阿德福韦治疗拉米夫定耐药慢性乙型肝炎的研究

目的观察阿德福韦治疗拉米夫定耐药(LAM-R)慢性乙型肝炎(慢乙肝)的疗效。方法以ADV与LAM联合与单独用药治疗LAM-R慢乙肝250例,以治疗中的维持联合应答(HBV-DNA阴转率与ALT复常率)同步作完成治疗分析(ITT)与意向治疗分析(PP)。结果ADV对LAM-R慢乙肝的维持联合应答率48周达55%,96周达75%,96周未发现ADV-R基因耐药。结论ADV是目前治疗LAM-R慢乙肝的有效药物。     

慢性乙型肝炎患者HBV DNA YMDD变异的检测及意义

目的应用PCRmnh-ELISA法对HBV DNA YMDD变异进行检测,并对其临床意义进行初步研究。方法对我院2006年249例服用拉米夫定的慢性乙肝患者,男187例,女62例,其中HBeAg阳性198例,阴性59例,采用PCRmnh-ELISA法进行YMDD变异株检测,并进行了肝功能及HBV DNA的随访。结果249例患者中,43例YMDD变异阳性,阳性率为17.3%,其中YVDD变异33例,YIDD变异10例。YMDD变株阳性结果中,29例ALT水平呈现反复现象,占阳性结果中的67.4%,34例患者HBV DNA反跳,占阳性结果中的79.1%。结论HBV DNA YMDD变异是拉米夫定产生耐药,使病情反复的主要原因,变异的主要形式可能是YVDD,变异的发生率与E抗原阳性率无关,与治疗前的HBV DNA水平有关。     

分子杂交技术在乙型肝炎拉米夫定治疗后YMDD变异检测中的应用

目的:采用分子杂交技术检测乙型肝炎拉米夫定治疗后发生的YMDD变异基因。方法:对100例服用拉米夫定12个月以上的乙型肝炎患者的血清,采用聚合酶链反应后进行分子杂交技术测定YMDD变异情况,同时采用乙肝P区基因测序技术进行结果比较。结果:100例拉米夫定治疗患者血清经分子杂交技术共检出33例YMDD变异,同测序结果吻合率达96.97%,灵敏度达103IU/ml。33例YMDD变异者共有6种不同的变异组合。结论:分子杂交技术检测HB-VYMDD变异具有简单、准确、快速、经济实用等特点,具有很好的临床应用价值。     

Successful pregnancy in a liver transplant recipient treated with lamivudine for de novo hepatitis B in the graft

Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy. Liver transplant recipients with recurrent hepatitis C or hepatitis B nonetheless appear to be at risk of a worse graft function in the event of pregnancy, and antiviral drugs are generally contraindicated in pregnancy because of their teratogenic effects. A 33-year-old woman had undergone liver transplantation for Carolis disease 6 years previously. Two years later the patient experienced de novo HBV hepatitis. Lamivudine treatment (100 mg/day) was started and clearance of HBsAg was documented 1 year later. Four years after starting antiviral treatment the patient became pregnant, despite of the risk of teratogenic effects; lamivudine, cyclosporine and azathioprine were not discontinued for risk of break-through hepatitis and acute or chronic rejection. The course of gestation was uneventful and caesarean section was performed after 36 weeks. The newborn infant was a healthy male weighing 3,080 g and measuring 50 cm.     

Mutations outside the YMDD motif in the P protein can also cause DHBV resistant to Lamivudine

AIM: To observe the Lamivudine resistance character of a DHBV strain in vitro and in vivo, and to analyze if the Lamivudine resistance character is caused by gene mutation or by abnormity of the Lamivudine metabolism. METHODS: Congenitally DHBV-negative Guangdong brown ducks and duck embryo liver cells were respectively taken as animal and cell model. The Lamivudine-susceptive DHBV and Lamivudine-resistant DHBV (LRDHBV) were infected and Lamivudine was administrated according to the divided groups. The changes of DHBV quantity in the animal and cell model were tested. Three Lamivudine-resistant and two Lamivudine-susceptive DHBV complete genomes were successfully amplified, sequenced and then submitted to GenBank. All the DHBV complete sequences in the GenBank at present were taken to align with the three LRDHBV to analyze the mutational points related to the Lamivudine-resistant mutation. RESULTS: Both the animal and cell model showed that the large and the small dosage Lamivudine have no significant inhibitory effect on the LRDHBV. Rve sequences of DHBV complete genomes were successfully cloned. The GenBank accession numbers of the three sequences of LRDHBV are AY521226, AY521227, and AY433937. The two strains of Lamivudine-susceptive DHBV are AY392760 and AY536371. The correlated mutational points are KorR86Q and AorE591T in the P protein. CONCLUSION: The Lamivudine resistance character of this DHBV strain is caused by genome mutation; the related mutational points are KorR86Q and AorE591T and have no relations with the YMDD motif mutation.     

Pharmacokinetics of antivirals in neonate

BACKGROUNDS: About 1000 neonates with HIV infection are born every day worldwide. The antiviral therapy for newborn infants is a real necessity. Pharmacokinetics is an important contribution to therapy and no review has been published on the pharmacokinetics of antivirals in neonates up to now. AIMS: This article provides a review on the pharmacokinetics of antivirals in the neonate. The pharmacokinetic parameters in the neonate are compared with those of the adult, and when possible, the pharmacokinetic parameters were compared in neonates of different ages. RESULTS: Zidovudine is the antiviral with the largest amount of information on its pharmacokinetics. The clearance (Cl; l/h/kg) of zidovudine is 0.15 (premature), 0.34 (1 day), 0.69 (7 days), 0.65 (< or =14 days), 1.14 (>14 days) and 1.56 (adult). t(1/2) (h) of zidovudine is 7.2 (premature), 4.2 (1 day), 4.0 (7 days), 3.1 (< or =14 days), 1.9 (>14 days) and 1.1 (adult). Zidovudine is mainly eliminated by conjugation with glucuronic acid and glucuronosyl transferase develops postnatally. Cl of lamivudine is 0.19 (1 day), 0.32 (7 days) and 0.30 (adult) and the Cl (l/h/m2) of didanosine is 65 (1 day) and 271 (7 days). A greater volume of distribution (Vd) has been observed in the neonate compared with the adult for nelfinavir, nevirapine and pleconaril. CONCLUSIONS: The pharmacokinetic parameters of antivirals differ in the neonate and in the adult. The Cl is reduced and t(1/2) is increased in the neonate compared with the adult for zidovudine, lamivudine and ganciclovir. t(max) is generally greater in the neonate than in the adult due to reduced absorption rate in the neonate. The Vd of nelfinavir, nevirapine and pleconaril is greater in the newborn than in the adult. The neonate is a developing organism and the pharmacokinetic parameters of antivirals vary during the first weeks of life.     

Current antiviral therapy for chronic hepatitis B

During the past decade, major breakthroughs have been achieved in treatment of chronic hepatitis B. Currently, three therapeutic agents are approved for chronic hepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. In patients with HBeAgpositive chronic hepatitis B, all of these drugs achieve HBeAg loss (24-33%) and anti-HBe seroconversion (12-30%) rates that are superior to those observed in untreated controls. Interferon-alpha has several drawbacks, such as the parenteral administration and the development of frequent and potentially serious side effects. Lamivudine is a safe drug with rare and generally mild side effects. Lamivudine induces an initial virological remission in 70-90% of patients, but only 30-40% of patients remain in remission after the third year due to progressively increasing viral resistance. The main advantage of adefovir dipivoxil is the rare emergence of resistance, which has been identified in less than 2% of patients at 2 yr of treatment. Adefovir is also effective against lamivudine-resistant strains. This review will focus on the natural history and recently gained knowledge on the treatment of chronic hepatitis B.     

拉米夫定和补肾方联合应用治疗慢性乙型肝炎的疗效及对YMDD区域的影响

目的：观察拉米夫定和补肾方联合应用治疗慢性乙型肝炎的疗效及对慢性乙型肝炎病毒P基因酪氨酸—蛋氨酸—天冬氨酸—天冬氨酸(YM)D)区域的影响。方法：收集乙型肝炎病毒(HBV)DNA阳性的慢性乙型肝炎患者88例,分为拉米夫定组、拉米夫定加补肾方l组和拉米夫定加补肾方2组共3组,分别检测血清HBV DNA、肝脏生化指标和P基因YMDD区域变异。结果：在治疗52周时,拉米夫定加补肾方2组无论是HBV DNA阳性率(6．45％),还是YMDD变异率(3．23％)都比拉米夫定组低。结论：初步表明,拉米夫定与补肾方联合用药能在一定程度上提高治疗慢性乙型对炎的疗效,并可能减少YMDD的变异。     

拉米夫定联合胸腺五肽治疗慢性乙型肝炎临床观察

目的:观察拉米夫定联合胸腺五肽治疗慢性乙型肝炎的疗效。方法:选择慢性乙型肝炎42例,分为治疗组20例,对照组22例,两组均给予拉米夫定100mg/d,同时治疗组给予胸腺五肽1mg,随后两组继续给予拉米夫定100mg/d,总疗程52周。结果:两组ALT、TBil复常率无显著性差异(P>0.05),但HBVDNA及HBeAg阴转率有显著性差异(P<0.05),治疗组完全应答率显著高于对照组(P<0.05)。结论:拉米夫定联合胸腺五肽能显著提高抗HBV的疗效。     

A study of the pharmacokinetic interaction between lamivudine and alpha interferon

Objective: This study was designed to investigate any possible pharmacokinetic interaction between lamivudine and alpha interferon as potential candidates for combination therapy for the treatment of hepatitis B virus (HBV). Methods: Nineteen healthy male, Caucasian volunteers, aged 20–41 years and weighing 60.5–83.5 kg completed this open, non-randomised study. They each received a single, abdominal, deep s.c. injection of 10 mIU alpha interferon on day 1, followed by a wash-out period of at least 1 week. Subjects then began a 7-day course of lamivudine (100 mg) followed by a further 10-mIU alpha-interferon injection directly after oral lamivudine dosing. Blood and urine samples were taken pre- and post-dose for alpha-interferon and/or lamivudine assay. Results: Lamivudine was safe and well tolerated in all subjects. No adverse events were reported in subjects on lamivudine, whereas 106 adverse events considered attributable to alpha interferon were recorded. Statistical analysis of pharmacokinetic parameters indicated no significant effect of lamivudine on alpha-interferon pharmacokinetics. There was a small statistically significant reduction (∼10%) in the area under the lamivudine concentration–time curve on co-administration with alpha interferon and a concomitant increase in clearance, which is not considered clinically relevant. Conclusions: Alpha interferon and lamivudine can be co-administered with no requirement for dose modification, as there was no clinically significant difference in the pharmacokinetics of either drug. Received: 22 November 1999 / Accepted in revised form: 22 March 2000