肝移植后乙肝复发的预防和治疗

目的 探讨原位肝移植治疗乙型肝炎相关疾病的效果及Lamivudine在防治肝移植后乙肝复发中的作用。方法 10例患者接受了原位肝移植,其中9例男性乙肝患者,1例女性为肝癌患者,术前无乙肝感染。9例乙肝患者6例并有不同程度的肝性脑病,1例并肝肾综合征,1例并上消化道大出血。9例乙肝中7例服用Lamivudine预防术后乙肝复发。结果8例存活2-15月,2例死亡。存活的8例中7例为乙肝患者,仅1例术后6月出现HBsAg（+）,但全部均肝功能良好;另1例为肝癌患者,术后出现乙肝。死亡的2例中1例为术后乙肝复发暴发性肝功能衰竭所致,另1例死于术后多器官功能衰竭。结论 原位肝移植加Lamivudine是治疗乙肝的有效方法,Lamivudine在观察期内可预防乙肝移植后乙肝复发。

核苷(酸)类似物长期治疗对慢性乙型肝炎肝纤维化的影响

全世界约1/3的人群有既往或现症乙型肝炎病毒（hepatitis B virus, HBV）感染的血清学证据，其中3.5亿人为慢性乙肝表面抗原（HBsAg）携带者，每年约有100万人死于HBV感染所致的肝衰竭、肝硬化和肝细胞癌（hepatocellular carcinoma, HCC）[1，2]。目前认为，HBV活跃复制是决定临床结局的HBV相关免疫事件的关键驱动因素[3]。因此，慢性乙型肝炎（chronic hepatitis B, CHB）治疗的总体目标是：最大限度地长期抑制HBV，减轻肝细胞炎症坏死及肝纤维化，延缓和减少肝脏失代偿、肝硬化、HCC及其并发症的发生，从而改善生活质量和延长存活时间[4]。国内外已经应用于临床的核苷（酸）类似物包括：拉米夫定（lamivudine, LAM）、阿德福韦酯（adefovir dipivoxil, ADV）、恩替卡韦（entecavir, ETV）、替比夫定（telbivudine, LdT）和替诺福韦酯（teno-fovir disoproxil fumarate, TDF）。越来越多的证据表明，应用核苷（酸）类似物长期抗病毒治疗可以延缓甚至逆转肝纤维化、肝硬化，降低HCC发生，改善患者临床结局。

Lamivudine的治疗进展

本文就近年来核苷类似物Lamivudine治疗慢性乙型肝炎和HIV感染的初步疗效及副反应作一初步综述。该药似有替代干扰素治疗的倾向。

拉米夫定抗乙型肝炎病毒耐药性的研究

乙型肝炎是引起慢性肝炎、肝硬化及肝癌的主要因素。乙型肝炎的发病机理复杂,但病毒复制是肝损伤的起动因素。干扰素(IFN)作为抗HBV制剂已广泛用于临床,经过近20年的研究证明,α-IFN是治疗慢性乙型肝炎(CHB)的有效药物。但IFN疗效仅30％～40％,由于IFN的疗效、毒副反应、价格以及使用不便等因素使其应用受限。目前,对HBV逆转录酶有抑制作用的药物拉米夫定(Lamivudin,3TC)作为新核苷类抗病毒药已受到关注。在体外和动物模型中证明有很强的抗HBV复制作用。临床实验也证明3TC可迅速降低HBV DNA的浓度,改善肝组织学的病变。

拉米夫定的抗病毒临床应用研究

拉米夫定(Lamivudine,以下简称LAM)是一种双脱氧核苷酸类似物,最初用于HIV感染的治疗,后来发现有抑制HBV复制的作用,它具有强大的抗病毒功能,能干扰HIV,直接抑制乙肝病毒逆转录酶活性,在治疗慢性乙型肝炎,预防肝移植后HBV感染,以及抗HIV感染都有很好的疗效。它口服后能迅速吸收,且吸收后的LAM大部分以原形自尿中排泄。与第一代核酸类似物不同,它不抑制线粒体的DNA,在阻滞HBV DNA时不抑制骨髓母细胞。口服方便,比较安全,副作用少。

肝纤维化及肝硬化的可逆性

王宝恩,北京友谊医院名誉院长,首都医科大学第二临床医学院主任教授、博士生导师、美国约翰·霍普金斯大学医学院客座教授。

肝移植术后防治乙肝复发的策略

目的探讨乙肝标志物阳性患者行肝肝移植治疗后如何防治乙肝复发的问题。方法回顾性分析该研究院2000年10月￣2003年10月40例乙肝病毒相关终末期肝病肝移植术后,联合应用乙肝免疫球蛋白和Lamivudine对预防乙肝病毒复发的疗效。结果40例患者随访12～36个月,2例肝癌肝移植患者因肝癌复发分别于移植后8个月和13个月死亡。术后2周31例患者HBsAg、HBeAg及HBV-DNA均为阴性;6例因经济原因未能继续使用Lamivudine和HBIG的患者术后2￣9个月HBsAg阳性,并出现明显的肝功能损害,经加用Lamivudine和HBIG并护肝治疗后转阴,肝功能明显好转;3例在术后4个月内HBV-DNA、HBsAg和HBeAg阳性,4个月后HBV-DNA降至104copies/mL以下,HBsAg转阴,肝功能良好。结论乙肝病毒相关终末期肝病肝移植术后,联合应用乙肝免疫球蛋白和Lamivudine对预防乙肝病毒复发有良好的疗效。

慢性乙型肝炎抗病毒治疗的现况

乙型肝炎病毒(HBV)是乙型肝炎发病的始动因子。既往的治疗重点仅放在保肝降酶上,不能阻止肝硬化、肝癌的发生。而新近对慢性乙肝病人进行抗病毒治疗越来越被人们所重视,以期通过抗病毒药物的应用为HBV治疗带来新的前景。

A meta-analysis of lamivudine for interruption of mother-to-child transmission of hepatitis B virus

AIM： To determine the therapeutic effect of lamivu- dine in late pregnancy for the interruption of motherto-child transmission （MTCT） of hepatitis B virus （HBV）. METHODS： Studies were identified by searching available databases up to January 2011. Inclusive criteria were HBV-carrier mothers who had been involved in randomized controlled clinical trials （RCTs） with lamivudine treatment in late pregnancy, and newborns or infants whose serum hepatitis B surface antigen （HBsAg）, hepatitis B e antigen （HBeAg） or HBV DNA had been documented. The relative risks （RRs） for inerruption of MTCT as indicated by HBsAg, HBV DNA or HBeAg of newborns or infants were calculated with 95% confidence interval （CI） to estimate the efficacy of lamivudine treatment. RESULTS： Fifteen RCTs including 1693 HBV-carrier mothers were included in this meta-analysis. The overall RR was 0.43 （95% CI, 0.25-0.76; 8 RCTs; Phet- erogeneity= 0.04） and 0.33 （95% CI, 0.23-0.47; 6 RCTs; Pheterogeneity = 0.93） indicated by newborn HBsAg or HBV DNA. The RR was 0.33 （95% CI, 0.21-0.50; 6 RCTs; Pheterogeneity = 0.46） and 0.32 （95% CI, 0.20-0.50; 4 RCTs; Pheterogeneity = 0.33） indicated by serum HBsAg or HBV DNA of infants 6-12 mo after birth. The RR （lamivudine vs hepatitis B immunoglobulin） was 0.27 （95% CI, 0.16-0.46; 5 RCTs; Pheterogeneity = 0.94） and 0.24 （95% CI, 0.07-0.79; 3 RCTs; Pheterogeneity = 0.60） indicated by newborn HBsAg or HBV DNA, respectively. In the mothers with viral load 〈 106 copies/mL after lamivudine treatment, the efficacy （RR, 95% CI） was 0.33, 0.21-0.53 （5 RCTs; Pheterogeneity = 0.82） for the interruption of MTCT, however, this value was not significant if maternal viral load was 〉 106 copies/mL after lamivudine treatment （P = 0.45, 2 RCTs）, as indicated by newborn serum HBsAg. The RR （lamivudine initiated from 28 wk of gestation vs control） was 0.34 （95% CI, 0.22-0.52; 7 RCTs; Pheterogeneity = 0.92） and 0.33 （95% CI, 0.22-0.50; 5 RCTs; Pheterogeneity = 0.86） indicated by newborn HBsAg or HBV DNA. The incidence of adverse effects of lamivudine was not higher in the mothers than in controls （P = 0.97）. Only one study reported side effects of lamivudine in newborns. CONCLUSION： Lamivudine treatment in HBV carrier- mothers from 28 wk of gestation may interrupt MTCT of HBV efficiently. Lamivudine is safe and more efficient than hepatitis B immunoglobulin in interrupting MTCT. HBV MTCT might be interrupted efficiently if maternal viral load is reduced to 〈 106 copies/mL by lamivudine treatment.

De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis

AIM:To compare efficacy of combined lamivudine(LAM)and adefovir dipivoxil(ADV)therapy with that of entecavir(ETV)monotherapy for hepatitis B virus(HBV)-related decompensated liver cirrhosis.METHODS:A total of 120 na ve patients with HBVrelated decompensated cirrhosis participated in this study.Sixty patients were treated with combined LAM and ADV therapy(LAM+ADV group),while the other60 were treated with ETV monotherapy(ETV group)for two years.Tests for liver and kidney function,alpha-fetoprotein,HBV serum markers,HBV DNA load,prothrombin time(PT),and ultrasonography or computed tomography scan of the liver were performed every1 to 3 mo.Repeated measure ANOVA and theχ2test were performed to compare the efficacy,side effects,and the cumulative survival rates at 48 and 96 wk.RESULTS:Forty-five patients in each group were observed for 96 wk.No significant differences in HBV DNA negative rates and alanine aminotransferase(ALT)normalization rates at weeks 48(χ2=2.12 and 2.88)and96(χ2=3.21 and 3.24)between the two groups were observed.Hepatitis B e antigen seroconversion rate in the LAM+ADV group at week 96 was significantly higher in the ETV group(43.5%vs 36.4%,χ2=4.09,P<0.05).Viral breakthrough occurred in 2 cases(4.4%)by week 48 and in 3 cases(6.7%)by week 96 in the LAM+ADV group,and no viral mutation was detected.In the ETV group,viral breakthrough occurred in 1 case(2.2%)at the end of week 96.An increase in albumin(F=18.9 and 17.3),decrease in total bilirubin and in ALT(F=16.5,17.1 and 23.7,24.8),reduced PT(F=22.7 and 24.5),and improved Child-Turcotte-Pugh and the model for end-stage liver disease scores(F=18.5,17.8,and 24.2,23.8)were observed in both groups.The cumulative rates of mortality and liver transplantation were 16.7%(10/60)and 18.3%(11/60)in the LAM+ADV and ETV groups,respectively.CONCLUSION:Both LAM+ADV combination therapy and ETV monotherapy can effectively inhibit HBV replication,improve liver function,and decrease mortality.

Antiviral therapy delays esophageal variceal bleeding in hepatitis B virus-related cirrhosis

AIM:To investigate the effect of antiviral therapy with nucleoside analogs in hepatitis B virus(HBV)-related cirrhosis and esophageal varices.METHODS:Eligible patients with HBV-related cirrhosis and esophageal varices who consulted two tertiary hospitals in Beijing,China,the Chinese Second Artillery General Hospital and Chinese PLA General Hospital,were enrolled in the study from January 2005 to December 2009. Of 117 patients,79 received treatment with different nucleoside analogs and 38 served as controls. Bleeding rate,change in variceal grade and non-bleeding duration were analyzed. Multivariate Cox proportional hazard regression was used to identify factors related to esophageal variceal bleeding.antiviral group compared to the control group(29.1%vs 65.8%,P < 0.001). Antiviral therapy was an independent factor related to esophageal bleeding in multivariate analysis(HR = 11.3,P < 0.001). The mean increase in variceal grade per year was lower in the antiviral group(1.0 ± 1.3 vs 1.7 ± 1.2,P = 0.003). Nonbleeding duration in the antiviral group was prolonged in the Kaplan-Meier model. Viral load rebound was observed in 3 cases in the lamivudine group and in 1 case in the adefovir group,all of whom experienced bleeding. Entecavir and adefovir resulted in lower bleeding rates(17.2% and 28.6%,respectively) than the control(P < 0.001 and P = 0.006,respectively),whereas lamivudine(53.3%) did not(P = 0.531).CONCLUSION:Antiviral therapy delays the progression of esophageal varices and reduces bleeding risk in HBV-related cirrhosis,however,high-resistance agents tend to be ineffective for long-term treatment.

Breastfeeding and chronic HBV infection: Clinical and social implications

Mother-to-child transmission of hepatitis B virus (HBV) is among the most important causes of chronic HBV infection and is the commonest mode of transmission worldwide. Currently, the presence of HBsAg, HBeAg and HBV DNA in breast milk is confirmed. Several studies have reported that breastfeeding carries no additional risk that might lead to vertical transmission. Beyond some limitations, the surveys have not demonstrated any differences in HBV transmission rate regarding feeding practices in early childhood. Promotion of breastfeeding is substantial, especially for low-income individuals and regions with uncertain, unfeasible, and unsafe water supplies. Lactoferrin, minimal inflammation or activation within the infant gut during exclusive breastfeeding, and nonspecific biological molecules in the milk are identified as major factors of breast-milk defense. This review discusses preemptive antiviral therapy during pregnancy and lactation. Long-term follow up of breast-milk HBV concentrations and correlation with serum viral load; nucleos(t)ide analogue concentrations in breast milk in HBV-positive mothers in the setting of chronic HBV infection; safety of antiviral therapy during pregnancy and lactation; and the difference in viral load in the milk in exclusive or non-exclusive breastfeeding are still open questions. The paper reviews the current data and outlines the course of further investigation into this often underestimated issue.

Entecavir vs lamivudine therapy for na?ve patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure

AIM:To investigate the short-term and long-term efficacy of entecavir versus lamivudine in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure(ACLF).METHODS:This was a single center,prospective cohort study.Eligible,consecutive hospitalized patients received either entecavir 0.5 mg/d or lamivudine 100mg/d.All patients were given standard comprehensive internal medicine.The primary endpoint was survival rate at day 60,and secondary endpoints were reduction in hepatitis B virus(HBV)DNA and alanine aminotransferase(ALT)levels,and improvement in Child-Turcotte-Pugh(CTP)and model for end-stage liver disease(MELD)scores at day 60 and survival rate at week 52.RESULTS:One hundred and nineteen eligible subjects were recruited from 176 patients with severe acute exacerbation of chronic hepatitis B:65 were included in the entecavir group and 54 in the lamivudine group(full analysis set).No significant differences were found in patient baseline clinical parameters.At day 60,entecavir did not improve the probability of survival(P=0.066),despite resulting in faster virological suppression(P<0.001),higher rates of virological response(P<0.05)and greater reductions in the CTP and MELD scores(all P<0.05)than lamivudine.Intriguingly,at week 52,the probability of survival was higher in the entecavir group than in the lamivudine group[42/65(64.6%)vs 26/54(48.1%),respectively;P=0.038].The pretreatment MELD score(B,1.357;95%Cl:2.138-7.062;P=0.000)and virological response at day30(B,1.556;95%Cl:1.811-12.411;P=0.002),were found to be good predictors for 52-wk survival.CONCLUSION:Entecavir significantly reduced HBV DNA levels,decreased the CTP and MELD scores,and thereby improved the long-term survival rate in patients with spontaneous reactivation of hepatitis B presenting as ACLF.

Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: Meta-analysis

AIM:To compare the effects of entecavir(ETV)and lamivudine(LAM)for the treatment of hepatitis B decompensated cirrhosis using a meta-analysis.METHODS:We conducted a literature search for all eligible studies published prior to May 30,2013 using PUBMED,MEDLINE,EMBASE,the China National Knowledge Infrastructure(CNKI),the VIP database,the Wanfang database and the Cochrane Controlled Trial Register.Randomized controlled trials(RCTs)comparing ETV with LAM for the treatment of hepatitis B decompensated cirrhosis were included.The data were analyzed with Review Manager Software 5.0.2.We used RR as an effect measure,and reported its95%CI.The meta-analysis was performed using either a fixed-effect or random-effect model,based on the absence or presence of significant heterogeneity.Two reviewers assessed the risk of bias and extracted data independently and in duplicate.The analysis was executed using the main outcome parameters including hepatitis B virus(HBV)DNA undetectability,HBV DNA level,hepatitis B e antigen(HBeAg)seroconversion,alanine aminotransferase(ALT)level,albumin level,total bilirubin(TBIL)level,prothrombin time activity(PTA)level,Child-Turcotte-Pugh(CTP)score,mortality,drugresistance,and adverse reactions.Meta-analysis of the included trials and subgroup analyses were conducted to examine the association between pre-specified characteristics and the therapeutic effects of the two agents.RESULTS:Thirteen eligible trials(873 patients in total)were included and evaluated for methodological quality and heterogeneity.Of these studies,all had baseline comparability,12 of them reported baseline values of the two treatment groups in detail.Following various treatment durations(12,24,36,48 and>48 wk),both ETV and LAM significantly reduced HBV DNA level,however,reductions were greater in the ETV group(MD=-0.66,95%CI:-0.83-0.50,P<0.00001),(MD=-0.93,95%CI:-1.36-0.51,P<0.0001),(MD=-1.4,95%CI:-1.78-1.01,P<0.00001),(MD=-1.18,95%CI:-1.90-0.46,P=0.001),(MD=-0.14,95%CI:-0.17-0.11,P<0.00001,respectively).At 12,24 and48 wk of treatment,ETV had a significant effect on the rate of HBV DNA undetectability(RR=1.55,95%CI:1.22-1.99,P=0.0004),(RR=1.25,95%CI:1.13-1.38,P<0.0001),(RR=1.2,95%CI:1.10-1.32,P<0.0001,respectively).Although HBeAg seroconversion in the ETV group was more pronounced than that in the LAM group at 24 wk(27.90%vs 26.19%)and 48 wk(31.52%vs 25.00%)of treatment,there was no statistically significant difference between them(RR=1.49,95%CI:0.98-2.28,P=0.07),(RR=1.27,95%CI:0.98-1.65,P=0.07,respectively).Following various treatment durations,both the ETV group and the LAM group showed significantly improved liver function(ALT,AIB,TBIL,PTA and CTP levels)and reduced mortality(ETV 6.37%,LAM 7.89%).The effects in the ETV group(0.33%)were statistically lower than those in the LAM group(14.33%)regarding the rate of drug-resistance(RR=0.1,95%CI:0.04-0.24,P≤0.00001).In addition,no severe adverse reactions were observed in the two treatment groups.CONCLUSION:ETV and LAM significantly improved liver function and reduced mortality.Both drugs produced similar serological responses,and were safe and well tolerated.However,ETV resulted in a better virological response and lower drug-resistance,but is more expensive.

Telbivudine:A new treatment for chronic hepatitis B

Three hundred and fifty million people worldwide are estimated to be chronically infected with hepatitis B virus. 15%-40% of these subjects will develop cirrhosis, liver failure or hepatocellular carcinoma during their life. The treatment of chronic hepatitis B has improved dramatically over the last decade merits to the advent of nucleoside/nucleotide analogues and the use of pegylated interferons. Approved drugs for chronic hepatitis B treatment include： standard interferon- alpha 2b, pegylated interferon-alpha 2a, lamivudine, adefovir dipivoxil, and entecavir. Unfortunately, these agents are not effective in all patients and are associated with distinct side effects. Interferons have numerous side effects and nucleoside or nucleotide analogues, which are well tolerated, need to be used for prolonged periods, even indefinitely. However, prolonged treatment with nucleoside or nucleotide analogues is associated with a high rate of resistance. Telbivudine is a novel, orally administered nucleoside analogue for use in the treatment of chronic hepatitis B. In contrast to other nucleoside analogues, Telbivudine has not been associated with inhibition of mammalian DNA polymerase with mitochondrial toxicity. Telbivudine has demonstrated potent activity against hepatitis B with a significantly higher rate of response and superior viral suppression compared with lamivudine, the standard treatment. Telbivudine has been generally well tolerated, with a low adverse effect profile, and at its effective dose, no dose- limiting toxicity has been observed. Telbivudine is one of the most potent antiviral agents for chronic hepatitis B virus and was approved by the FDA in late 2006.

Inhibitory effect of emodin and Astragalus polysaccharide on the replication of HBV

AIM: To evaluate the anti-viral effect of emodin plus Astragalus polysaccharide (APS) in hepatitis B virus (HBV) transgenic mice.METHODS: Sixty HBV transgenic mice (HBV TGM) whose weight varied between 18 and 24 g were randomly divided into 3 groups, with 20 mice in each group. Group A was the normal control, where the mice were treated with physiological saline; group B was the positive control where the mice were treated with lamivudine solution (100 mL/kg per day). Group C was the experimental group where the mice were treated with physiological saline containing emodin and APS (57.59 mg/kg per day and 287.95 mg/kg per day, respectively). The mice were treated daily for 3 wk. After 1 wk recovery time, the mice were sacrifi ced and serum as well as liver tissues were collected for ELISA and histological examination.RESULTS: After 21 d treatment, HBV DNA levels in group B and group C significantly declined when compared with group A (P < 0.05). However, a signif icant increase in HBV DNA content was observed in group B, whereas this phenomenon was not observed in group C. A reduction in the contents of HBsAg, HBeAg and HBcAg in the mice from group B and C was observed when compared with group A.CONCLUSION: Emodin and APS have a weak but persistent inhibitory effect on HBV replication in vivo, which may function as a supplementary modality in the treatment of hepatitis B infection.

Efficacy of combined therapy in patients with hepatitis B virus-related decompensated cirrhosis

AIM: To investigate the efficacy and safety of combined de novo lamivudine (LAM) and adefovir dipivoxil (ADV) therapy in hepatitis B virus (HBV)-related decompensated liver cirrhosis patients. METHODS: One hundred and forty patients with HBVrelated decompensated cirrhosis were recruited, 70 patients were treated with combined LAM and ADV de novo therapy, and the other 70 patients were treated with LAM alone as controls. The follow-up period was 144 wk. All patients with LAM resistance were shifted to ADV. RESULTS: The percentage of HBV-related decompensated cirrhosis patients with undetectable HBV DNA inde novo combination group was 51.6% (33/64), 84.2% (48/57), and 92.3% (49/53) by weeks 48, 96, and 144, respectively. In monotherapy group, HBV DNA negativity rate was 46.1% (30/65), 56.1% (32/57), and 39.2% (20/51) by weeks 48, 96 and 144, respectively. There was a significant difference between the two groups by weeks 96 and 144 (P = 0.012 and 0.001). The hepatitis B e antigen seroconversion rate was 28.1% (9/32), 40.0% (12/30), and 53.6% (15/28) in the combination group by weeks 48, 96 and 144, respectively, and 24.2% (8/33), 31.0% (9/29), and 37.0% (10/27) by weeks 48, 96 and 144, respectively, in monotherapy group. A total of 68.6% (44/64), 84.2% (48/57), and 92.5% (49/53) patients achieved alanine aminotransferase (ALT) normalization by weeks 48, 96 and 144, respectively in the combination group. In monotherpy group, the ALT normalization rate was 64.6% (42/65) by week 48, 73.7% (42/57) by week 96, and 80.4% (41/51) by week 144. No patients in the combination group exhibited detectable resistance for at least 144 wk. The cumulative resistance rate in monotherapy group at weeks 48, 96, and 144 was 20.0%, 36.8%, and 56.9%. Both combination group and monotherapy group demonstrated an improvement in Child-Turcotte Pugh and Model for End-Stage Liver Disease scores at weeks 48, 96, and 144. All patients tolerated both combination and monotherapy. The ceratinine levels and glomerular filtration rate remained normal in all patients during the follow-up period. CONCLUSION: In HBV-related decompensated liver cirrhosis patients, the combined de novo LAM and ADV therapy is more efficacious and safer compared to LAM alone.

Orthotopic liver transplantation for fulminant hepatitis B

INTRODUCTION When fulminant hepatitis progress to deep encephalopathy,with stage Ⅲ or Ⅳ coma,it is commonly irreversible with a high mortality rate(80%-100%).Liver transplantation may be

Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies

AIM: To evaluate the long-term efficacy adefovir(ADV)-based combination therapies in entecavir(ETV)-resistant chronic hepatitis B(CHB) patients. METHODS: F i fty CHB pat ient s wi t h genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV(ADV/ETV,n = 23) or ADV plus lamivudine(LMV)(ADV/LMV,n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus(HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response(VR; HBV DNA < 20 IU/m L) were calculated using the Kaplan-Meier method,and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR,respectively.RESULTS: Baseline median HBV DNA levels were 5.53(2.81-7.63) log10 IU/m L. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27(12-45) mo. Overall,cumulative VR rates at 6,12,24,and 36 mo were 26%,36%,45%,and 68%,respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates(35%,43%,65%,and 76%,respectively) than those with the ADV/LAM combination(18%,30%,30%,and 62%,respectively; P = 0.048). In the multivariate analysis,low baseline HBV DNA levels(< 5.2 log10 IU/m L) and initial virologic response at 3 mo(IVR-3; HBV DNA < 3.3 log10 IU/m L after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period,the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.CONCLUSION: If tenofovir is not available,ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers,and may becontinued if IVR-3 is achieved.

Hepatitis B in pregnancy

Chronic hepatitis B virus (HBV) infection affects about 350 million individuals worldwide. Management of HBV infection in pregnancy is difficult because of several peculiar and somewhat controversial aspects. The aim of the present review is to provide a tool that may help physicians to correctly manage HBV infection in pregnancy. This review focuses on (1) the effect of pregnancy on HBV infection and of HBV infection on pregnancy; (2) the potential viral transmission from mother to newborn despite at-birth prophylaxis with immunoglobulin and vaccine; (3) possible prevention of mother-to-child transmission through antiviral drugs, the type of antiviral drug to use considering their efficacy and potential teratogenic effect, and the timing of their administration and discontinuation; and (4) the evidence for the use of elective caesarean section vs vaginal delivery and the possibility of breastfeeding.