Interferon/long-term lamivudine combination therapy in anti-HBe positive chronic hepatitis B patients

BACKGROUND: Monotherapy with a single antiviral agent is insufficient in controlling hepatitis B virus infection in the majority of patients with anti-HBe positive chronic hepatitis B. Interferon/long-term lamivudine combination therapy was evaluated to determine if this strategy would improve treatment efficacy and reduce the emergence of lamivudine resistance. METHODS: In total, 36 consecutive anti-HBe positive patients were treated with interferon (3 MU subcutaneously three times weekly) and lamivudine (100 mg orally once a day) for 12 months. After completion of the combined treatment, all patients continued to receive lamivudine monotherapy indefinitely. RESULTS: Overall, 35 patients (97%) showed virological response at 12 months. Four patients (11%) cleared HBsAg and developed anti-HBs. During the follow-up time, after the discontinuation of interferon, of 30 +/- 12 months (range: 7-57 months), 13 patients (36%) exhibited breakthrough infection. The cumulative rates of breakthrough infection at the end of 1, 2, 3 and 4 years of treatment were 0%, 14%, 32%, and 59%, respectively. CONCLUSIONS: Combination therapy appears to be effective and may also delay the selection of lamivudine-resistant variants. However, controlled trials are definitely warranted to clarify the potential benefits of combination antiviral treatment over monotherapy.     

Two years of lamivudine therapy in anti-HBe-positive patients with chronic hepatitis B

There is no standard therapy for patients with anti-HBe-positive chronic hepatitis B. The aims of this study were to analyse the efficacy of lamivudine therapy for two years in these patients and to study the sequence variations in the precore and polymerase hepatitis B virus (HBV) regions in relation to therapy. Sixteen patients with chronic anti-HBe-positive hepatitis were treated with lamivudine (100 mg) once daily for 2 years. Levels of alanine aminotransferase (ALT), HBV-DNA and HBsAg were monitored during therapy. The polymerase and precore genes were amplified by polymerase chain reaction and their products were sequenced directly. Thirteen of 16 patients (81%) had a virological and biochemical response after 1 year of therapy and 11 (69%) maintained the complete response after 2 years of lamivudine therapy. Among the three patients without initial virological or biochemical response at year 1, prolonging therapy to 2 years was not associated with an increase in the response. YMDD variants were detected in 19% of cases in the first year and in 44% in the second year: YVDD being the most frequent mutations detected during year 1 and YIDD during year 2 of therapy. YMDD variants were found in 7–27% of cases with complete response depending on the duration of therapy. Our results show that prolonging lamivudine therapy is safe, well tolerated and maintains viral inhibition in anti-HBe-positive patients. However, its efficacy tends to decrease overtime and it is associated with an increase in YMDD variants, even in some cases, of complete response.     

Three-phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B

Alpha-interferon (IFN) or lamivudine monotherapy are ineffective in treating chronic HBeAg positive patients with high viral load and low alanine aminotransferase (ALT) levels. We investigated whether priming lamivudine treatment might enhance the antiviral and immunostimulant action of lamivudine/IFN combination in young tolerant patients. Eleven chronic HBeAg positive patients received: 100 mg/day lamivudine for 3 months followed by IFN 5 MU/m2/tiw with lamivudine 100 mg/day for 6 months and then lamivudine alone 100 mg/day for 9 months. Quantitative hepatitis B virus (HBV)-DNA was evaluated during treatment and core-promoter, precore and polymerase HBV mutants were detected by direct sequencing at the end of therapy. Serum HBV-DNA levels dropped during lamivudine monotherapy and in combination with IFN. After IFN withdrawal, viraemia transiently increased to high levels in five of 11 (45%) patients who showed rt M204V/I lamivudine mutant resistant. Two patients cleared HBeAg without anti-HBe seroconversion. One patient presented core-promoter (A1762T/G1764A) and precore stop codon mutations. Hence, three-phase sequential combined lamivudine/IFN treatment reduced HBV-DNA serum level, but did not lead to HBeAg and HBV-DNA clearance in these highly viraemic, normal ALT patients. Lamivudine/IFN combination did not prevent the emergence of YMDD lamivudine resistance. New schedules of antiviral treatments must be evaluated in this population at risk of disease progression.     

Hepatitis B surface antigen seroconversion is associated with favourable long-term clinical outcomes during lamivudine treatment in HBeAg-negative chronic hepatitis B patients

The aims of this study were to assess hepatitis B surface antigen (HBsAg) seroconversion and to determine its impact on the natural course of the disease in patients with HBeAg-negative chronic hepatitis B (CHB) during lamivudine (LMV) treatment. A total of 183 consecutive patients with HBeAg-negative CHB who were treated with LMV were included in the study. Data were retrospectively collected from outpatient visit charts. The primary endpoint was HBsAg seroconversion to anti-HBs. The secondary endpoint was to determine the development of cirrhosis. Loss of HBsAg was confirmed in 10 patients and seroconversion to anti-HBs in nine patients during LMV treatment or after its discontinuation. HBsAg seroconversion was achieved on-treatment in four patients after a median treatment duration of 30 months and off-treatment in the remaining five patients in a median 61 months after LMV discontinuation. The cumulative probability of HBsAg seroconversion increased from 0.6% at 1 year and 1.9% at 5 years to 21.5% at 10 years of LMV during and after LMV treatment. HBsAg clearance was preceded by undetectable serum hepatitis B virus (HBV) DNA. The majority of the patients responding to treatment had undetectable HBV DNA levels at 24 weeks of treatment. The cumulative probability of LMV resistance increased from 2.2% at 1 year to 37.3% at 5 years. No baseline parameter predicting either HBsAg seroconversion or the emergence of LMV resistance was identified. None of the patients with HBsAg seroconversion experienced virological breakthrough or disease progression during the follow-up period. These results indicate that HBsAg seroclearance can occur in patients with HBeAg-negative CHB under LMV therapy and predicts better clinical outcome.     

Monitoring of HBeAg levels may help to predict the outcomes of lamivudine therapy for HBeAg positive chronic hepatitis B

The aim of this study was to determine whether the changing patterns of quantitative hepatitis B e antigen (HBeAg) levels by serial monitoring could predict HBeAg seroconversion and viral breakthrough during lamivudine therapy. We retrospectively analysed 340 HBeAg positive naive chronic hepatitis B patients treated with lamivudine. The mean duration of lamivudine therapy was 18.7 (range 6-56) months. The changing patterns and reduction rates of pretreatment HBeAg levels by serial monitoring were categorized into three groups: Decrescendo group (n = 195), Decrescendo-crescendo group (n = 65) and no changing or fluctuating group (n = 80). Of 109 patients who had achieved HBeAg seroconversion, 105 (96.3%) were included in the decrescendo group. The decrescendo group, pretreatment quantitative HBeAg levels, alanine aminotransferase levels, and the duration of lamivudine therapy were independent predictive factors for HBeAg seroconversion. Of 82 patients who had viral breakthrough, 53 (64.6%) were in the decrescendo-crescendo group and 21 (25.6%) were in the no changing or fluctuating group. The only predictive factor for viral breakthrough was the changing patterns of quantitative HBeAg levels, especially, the decrescendo-crescendo group and the no changing or fluctuating group. The mean time of turning points in the decrescendo-crescendo group was 7.1 months earlier than the mean time of viral breakthrough (9.0 months vs 16.5 months). Therefore, the changing patterns of quantitative HBeAg levels by serial monitoring during lamivudine therapy may allow not only the prediction of treatment responses, but also an early recognition of a viral breakthrough.     

Dynamics of hepatitis B e antigen index ratio correlate with treatment response in chronic hepatitis B patients.

BACKGROUND/AIM: Hepatitis B e antigen (HBeAg) seroconversion is an important event in the natural history of chronic hepatitis B virus (HBV) infection. Whether early dynamics of HBeAg index ratio could predict therapeutic endpoint of HBeAg seroconversion in patients receiving lamivudine remains unclear and thus deserves investigation. METHODS: A total of 52 patients (males/females, 40/12; mean age, 31.1+/-7.5 years) with HBeAg-positive chronic hepatitis B and serum alanine aminotransferase (ALT) level > or = 5 x upper limit of normal were enrolled. They received daily 100 mg lamivudine for at least 1 year. Pretreatment HBeAg index ratio and the dynamics during treatment [early serologic response (ESR) and serologic breakthrough (SB)] between responders and non-responders were compared. RESULTS: Of these 52 patients, mean pretreatment serum ALT level was 580 IU/l and baseline HBeAg index ratio (S/N) was 37.9. The overall 1-year on-treatment combined response rate was 50%. By using linear regression analysis, HBeAg index ratio was positively correlated with serum HBV DNA level (Pearson's correlation coefficient: 0.62, P<0.0001). By using multivariate logistic regression analysis, ESR could predict the success of treatment response (P=0.0302), and SB had a 90% positive predictive value of treatment failure. CONCLUSIONS: HBeAg index ratio is closely correlated with serum HBV DNA level, and the dynamics of HBeAg index ratio may predict 1-year on-treatment combined response to lamivudine in HBeAg-positive chronic hepatitis B patients.     

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.     

替比夫定与拉米夫定对慢性乙型肝炎患者血清抗原蛋白影响的对照研究

目的:观察和比较替比夫定、拉米夫定对慢性乙型肝炎患者的疗效以及对血清乙肝抗原蛋白水平的影响。方法:采用1∶1随机、对照设计。共入组慢性乙型肝炎患者100例,随机分为替比夫定组50例,拉米夫定组50例;对照观察两组临床疗效及不良反应;并动态监测患者血清HBsAg、HBeAg水平的变化。结果:治疗1年时,替比夫定组患者血清HBV DNA PCR法检测不到的比率、ALT复常率均较拉米夫定组稍高,但无统计学意义;HBeAg阴转率及血清学转化率以及病毒突破率分别为34%、28%和8%,均优于拉米夫定组的16%、12%和22%,差异均有显著性意义(P分别为0.0377、0.0455和0.0498)。两组患者治疗后血清抗原蛋白HBsAg及HBeAg水平均有不同程度的下降,但替比夫定组患者治疗1个月时,血清HBsAg和HBeAg水平较基线下降分别为(30.2±16.1)S/N和(80.8±12.9)S/CO,均高于拉米夫定组的(7.8±12.4)S/N和(10.9±27.9)S/CO,差异有统计学意义;至治疗12个月时,其降幅差异更为明显,分别达到(146.7±32.5)S/N和(202.3±62.8)S/CO及(68.4±39.5)S/N和(90.4±52.8)S/CO,差异有非常显著的统计学意义;替比夫定不良反应轻微,与拉米夫定类似。结论:替比夫定较拉米夫定具有更强地抑制HBV DNA复制能力以及较少的耐药率和病毒反跳率;同时替比夫定能更强地抑制病毒抗原蛋白的表达,可能与较高的HBeAg血清学转换率有关。     

A 7‐year study of lamivudine therapy for hepatitis B virus e antigen‐positive chronic hepatitis B patients in China

OBJECTIVE: To evaluate the long‐term efficacy and safety of lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily or a placebo in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were administered with lamivudine 100 mg/d for 5 years and followed up for 2 years. RESULTS: After 12 weeks of the lamivudine treatment, serum HBV DNA levels decreased rapidly and HBV DNA negativity (<1.6 pg/mL) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. At the end of 5 years, serum HBV DNA continued to be substantially suppressed. The loss of HBeAg and seroconversion were significantly correlated with baseline alanine aminotransferase (ALT) levels, in patients with baseline ALT > 2 × upper limits of normal, the loss of HBeAg was 54% and seroconversion rate was 50%, respectively. YMDD mutation developed in 70.8% of the patients at years 5. In YMDD mutant patients, HBV DNA levels were increased moderately and with mild to moderate elevations of ALT. ALT flares (ALT > 5ULN) occurred in 22 patients, 16 with YMDD variants and six with non‐variants. One year durability of seroconversion after stopping lamivudine was 80%. CONCLUSION: Lamivudine is effective and tolerable for chronic hepatitis B.     

Efficacy of lamivudine re-treatment for relapsed patients after an initial lamivudine therapy in HBeAg-positive chronic hepatitis B

The efficacy of lamivudine re-treatment in chronic hepatitis B (CHB) patients who relapse after HBeAg seroconversion with lamivudine has not been investigated. The aim of this study was to evaluate the efficacy of lamivudine re-treatment in relapsed patients. Among 192 patients who had achieved HBeAg seroconversion with lamivudine at a dose of 100 mg/day, 121 patients discontinued lamivudine. Relapse occurred in 49 patients (40.5%). Thirty-three relapsed patients received lamivudine re-treatment for at least 6 months. The mean duration of lamivudine re-treatment was 16 months and the follow-up period was 8.9 months. HBeAg seroconversion was achieved in 23 patients (69.7%). The cumulative HBeAg seroconversion rates at 5, 9, and 12 months were 60, 64, and 67%, respectively. The mean time to HBeAg seroconversion in lamivudine re-treatment was shorter than that in the initial therapy (4.7 months vs. 9.7 months). Viral breakthrough occurred in six (18.2%) patients. All patients with viral breakthrough were accompanied by elevation of serum alanine aminotransferase (ALT) levels. Among 15 patients who discontinued lamivudine re-treatment after HBeAg seroconversion, relapse occurred in six patients (40%). All relapses occurred within 9 months after the discontinuation of lamivudine re-treatment. In conclusion, lamivudine re-treatment in relapsed patients after initial lamivudine therapy had a higher response rate and shorter duration to HBeAg seroconversion than during the initial therapy. However, HBeAg seroconversion induced by lamivudine re-treatment was not durable.     

拉米夫定治疗HBeAg阳性及阴性慢性乙型肝炎患者复发率的比较

探讨HBeAg阳性及阴性慢乙肝患者拉米夫定治疗中复发率及其影响因素。选择服用拉米夫定一年以 上的100例(其中,HBeAg阳性69例,HBeAg阴性31例)慢乙肝患者,检测复发率并分析了影响复发率的有关因素。 结果显示当服用拉米夫定12个月时HBeAg阴性及阳性群复发率分别为0％和12％,当74个月时分别为7％和 39％,两者之间有显著性差异(P<0．01) 另外,复发率仅与HBeAg存在与否有关(P<0．05),而与年龄、性别、治疗 前ALT、治疗前HBV DNA值无关。说明拉米夫定对HBeAg阴性慢乙肝远期效果比HBeAg阳性慢乙肝为好,HBeAg 存在与否影响其复发率。     

拉米夫定治疗HBeAg阳性慢性乙型肝炎患者血清转换持久性的研究

目的观察拉米夫定长期治疗慢性乙型肝炎(CHB)3年以上患者的血清转换率和停药后持久率,及影响疗效的有关因素.方法167例CHB患者,每天服用拉米夫定100mg,持续3年以上,连续2次以上出现血清转换(间隔3个月),即HBeAg转阴和抗HBe转阳,继续服药6～12个月后,停药并随访1年以上.服药第1年每月,以后第3个月观察临床症状和血清病毒学标志、丙氨酸转氨酶(ALT)、HBV DNA定量及YMDD变异等项目.HBV基因分型应用型特异性PCR方法.结果共有45例患者出现血清转换(27.0%),继续服药6～12个月后停药并随访1年以上,9例出现血清学重新激活,血清转换持久率为80.0%.经单因素统计和Logistic多元回归分析,得出血清转换率和停药后持久率与基线ALT水平呈正相关,与基线HBV DNA水平和治疗后YMDD变异呈负相关.结论CHB患者出现血清转换后继续应用拉米夫定治疗6个月以上,大多数患者可达到持续转换.对血清转换率和持久率有显著影响意义的因子为基线ALT、治疗后YMDD变异.     

A higher alanine aminotransferase level correlates with earlier hepatitis B e antigen seroconversion in lamivudine‐treated chronic hepatitis B patients

Background/Aims: A pretherapy serum alanine aminotransferase (ALT) level above five times the upper limit of normal (ULN) is known to predict hepatitis B e antigen (HBeAg) seroconversion during lamivudine therapy for chronic hepatitis B patients. However, whether an even higher pretherapy serum ALT value or other viral factors could affect treatment responses remains unclear. Patients and methods: A total of 253 HBeAg‐positive chronic hepatitis B patients who had a pretherapy serum ALT level over five times ULN and received lamivudine for 12–18 months were retrospectively collected. Among these patients, 38% had received prior lamivudine treatment. HBeAg seroconversion was the primary endpoint of treatment. Baseline clinical and viral features were compared between responders and non‐responders at the end of treatment and 6 months post‐treatment. Results: At the end of therapy, the overall HBeAg seroconversion rate was 33.6%. For lamivudine‐naïve patients, the HBeAg seroconversion rate was 37.8%. Subgroup analysis showed that patients with pretherapy ALT levels over 10 times ULN had a significantly higher HBeAg seroconversion rate than those with a pretherapy ALT level between five and 10 times ULN at 3 months (P=0.045) and 6 months (P=0.037) of lamivudine treatment. No significant difference was found in terms of pretherapy serum ALT values, viral load and genotypes between seroconverters and non‐seroconverters. Conclusions: For lamivudine‐treated HBeAg‐positive patients with pretherapy ALT levels over five times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however, neither ALT levels nor viral factors correlate with higher response rates after 12–18 months of treatment.     

拉米夫定联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎患者48周临床观察

我国现有慢性乙型肝炎（CHB）患者约2000万例,其中HBeAg阳性CHB患者近60%,常常表现为ALT持续或间歇升高,HBV复制活跃,肝组织重度炎症坏死,与HBeAg阴性患者相比,有较高的肝硬化比率[1]及较快速的病情进展[2]。而持续的高病毒载量又与肝细胞癌（HCC）直接相关[3],那么最大限度地长期抑制HBV,减轻肝细胞炎症坏死及纤维化,延缓和减少肝脏失代偿、肝硬化、HCC及其并发症的发生,从而改善生存质量和延长生存时间[4]成为CHB治疗的总体目标。核苷和核苷     

Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy

Aim: The clinical significance of hepatitis B virus (HBV) core-related antigen (HBcrAg) in predicting the reactivation of hepatitis after halting lamivudine administration was analyzed. Methods: A total of 34 patients with chronic hepatitis B were enrolled. Lamivudine was administered for at least 6 months before cessation, and reactivation of hepatitis was defined as elevation of alanine aminotransferase levels to more than 80 IU/L within 12 months of cessation. Results: In total, 20 (59%) patients experienced hepatitis reactivation. Although concentrations of HBV DNA and HBcrAg in serum did not differ between the two groups of patients at the onset of lamivudine administration, HBcrAg serum levels were significantly higher (P = 0.009) in the reactivation patients (median 4.9, 25-75% range 4.7- 5.9 log unit/mL) than the non-reactivation patients (median 3.2, 25-75% range <3.0-4.5 log unit/mL) post-lamivudine treatment. The concentration of HBV DNA did not differ between the two groups (median <3.7, 25-75% range <3.7-<3.7 log copy/mL in the reactivation group vs. median <3.7, 25-75% range <3.7-<3.7 log copy/mL in the non- reactivation group). Receiver operating characteristic analysis of HBcrAg concentration showed an area under the curve of 0.764 in predicting patients without reactivation of hepatitis. Conclusion: HBcrAg can be a useful marker to identify patients who are not at risk of reactivation of severe hepatitis after discontinuation of lamivudine administration.     

Stringent cessation criterion results in better durability of lamivudine treatment: a prospective clinical study in hepatitis B e antigen‐positive chronic hepatitis B patients

Summary. The cessation criteria for lamivudine treatment vary in published articles and their results are contradictory, especially factors predicting relapse. To clarify these contradictions, this long‐term follow‐up study of 125 Chinese hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients was designed with stringent cessation criterion. All patients received lamivudine and achieved HBeAg seroconversion (group A, n = 82) or loss (group B, n = 43) with undetectable hepatitis B virus (HBV) DNA by PCR assay during the treatment. Lamivudine was withdrawn ≥6 months after HBeAg seroconversion/loss occurred. The median treatment durations were 24 (12–54) months and 36 (18–89) months in group A and group B, respectively. Patients were followed up for median 24 (2–84) months. The cumulative relapse (defined as serum HBV DNA ≥10⁴ copies/mL) rates in the two groups at months 12, 24, 36 and 48 were 23.4%vs 35.0%, 25.0%vs 37.7%, 25.0%vs 41.1% and 29.4%vs 41.1%, respectively (log‐rank test, P = 0.119). For patients whose total treatment duration ≥18 months in group A, the cumulative relapse rates at months 12, 24, 36 and 48 were 18.3%, 20.1%, 20.1% and 25.1%, which was significantly lower than those with a shorter duration (log‐rank test, P = 0.002). The mean age and median total duration were statistically different between relapsers and nonrelapsers in group A (33.9 ± 13.6 vs 23.1 ± 11.0 years, P < 0.001 and 24 vs 26 months, P = 0.003). Cox regression revealed that age was the only predictive factor for relapse (RR, 1.069; 95% CI, 1.032–1.106, P < 0.001). Patients aged <30 years relapsed less frequently in 5 years (12.3%vs 53.5%, P = 0.001). In conclusion, for patients who maintained HBeAg seroconversion for ≥6 months and total duration for ≥18 months, lamivudine withdrawal is a reasonable option. Prolonged treatment may be required for patients aged greater than 30 years to reduce relapse.     

Clinical importance of serum hepatitis B surface antigen levels in chronic hepatitis B

Quantitative serology for hepatitis B surface antigen (HBsAg) is a new candidate marker for prediction of clinical outcome. The aim of this study was to investigate the clinical significance of quantifying HBsAg in patients with hepatitis B virus (HBV) infection. A total of 424 patients who tested positive for HBsAg and were referred to Chiba University Hospital between January 1985 and April 2008 were included in the study, and the following characteristics were analyzed: age, gender, status of hepatitis B e antigen (HBeAg), alanine aminotransferase level (ALT), HBV DNA level, number of platelets and development of hepatocellular carcinoma. Measurement of HBsAg was performed using the chemiluminescent enzyme immunoassay method. The study group consisted of 239 men and 185 women, and their average age was 40.6 ± 14.0 years. HBsAg showed a positive correlation with HBV DNA level (Pearson's product moment correlation, r = 0.586, P < 0.001) and a weak inverse correlation with age (r = 0.3325, P < 0.001). A control study, matched with age and sex, was performed between two groups with and without HBeAg seroconversion during follow-up period. Compared with the age and sex-matched controls, the change in HBsAg levels per year showed a significant decrease 2 years before seroconversion (paired t-test, P < 0.05). The serial measurement of quantitative HBsAg level has the possibility of predicting the occurrence of HBeAg seroconversion.     

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.