Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B

BACKGROUND AND AIMS: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). METHODS: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level > or =1.2 times the upper limit of normal, and serum HBV DNA level > or =6 log(10) copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. RESULTS: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG(16) was -0.07 in the lamivudine group compared with -2.45 and -2.46 log(10) copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, -3.59, and -4.04 log(10) copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. CONCLUSIONS: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.     

Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B

BACKGROUND & AIMS: Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV. METHODS: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal). RESULTS: Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was -5.11 log(10) copies/mL for entecavir-treated patients and -0.48 log(10) copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment. CONCLUSIONS: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile.     

Long-term safety of lamivudine treatment in patients with chronic hepatitis B

BACKGROUND & AIMS: Data on the long-term safety of lamivudine are limited. The aim of this analysis was to determine the incidence of hepatitis flares, hepatic decompensation, and liver-disease-related (LDR) serious adverse events (SAE) during long-term lamivudine treatment. METHODS: We reviewed data on 998 patients with HBeAg-positive compensated chronic hepatitis B who received lamivudine for up to 6 years (median, 4 years) and 200 patients who received placebo for 1 year. RESULTS: Hepatitis flares occurred in 10% of the lamivudine-treated patients in year 1 and in 18%-21% in years 2-5. A temporal association between hepatitis flares and lamivudine-resistant mutations increased from 43% in year 1 to >80% in year 3. Ten hepatic decompensation events occurred in 8 (<1%) lamivudine-treated patients. Fifty-three (5%) lamivudine-treated patients experienced a total of 60 LDR SAEs. Four patients died, 2 from liver-related causes. The proportion of patients with a documented lamivudine-resistant mutation increased from 23% in year 1 to 65% in year 5. During each year of the study, patients with lamivudine-resistant mutations experienced significantly more hepatitis flares than patients without lamivudine-resistant mutations (P < 0.005). The occurrence of hepatic decompensation (0%-2%) and LDR SAEs (1%-10%) among patients with lamivudine resistance remained stable during the first 4 years with mutations and increased afterward to 6% (P = 0.03) and 20% (P = 0.009), respectively. CONCLUSIONS: This study demonstrated that lamivudine treatment for up to 6 years has an excellent safety profile in patients with HBeAg-positive compensated liver disease, but patients with long-standing lamivudine-resistant mutations may experience worsening liver disease.     

Long-term outcomes of add-on adefovir dipivoxil therapy to ongoing lamivudine in patients with lamivudine-resistant chronic hepatitis B

Aim: Add-on adefovir dipivoxil (ADV) therapy has been a standard rescue treatment for patients with lamivudine (LAM)-resistant chronic hepatitis B, but the overall benefits of long-term add-on ADV therapy are still limited. The aim of this study was to evaluate the long-term efficiency of add-on ADV treatment and to explore predictive factors associated with it. Methods: A total of 158 patients with LAM-resistant chronic hepatitis B were included in this retrospective, multicenter, nationwide study in Japan. After confirming LAM resistance, ADV was added to LAM treatment. Three types of events were considered as outcomes: virological response, hepatitis B e antigen (HBeAg) clearance and alanine aminotransferase (ALT) normalization. Virological response was defined as serum hepatitis B virus (HBV) DNA levels of less than 3 log copies/mL. Baseline factors contributing to these outcomes were examined by univariate and multivariate analyses. Results: The median total duration of ADV treatment was 41 months (range, 6–84). The rate of virological response was 90.8% at 4 years of treatment; HBeAg clearance and ALT normalization were achieved by 34.0% and 82.7%, respectively, at the end of follow up. Each outcome had different predictive factors: baseline HBV DNA and albumin level were predictive factors for virological response, history of interferon therapy and ALT level for HBeAg clearance, and sex and baseline albumin level for ALT normalization. Conclusion: Long-term add-on ADV treatment was highly effective in LAM-resistant chronic hepatitis B patients in terms of virological and biochemical responses. Lower HBV replication and lower albumin level at baseline led to better outcomes.     

Pegylated IFN-α 2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

AIM: To investigate the role of pegylated-interferon (IFN) alpha-2b in the management of patients with lamivudine-resistant chronic hepatitis B.METHODS: Twenty consecutive anti-HBe positive patients were treated with pegylated IFN alpha-2b (100 mug sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison.RESULTS: Nine patients (45%) had a partial virological end-treatment response; seven patients (35%) showed complete virological end-treatment response. Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients, respectively; P=0.1). Patients without virological end-treatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n=5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms.CONCLUSION: Pegylated IFNalpha-2b, when added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B, induces sustained responses only in a small minority of cases.     

Factors contributing to antiviral effect of adefovir dipivoxil therapy added to ongoing lamivudine treatment in patients with lamivudine-resistant chronic hepatitis B

Purpose  The antiviral effect of adefovir dipivoxil (ADV) added to ongoing lamivudine (LAM) treatment for LAM-resistant chronic hepatitis B (CHB) differs among patients. We investigated clinical factors affecting the response to ADV therapy in LAM-resistant CHB. Methods  The subjects were 75 LAM-resistant CHB patients treated with ADV in addition to LAM. Virological response (VR) was defined as HBV DNA clearance (<2.6 logcopies/ml) at 12 months after the start of ADV therapy. Clinical factors contributing to VR were examined by univariate and multivariate analyses. Results  Lower HBV DNA at baseline and negative hepatitis B e antigen (HBeAg) were significant factors affecting VR in univariate analysis. In multivariate analysis, lower HBV DNA at baseline (P = 0.005), negative HBeAg (P = 0.009), and higher ALT (P = 0.036) were significant independent factors contributing to VR. In HBeAg-positive patients, HBV DNA clearance was more frequently observed during ADV therapy in patients with baseline HBV DNA ≤7.0 logcopies/ml than in those with baseline HBV DNA >7.0 logcopies/ml. By contrast, the link of lower HBV DNA at baseline to better therapeutic response was not evident in HBeAg-negative patients. Conclusion  In ADV therapy added to ongoing LAM treatment for LAM-resistant CHB, lower baseline HBV DNA and negative HBeAg contributed to a better antiviral effect. Addition of ADV should be done promptly before marked increase in HBV DNA, especially in CHB patients showing LAM resistance positive for HBeAg.     

Pegylated IFN-α 2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

AIM: To investigate the role of pegylated-interferon (IFN)α-2b in the management of patients with lamivudineresistant chronic hepatitis B.METHODS: Twenty consecutive anti-HBe positive patients were treated with pegylated IFN α-2b (100 μg sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry,serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison.RESULTS: Nine patients (45%) had a partial virological end-treatment response; seven patients (35%)showed complete virological end-treatment response.Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients,respectively; P=0.1). Patients without virological endtreatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n = 5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms.CONCLUSION: Pegylated IFNα-2b, when added to ongoing lamivudine therapy in patients with lamivudineresistant chronic hepatitis B, induces sustained responses only in a small minority of cases.     

阿德福韦酯治疗对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者48周临床疗效

目的评价阿德福韦酯治疗对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者的临床疗效。方法 75例对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者,联合组（48例）加用阿德福韦酯（10 mg/d）治疗48周;单药组（27例）改用阿德福韦酯（10 mg/d）治疗48周,分别检测治疗前及治疗12周、24周和48周时患者血清HBVDNA定量、HBV血清标志物及肝功能。结果治疗48周时,联合组与单药组HBVDNA阴转率分别为62.5%和29.6%（P〈0.01）,HBeAg阴转率分别为31.3%和11.1%（P〈0.05）,HBeAg血清转换率为16.7%和7.4%（P〉0.05）,ALT复常率分别为91.7%和88.9%（P〉0.05）。治疗48周无肾脏安全性问题发生。结论加用阿德福韦酯可作为对拉米夫定耐药患者治疗的首选方案之一。     

阿德福韦酯治疗HBeAg阳性的中国慢性乙型病毒性肝炎患者52周的多中心临床研究

目的评价阿德福韦酯（ADV）片10mg／d治疗HBeAg阳性的中国慢性乙型病毒性肝炎患者52周的疗效和安全性。方法采用多中心、随机、双盲、安慰剂平行对照的研究设计。第一阶段480例患者按3：1的比例随机进入ADV组（360例）或安慰剂组（120例）治疗12周；第二阶段所有患者均接受开放的ADV治疗28周；第三阶段则原接受ADV治疗的患者重新按2：1的比例随机接受ADV治疗（AAA组）或安慰剂治疗（AAP组）；而第一阶段服用安慰剂的患者（PAA组）将继续接受ADV治疗。根据不同的组别，患者分别口服ADV10mg或安慰剂1片，1日1次。主要疗效评估指标为血清HBV DNA的变化情况。次要疗效评估指标为丙氨酸转氨酶（ALT）的复常率与HBeAg转阴率、HBeAg的血清转换率。结果12周时，AAA组和AAP组HBV DNA中位数水平较基线分别降低3．4lg拷贝／ml和3．3lg拷贝／ml；40周时，三组血清HBV DNA中位数水平降低程度相似，较基线降低了4．O～4．6lg拷贝／ml；52周时，PAA组和AAA组HBV DNA中位数水平较基线分别降低5．0lg拷贝／ml和4．5lg拷贝／ml，而AAP组HBV DNA中位数水平则恢复到接近基线水平；PAA组和AAA组患者分别有30．3％和28．4％的患者HBV DNA转阴，而AAP组HBV DNA转阴率从40周的19．3％（23／119）降低到0．8％（1／119）；PAA组和AAA组ALT复常率分别为69．2％（74／107）和78．6％（176／224），而AAP组的ALT复常率由40周时的74．3％（81／109）下降为52周的21．1％（23／109）；PAA组和AAA组HBeAg转阴率分别为20％（24／119）和13％（30／237），血清转换率分别为17％（20／116）和8%（19／232），而AAP组的HBeAg转阴率和血清转换率分别从40周的14％（16／114）和11％（12／112）降低到52周时的9％（10／114）和4％（5／112）。45例血清HBV DNA水平较治疗最低水平增高≥1lg的患者中未发现与ADV耐药相关的基因突变。安全性方面，各组至少发生1个与药物相关不良事件的发生率为5％～11％，大多为轻、中度。研究期间各治疗组血清肌酐及血磷值平均水平同基线相比无变化。结论阿德福韦酯片10mg／d剂量服用52周，可以安全、有效地治疗中国HBeAg阳性的慢性乙型肝炎患者，未发现与ADV耐药相关的病毒基因突变。     

Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in chronic hepatitis B patients treated with lamivudine.

Aim: Lamivudine (LAM) has been widely used to treat chronic hepatitis B (CHB) patients, but the emergence of a LAM-resistant virus greatly limits its therapeutic efficacy. In this study, we tried to identify factors affecting the emergence of a LAM-resistant virus in CHB patients treated with LAM. Methods: The subjects were 190 CHB patients in continuous LAM therapy (139 males, mean age 50 years, 87 HBeAg-positive). The mean duration of follow-up was 39 months (range 12-104). The initial viral response (IVR) was defined as HBV DNA < 4.0 logcopies/mL, and the initial biochemical response (IBR) as normalization of alanine aminotransferase (ALT) (<40 IU/L) at 6 months. Results: IVR was positive in 86% of the patients. The cumulative emergence rates of LAM-resistant virus were 10% at 1 year, 30% at 2 years and 46% at 3 years. In univariate analysis, factors contributing to the emergence of LAM-resistant virus were baseline HBV DNA > 6.5 logcopies/mL (P = 0.0044), HBeAg-positivity (P = 0.0062), IBR (P = 0.01) and IVR (P < 0.0001). The cumulative emergence rates of LAM-resistant virus in IVR-positive and -negative patients were 4% and 41% at 1 year, and 41% and 79% at 3 years. In multivariate analysis, only IVR was an independent factor affecting the emergence of LAM-resistant virus (P < 0.0001). Conclusion: IVR is a useful factor for predicting the emergence of LAM-resistant virus in CHB patients treated with LAM. For IVR-negative patients, therapeutic options other than LAM monotherapy should be used because of the high incidence of the emergence of LAM-resistant virus.     

Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years

BACKGROUND & AIMS: Treatment with adefovir dipivoxil for 48 weeks resulted in clinical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B that was lost when treatment was discontinued. We investigated the efficacy, safety, and resistance profile of adefovir dipivoxil treatment for up to 240 weeks. METHODS: HBeAg-negative patients were treated double blind with placebo or adefovir dipivoxil 10 mg once daily for 48 weeks, followed by adefovir dipivoxil from week 49 to 96. At week 97, 125 patients enrolled in a 144-week, open-label phase. Patients received adefovir dipivoxil for up to 192 or 240 weeks. RESULTS: Serum hepatitis B virus (HBV) DNA levels were less than 1000 copies per milliliter in 67% of patients, and alanine aminotransferase (ALT) levels normalized in 69% after 240 weeks. After 192 or 240 weeks of treatment, over 83% of patients had improvement in necroinflammation, and over 73% had improvement in fibrosis. Ishak fibrosis scores improved compared with baseline in 35%, 55%, and 71% of patients after 48, 192, and 240 weeks of adefovir dipivoxil, respectively. After 240 weeks, the cumulative probability of HBV polymerase mutations was 29%, but the cumulative probability of mutations with virologic resistance was 20% and of mutations, virologic resistance, and ALT elevations was 11%. Slight elevations in creatinine were confirmed in 4 (3%) patients. CONCLUSIONS: Treatment with adefovir dipivoxil for up to 240 weeks was well tolerated and produced significant, increasing improvement in hepatic fibrosis, durable suppression of HBV replication, normalization of liver enzymes, and delayed development of resistance.     

Clinical outcomes of chronic hepatitis B patients with persistently detectable serum hepatitis B virus DNA during lamivudine therapy

BACKGROUND AND AIM: A small proportion of chronic hepatitis B patients have persistently detectable serum hepatitis B virus (HBV) DNA despite lamivudine therapy. The incidence and clinical outcomes of patients who persistently have detectable serum HBV-DNA during lamivudine therapy was investigated. METHOD: We enrolled 221 chronic hepatitis B patients who underwent lamivudine therapy for more than 6 months. Among them, 180 were HBeAg positive. Serum HBV-DNA, HBeAg, anti-HBe and alanine aminotransferase (ALT) levels were serially monitored. The study groups were defined, using a hybridization assay, as patients with reductions in serum HBV-DNA below the detectable level (group I) or patients with persistently detectable serum HBV-DNA (group II) during the initial 6 months of lamivudine therapy. RESULTS: The incidence of patients who had persistently detectable HBV-DNA was 7.7%. After the first year, the rates of viral breakthrough, HBeAg loss and serum ALT normalization of group I versus group II were 21% versus 63%, 38% versus 0%, and 71% versus 28%, respectively (P < 0.001). The log(10) reduction of serum HBV-DNA at 6 months was -4.58 log(10) for group I and -1.97 log(10) for group II (P < 0.001, bDNA assay). There were no pretreatment lamivudine-resistant mutants in group II. CONCLUSION: Lamivudine had little effect on serum HBV-DNA suppression, viral breakthrough suppression and rate of HBeAg loss and ALT normalization in chronic hepatitis B patients with persistently detectable serum HBV-DNA during the initial 6 months of therapy. Early termination of lamivudine therapy is advocated for these patients.     

恩替卡韦联合阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎患者的疗效观察

目的观察恩替卡韦联合阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎(CHB)患者的疗效和安全性。方法选取昆山市人民医院2011年5月至2013年5月门诊和住院的拉米夫定耐药患者45例,随机分成两组,治疗组23例应用恩替卡韦联合阿德福韦酯挽救治疗,对照组22例应用拉米夫定联合阿德福韦酯挽救治疗,观察两组治疗前及治疗后4、12、24、48周HBV DNA、ALT、AST、TBil、Alb、HBV血清学标志物含量变化以及治疗48周时非rtM204I位点变异发生率。计量资料组间比较用t检验,计数资料的组间比较用四格表χ2检验。结果治疗组挽救治疗后4、12周ALT、AST下降较对照组相比差异有统计学意义(t值为3.124、5.271、4.476、5.125,P值均0.01),挽救治疗24、48周后较对照组相比差异有统计学意义(t值为2.240、2.307、2.886、2.908,P值均0.05)。治疗4、12、24、48周后,治疗组HBV DNA转阴率分别为73.9%、86.8%、95.7%、100%,较对照组差异有统计学意义(χ2值为11.79、5.75、10.29、5.89,P值均0.05)。HBeAg阳性患者阴转率在治疗组及对照组间差异无统计学意义。治疗组48周后未出现新的非rtM204I位点变异,而对照组非rtM204I位点变异情况为4例,两组相比差异有统计学意义(χ2=4.59,P0.05)。结论恩替卡韦联合阿德福韦酯用于既往拉米夫定耐药的CHB患者的挽救治疗疗效明显,值得临床推广。     

拉米夫定耐药慢性乙型肝炎患者改用或加用阿德福韦酯治疗48周疗效比较

目的观察拉米夫定(LAM)与阿德福韦酯(ADV)联合应用和单用ADV治疗LAM耐药HBeAg阳性慢性乙型肝炎患者的疗效及安全性。方法收集2006年1月至2011年12月在本院就诊的LAM耐药HBeAg阳性慢性乙型肝炎患者40例,单药组与联合组各20例,分别以ADV与LAM联合或单用ADV进行治疗。观察治疗24周、48周时的血清HBV DNA水平及转阴率、HBeAg转阴率、ALT复常率以及治疗过程中药物的不良反应和耐药性。组间比较计量资料采用t检验,计数资料采用卡方检验。结果两组患者在性别、年龄、治疗前的HBV DNA及ALT水平上差异均无统计学意义(P0.05);治疗结束时联合组的血清HBV DNA转阴率和ALT复常率分别为90%及95%,而单药组的血清HBV DNA转阴率和ALT复常率分别为60%及65%,两组比较差异有统计学意义(P0.05);治疗结束时联合组血清HBeAg转阴率为45%,单药组为35%,两组比较差异无统计学意义(χ2=0.417,P=0.519)。结论 ADV联合LAM或ADV单药治疗LAM耐药HBeAg阳性慢性乙型肝炎患者均有较好的临床疗效,但ADV与LAM联合治疗可提高HBV DNA转阴率及ALT复常率,其安全性良好,值得借鉴。     

乙型肝炎核心相关抗原对慢性乙型肝炎患者拉米夫定耐药的预测作用

目的评价乙型肝炎核心相关抗原（HBcrAg）对慢性乙型肝炎患者拉米夫定（LAM）耐药的预测作用。方法收集2009年1月至2011年12月期间住院和门诊收治的43例慢性乙型肝炎初治患者,拉米夫定治疗≥6个月,随访≥6个月,根据随访期间HBV DNA测序结果分为耐药组2l例,非耐药组22例。分别检测各研究节点ALT、HBsAg、HBeAg、HBcrAg、HBV DNA水平。计量资料两组问比较采用独立样本t检验,方差不齐采用Mann—Whitney U检验;计数资料采用卡方检验。相关性分析采用Spearman分析。影响因素采用Logistic回归分析。结果LAM抗病毒前HBcrAg与HBV DNA水平有较好的一致性,Spearman相关系数为0．863（P〈0．001）。LAM抗病毒治疗后,外周血HBcrAg与HBV DNA水平均有所下降,但HBcrAg下降速度与幅度均低于HBV DNA。Logistic回归分析显示,随访结束时HBcrAg水平可能为LAM耐药的影响因素（P〈0．01）。HBcrAg对LAM耐药预测价值较高,ROC曲线下面积为0．872（P〈0．001）。结论LAM抗病毒前外周血HBcrAg与HBV DNA有较好的一致性,随访结束时HB—crAg水平可较好的预测LAM耐药。     

Extended treatment with lamivudine and adefovir dipivoxil in chronic hepatitis B patients with lamivudine resistance

Purpose

We and others have reported that adding adefovir dipivoxil (adefovir) to lamivudine results in virological and biochemical improvement in cases of lamivudine resistance. The current study assessed the efficacy and safety of combined therapy after 104 weeks of combined treatment and analyzed the frequency of persistent lamivudine resistant HBV.

Methods

A total of 78 patients with compensated CHB (Group A) were maintained on either adefovir 10 mg daily (n = 38) or placebo (n = 40) while continuing lamivudine. An additional 38 patients with decompensated cirrhosis or post liver transplantation (Group B) received lamivudine plus adefovir. The primary endpoint was HBV DNA response at year 2.

Results

At week 104 of therapy, a significantly greater proportion of patients in Group A on combination therapy (76%) had a decline in serum HBV DNA to ≤10⁵ copies or >2 log₁₀ reduction from baseline compared to those receiving lamivudine alone (13%; p < 0.001). Fifty-two percent of Group A patients on combination treatment continued to have the M204V/I HBV mutation compared to 92% receiving lamivudine alone (p = 0.0013). Virologic response occurred less frequently in patients expressing persistent lamivudine resistant HBV. In Group B, 87% of patients had HBV DNA response at week 104 (median change from baseline of −5.84 log₁₀ copies/mL).

Conclusions

The combination of lamivudine and adefovir for 2 years generally proved effective in lamivudine-resistant cases, but there was a persistently high rate of detection of lamivudine resistant mutants and impaired virologic response in compensated patients.