者，視程度決定是否給予抗病毒治療，在充分告知風(fēng)險、權(quán)衡利弊，患者知情同意情況下，可用拉米夫定，替比夫定或替諾福韋治療（III）。中華醫(yī)學(xué)會肝病學(xué)分會，中華醫(yī)學(xué)會感染病學(xué)分會. 慢性乙型肝炎防治指南(2010年版) .中國病毒病雜志, 2011, 1(1):9-23.妊娠相關(guān)情況處理 育齡期婦女有指征者治療中妊娠者妊娠中乙肝發(fā)作者IFN或NUC LAM/LdT/TDF 充分告知簽署知情同意 有效避孕繼續(xù)治療 充分告知簽署知情同意 慢性乙型肝炎防治指南(2010更