Adefovir抗乙型肝炎病毒的体外实验研究

目的 在体外细胞培养研究中 ,观察Adefovir抗HBV的作用。方法 以乙型肝炎病毒 (HBV)DNA转染的细胞株 2 .2 .15细胞为靶细胞 ,给药后通过检测细胞培养液中HBsAg、HBeAg和HBVDNA ,对Adefovir抗HBV效果进行评价。在2 .2 .15细胞培养基中分别加入不同浓度的药物 ,培养数天后检测上清液中HBsAg和HBeAg滴度 ,细胞DNA抽提液检测HBVDNA ;用四甲基偶氮唑盐 (MTT)比色分析法检测药物对细胞的毒性。结果 Adefovir加入细胞培养 12d ,最大无毒浓度为 2 0 μg/ml,对HB sAg抑制率为 5 2 .4 4 % ,对HBeAg抑制率为 5 4 .87% ,对HBVDNA抑制率为 4 5 .6 8% ,并有剂量依赖效应。结论 Adefovir在体外细胞培养的实验中有抗HBV病毒作用。

Safety and Tolerance of Adefovir Dipivoxil in Chinese Healthy Volunteers: A PhaseⅠRandomized and Open-Label Trial

Aim To assess the safety and tolerance of adefovir dipivoxil （ADV） in Chinese healthy volunteers. Methods A total of 52 healthy volunteers, 26 males and 26 females, aged from 19 to 26 were enrolled in the study. Forty-two subjects were randomized into 5, 10, 20, 40, and 60 mg dose groups （6 - 10 subjects in each） matched by sex and weight for single-dose trial. Ten subjects were orally given 10 mg of ADV tablets once daily for 7 d for multiple-dose trial. Physical examination, vital signs examination, electrocardiography, type-B ultrasonography, chest fluoroscopy, routine blood test, routine urine test, coagulation tests, and blood biochemical test were conducted on schedule and statistically evaluated. Results Asthenia frequently occurred in multiple-dose trial, nausea, abdominal pain, and diarrhea occurred in both single- and multiple-dose trials. ALT, bilirubin, CK, and LDH were slightly elevated. All adverse reactions and laboratory abnormalities were mild, and the frequency and severity were not related to doses. Conclusion ADV is safe and well tolerated in Chinese healthy volunteers at dose of 5 - 60 mg oncedaily or 10 nag once daily for 7 d. The recommended oral dosage regimen is 10 mg once daily. Attention should be paid to renal and liver functions, CK, AMY and LDH, if we take ADV for a long period of time.

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.

Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B

AIM: To evaluate urine β2-microglobulin(β2-M), retinol-binding protein(RBP) excretion, and renal impairment with adefovir dipivoxil(ADV) for chronic hepatitis B. METHODS: We enrolled 165 patients with chronic hepatitis B infection who were treated with ADV monotherapy(n = 90) or ADV plus lamivudine combination therapy(n = 75). An additional 165 chronic hepatitis B patients treated with entecavir were recruited as controls. We detected serum creatinine, urine β2-M, and RBP levels, and estimated the glomerular filtration rate(e GFR) at the initiation of antiviral therapy and every 6 mo for a period of five years. RESULTS: Urine β2-M abnormalities were observed in patients during the first(n = 3), second(n = 7), third(n = 11), fourth(n = 16), and fifth(n = 21) year of ADV treatment. Urinary RBP abnormalities were observed in patients during the first(n = 2), second(n = 8), third(n = 12), fourth(n = 15), and fifth(n = 22) year of ADV treatment. e GFR decreased 20%-30% from baseline in 20 patients, 30%-50% in 12 patients, and > 50% in 3 patients during the five years of treatment. Further analysis indicated that decreases in e GFR of ≥ 30% relative to the baseline level correlated significantly with urine RBP and β2-M abnormalities. In contrast, both serum creatinine and e GFR remained stable in patients treated with entecavir, and only one of these patients developed a urine β2-M abnormality, and two developed urine RBP abnormalities during the five years of treatment. CONCLUSION: Urine RBP and β2-M are biomarkers of renal injury during long-term ADV treatment for chronic hepatitis B, and indicate when treatment should be switched to entecavir.

Predictors of kidney tubular dysfunction induced by adefovir treatment for chronic hepatitis B

AIM:To investigate the predictors of proximal kidney tubular dysfunction(PKTD)induced by adefovir dipivoxil(ADV)treatment for chronic hepatitis B.METHODS:Seventy-nine patients(age at the evaluation of PKTD:56.9±10.7 years)with chronic hepatitis B undergoing long-term oral antiviral nucleos(t)ide analogue treatment were consecutively recruited.PKTD was defined by the presence of at least two of the following five abnormalities:phosphate diabetes,nondiabetic glucosuria,metabolic acidosis,β2-microglobulinuria,or renal hypouricemia.The single-nucleotide polymorphisms(SNPs)in the SLC22A6 gene encoding human organic anion transporter 1(h OAT1)and ABCC2 encoding multidrug resistance protein 2(MRP2)were analyzed using the Taq Man Allelic Discrimination Demonstration Kit.RESULTS:Nine(30.0%)of the 30 ADV-treated patients were diagnosed with PKTD,while no patients without ADV developed PKTD(P<0.001).Three patients with ADV were diagnosed with symptomatic osteomalacia.Among the patients who took ADV,those with PKTD were of higher age at initiation,had significantly longer treatment duration,and had a significantly lower body mass index than those without PKTD.The incidence of PKTD dramatically increased after 96 mo from the start of ADV administration.In contrast,the SNPs were not correlated with PKTD.Logistic regression analysis extracted older age at initiation(OR=5.0,95%CI:1.1-23.4;P=0.040)and longer treatment duration(OR=3.2,95%CI:1.2-8.6;P=0.020)as significant factors associated with PKTD.CONCLUSION:Our results suggest that the tubular function of the kidney of older patients undergoing longterm ADV treatment should be carefully evaluated.

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.

Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil

We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain,with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10mg/day. It was also found that ADV affected the metabolism of tacrolimus,a calcineurin-inhibitor,and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels,which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus.

Tenofovir disoproxil fumarate is superior to lamivudine plus adefovir in lamivudine-resistant chronic hepatitis B patients

AIM:To assess the efficacy of tenofovir disoproxil fumarate(TDF) in lamivudine(LAM)-resistant patients with a suboptimal response to LAM plus adefovir(ADV).METHODS:We retrospectively analyzed the efficacy of switching to tenofovir disoproxil fumarate in suboptimal responders to lamivudine plus adefovir.Charts were reviewed for LAM-resistant chronic hepatitis B(CHB) patients who visited the Zhejiang Province People's Hospital and The First Affiliated Hospital,College of Medicine,Zhejiang University,from June 2009 to May 2013.Patients whose serum hepatitis B virus(HBV) DNA remained detectable despite at least 6 mo of LAM plus ADV combination therapy were included.Patients with a suboptimal response to LAM plus ADV were randomized to switch to TDF monotherapy(300 mg/d orally; TDF group) or to continuation with LAM(100 mg/d orally) plus ADV(10 mg/d orally; LAM plus ADV group) and were followed for 48 wk.Serum HBV DNA was determined at baseline and weeks 4,12,24,36,and 48.HBV serological markers and biochemistry were assessed at baseline and weeks 12,24,and 48.Resistance surveillance and side effects were monitored during therapy.RESULTS:Fifty-nine patient were randomized to switch to TDF(n =28) or continuation with LAM plus ADV(n =31).No significant differences were found between the groups at baseline.Prior to TDF therapy,all patients had been exposed to LAM plus ADV for a median of 11 mo(range:6-24 mo).No difference was seen in baseline serum HBV DNA between the two groups [5.13 ± 1.08 log10 copies/m L(TDF) vs 5.04 ± 31.16 log10 copies/m L(LAM +ADV),P =0.639].There was no significant difference in the rates of achieving complete virological response(CVR) at week 4 between the TDF and LAM +ADV groups(17.86% vs 6.45%,P =0.24).The rate of achieving CVR in the TDF and LAM plus ADV groups was 75% vs 16.13% at week 12,82.14% vs 22.58% at week 24,89.29% vs 25.81% at week 36,and 96.43% vs 29.03% at week 48,respectively(P < 0.001).The rate of alanine aminotransferase normalization was significantly higher in the TDF than in the LAM plus ADV group at week 12(75% vs17.86%,P < 0.001),but not at week 24(78.57% vs 54.84%,P =0.097) or 48(89.26% vs 67.74%,P =0.062).Patients were hepatitis B e antigen(HBe Ag) positive at baseline.There was no significant difference in HBe Ag negativity between the TDF and LAM plus ADV groups at week 48(4% vs 0%,P =0.481).There were no drug-related adverse effects at week 48 in either group.CONCLUSION:Switching to TDF monotherapy was superior to continuous add-on therapy in patients with LAM-resistant CHB with a suboptimal response to LAM plus ADV.

Surgical treatment of HCC in a patient with lamivudine-resistant hepatitis B cirrhosis with adefovir dipivoxil

We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine.She was started on adefovir(10 mg daily)while still continuing lamivudine therapy.Four mo later her liver function improved and serum Hepatitis B virus(HBV)-DNA level became undetectable.Three years after the start of additional adefovir treatment,hepatocellular carcinoma (HCC)was detected and the patient underwent a successful hepa-tectomy.Our findings suggest tha-t the addition of adefovir to ongoing lamivudine therapy cannot completely suppress hepatocarcinogenesis,but is useful for improving liver function in patients with lamivudine-resistant HBV-related cirrhosis,allowing HCC surgery.

Resistant mutants induced by adefovir dipivoxil in hepatitis B virus isolates

AIM: To investigate the loci of adefovir dipivoxil (ADV)-induced resistance in hepatitis B virus (HBV) isolates and optimize the management of ADV-treated patients.

Treatment strategies using adefovir dipivoxil for individuals with lamivudine-resistant chronic hepatitis B

AIM:To investigate retrospectively the long-term efficacy of various treatment strategies using adefovir dipivoxil(adefovir) in patients with lamivudine-resistant chronic hepatitis B.METHODS:We included 154 consecutive patients in two treatment groups:the "add-on" group(n = 79),in which adefovir was added to ongoing lamivudine treatment due to lamivudine resistance,and the "switch/combination" group(n = 75),in which lamivudine was first switched to adefovir and then re-added later as needed.The "switch/combination" group was then divided into two subgroups depending on whether participants followed(group A,n = 30) or violated(group B,n = 45) a proposed treatment strategy that determined whether to add lamivudine based on the serum hepatitis B virus(HBV) DNA levels(< 60 IU/mL or not) after 6 mo of treatment(roadmap concept).RESULTS:The cumulative probability of virologic response(HBV DNA < 60 IU/mL) was higher in group A than in the "add-on" group and in group B(P < 0.001).In contrast,the cumulative probability of virologic breakthrough was lower in the "add-on" group than in group B(P = 0.002).Furthermore,the risk of virologic breakthrough in the multivariate analysis was significantly lower in the "add-on" group than in group A(hazard ratio = 0.096;95%CI,0.015-0.629;P = 0.015).CONCLUSION:The selective combination of adefovir with lamivudine based upon early treatment responses increased the odds of virologic breakthrough relative to the use of uniform combination therapy from the beginning of treatment.

Tenofovir vs lamivudine plus adefovir in chronic hepatitis B:TENOSIMP-B study

AIM To demonstrate the non-inferiority(15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate(TDF) vs the combination of lamivudine(LAM) plus adefovir dipivoxil(ADV) in the maintenance of virologic response in patients with chronic hepatitis B(CHB) and prior failure with LAM.METHODS This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups(TDF and LAM+ADV) of adult patients with hepatitis B e antigen(HBe Ag)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed.RESULTS Forty-six patients were evaluated [median age: 55.4 years(30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA(HBV-DNA) remained undetectable, all patients remained HBe Ag negative, and hepatitis B surface antigen(HBs Ag) positive. Alanine aminotransferase(ALT) values at the end of the study were similar in the 2 groups(25.1± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects(AEs)(53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively(P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment(€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001).CONCLUSION TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.

Establishment of a new quantitative detection approach to adefovir-resistant HBV and its clinical application

AIM:To establish the more feasible and sensitive assessment approach to the detection of adefovir (ADV) resistance-associated hepatitis B virus (HBV) quasispecies.METHODS: Based on the characteristics of rtA181V/T and rtN236T mutations, a new approach based on real-time fluorescent quantitative polymerase chain reaction (RT-PCR) was established for the detection of ADV-resistant HBV quasispecies, total HBV DNA, rtA181 and rtN236 mutations in blood samples from 32 chronic hepatitis B (CHB) patients with unsatisfactory curative effect on ADV and compared with routine HBV DNA sequencing.RESULTS: Both the sensitivity and specificity of this new detection approach to ADV-resistant HBV quasispecies were 100%, which were much higher than those of direct HBV DNA sequencing. The approach was able to detect 0.1% of mutated strains in a total plasmid population. Among the 32 clinical patients, single rtA181 and rtN236T mutation and double rtA181T and rtN236T mutations were detected in 20 and 8, respectively, while ADV-resistant mutations in 6 (including, rtA181V/T mutation alone in 5 patients) and no associated mutations in 26.CONCLUSION: This new approach is more feasible and efficient to detect ADV-resistant mutants of HBV and ADV-resistant mutations before and during ADV treatment with a specificity of 100% and a sensitivity of 100%.

Combination Therapy with Pegylated Interferon alpha-2b and Adefovir Dipivoxil in HBeAg-positive Chronic Hepatitis B versus Interferon Alone: A Prospective, Randomized Study

Currently available monotherapies of oral nucleoside/nucleotide analogs or interferon are unable to achieve a sustained and effective response in most of patients with chronic hepatitis B（CHB）. The objective of the present study was to compare the efficacy and safety of pegylated interferon（Peg-IFN） alpha-2b plus adefovir dipivoxil combination therapy versus Peg-IFN alpha-2b alone. Sixty-one HBeAg-positive chronic hepatitis B patients were randomized to receive Peg-IFN alpha-2b alone（1.5 μg/kg once weekly） or Peg-IFN alpha-2b plus adefovir（10 mg daily） for up to 52 weeks. Efficacy and safety analyses were performed on all participants who received at least one dose of study medication. The rate of HBeAg seroconversion and undetectable HBV-DNA were evaluated after 52 weeks of therapy. At the end of treatment, 11 of 30（36.7%） patients receiving combination therapy achieved HBeAg seroconversion versus 8 of 31（25.8%） in the monotherapy group（P=0.36）. In contrast, the percentage of patients with undetectable serum HBV DNA was significantly higher in the combination group than in the monotherapy group（76.7% vs. 29.0%, P〈0.001）. Thyroid dysfunction was more frequent in the combination group than in the monotherapy group（P〈0.05）. In HBeAg-positive CHB, combination of Peg-IFN alpha-2b and adefovir for 52 weeks resulted, at the end of treatment, in a higher virological response but without significant impact on the rate of HBeAg seroconversion and possibly an adverse effect on thyroid function.

Virological response to adefovir monotherapy and the risk of adefovir resistance

AIM:To evaluate virological response to adefovir(ADV) monotherapy and emergence of ADV-resistant mutations in lamivudine(LAM)-resistant chronic hepatitis B patients.METHODS:Seventy-seven patients with documented LAM resistance who were treated with 10 mg/d ADV for>96 wk were analyzed for ADV resistance.RESULTS:At week 48 and 96,eight(10%)and 14(18%)of 77 LAM-resistant patients developed the ADV-resistant strain(rtA181V/T and/or rtN236T mutations),respectively.Hepatitis B virus(HBV)DNA levels during therapy were significantly higher in patients who developed ADV resistance than in those who did not.Incidence of ADV resistance at week 96 was 11%,8%and 6%among patients with complete virological response(HBV DNA level<60 IU/mL);0%,5%and 19%among patients with partial virological response(HBV DNA level≥60 to 2000 IU/mL);and 32%,34% and 33%among patients with inadequate virological response(HBV DNA levels>2000 IU/mL)at week 12,week 24 and week 48,respectively.HBV DNA levels >2000 IU/mL at week 24 showed best performance characteristics in predicting ADV resistance.CONCLUSION:Development of ADV resistance mutations was associated with HBV DNA levels,which could identify patients with LAM resistance who are likely to respond to ADV monotherapy.

Antiviral efficacy of adefovir dipivoxil versus lamivudine in patients with chronic hepatitis B sequentially treated with lamivudine and adefovir due to lamivudine resistance

AIM： To compare the antiviral efficacy of adefovir （ADV） in lamivudine （LMV）-resistant patients with LMV treatment in nucleoside-naive patients, using serum samples collected sequentially during the course of treatment progressing from LMV to ADV.METHODS： Forty-four patients with chronic hepatitis B （CHB） were included. The patients were initially treated with LMV and then switched to ADV when LMV resistance developed. Antiviral efficacy was assessed by measuring the following： reduction in serum HBV DNA from baseline, HBV DNA negative conversion （defined as HBV DNA being undectable by the hybridization assay）, and HBV DNA response （either HBV DNA level ≤ 10^s copies/mL or a ≥ 2 log10 reduction from baseline HBV DNA level）.RESULTS： After two and six months of treatment, HBV DNA reduction was greater with LMV compared to ADV treatment （P = 0.021）. HBV DNA negative conversion rates were 64% and 27% after one month of LMV and ADV treatment respectively （P = 0.001）. Similarly, HBV DNA response rates were 74% and 51% after two months of LMV and ADV treatment respectively （P = 0.026）. The time taken to HBV DNA negative conversion and to HBV DNA response were both delayed in ADV treatment compared with LMV.CONCLUSION： The antiviral efficacy of ADV in LMV-resistant patients is slower and less potent than that with LMV in nucleoside-naive patients during the early course of treatment.

Efficacy of 3 years of adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance

AIM: To study the effect of rescue monotherapy with adefovir (ADV) in patients with chronic hepatitis B (CHB) who developed drug resistance to lamivudine (LAM).

Relationship Between Serum DNA Replication, Clinicopathological Characteristics and Prognosis of Hepatitis B Virus-associated Glomerulonephritis with Severe Proteinuria by Lamivudine Plus Adefovir Dipivoxil Combination Therapy

Objective To explore the relationship between HBV DNA and the clinical manifestations, pathological types, injury severity, and prognosis with HBV-GN. Methods 102 patients with HBV-GN were divided into 3 groups, according to the serum titer of the HBV DNA. 24-h urine protein excretion, and other parameters were measured. Renal biopsy were performed. The association between HBV DNA and the pathological stage of membranous nephropathy was analyzed in 78 patients with HBV-MN. 24-h urine protein excretion was used for the evaluation of the prognosis, and the relationship between HBV DNA and prognosis were analyzed. Results Several findings were demonstrated with the increase of serum HBV DNA： 24-h urine protein excretion, plasma cholesterol, and triglycerides increased significantly（P〈0.05）, while the plasma level of albumin decreased significantly（P〈0.05）; The changes of serum creatinine, C3 and C4 were found but no statistical significance. Glomerular deposition of HBVAg increased, and the pathological injury was more severe. The clinical remission rate was lower in the high replication group after treatment as compared with the low replication group（P〈0.01）. Conclusion With the increase of serum HBV DNA, the urine protein excretion and the kidney injury were more severe, and the clinical remission rate was decreased.

Low-dose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HBeAg-negative hepatitis B

AIM: To study the efficacy of tenofovir disoproxil fumarate (TDF) at low dose in a small open trial of chronic hepatitis B patients with advanced stage disease. METHODS: Eleven patients were treated with TDF 75 mg for a median period of 80 (range, 24-576) wk and then 7 cases were shifted to an adefovir 10 mg treatment group. All patients had been pre-treated with lamivudine: 5 had YMDD resistant mutants and 6 wild- type virus. When TDF was started, 4 patients had low- level viremia and 6 were PCR-negative. RESULTS: During TDF treatment, PCR remained negative in 10 patients, transaminase levels were normal and no significant viral breakthrough was observed. The drug was well tolerated in all cases. When TDF 75 mg was substituted with adefovir 10 mg, 3 out of 7 patients had a persistent viral rebound (2700-130 000 copies/mL), in whom lamivudine had to be reintroduced. CONCLUSION: Low-dose TDF monotherapy can control HBV viremia for an extended period of time without the emergence of resistance and is more potent than adefovir at the standard dosage. The use of a reduced dose of TDF could diminish the cost of therapy in low-income countries, but further studies in a larger population and in HBeAg-positive subjects are needed.

Short-term overlap lamivudine treatment with adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B

AIM： To evaluate the efficacy of short-term overlap lamivudine therapy with adefovir in patients with lamivudine-resistant and naive chronic hepatitis B, we compared patients receiving overlap therapy with those receiving adefovir alone. METHODS： Eighty patients who had received lamivudine treatment for various periods and had a lamivudineo resistant liver function abnormality were enrolled. Forty of these patients received adefovir treatment combined with lamivudine treatment for ≥ 2 mo, while the other 40 received adefovir alone. We assessed the levels of hepatitis B virus （HBV） DNA at 0, 12 and 48 wk and serum alanine aminotransferase （ALT） levels after 0, 12, 24 and 48 wk of adefovir treatment in each group. RESULTS： We found serum ALT became normalized in 72 （87.5%） of the 80 patients, and HBV DNA decreased by ≥ 2 Ioglo copies/mL in 60 （75%） of the 80 patients at the end of a 48-wk treatment. HBV DNA levels were not significantly different between the groups. The improvements in serum ALT were also not significantly different between the two groups. CONCLUSION： These findings suggest short-term overlap lamivudine treatment results in no better virological and biological outcomes than non-overlap adefovir monotherapy.