Response-guided treatment of cirrhotic chronic hepatitis B patients: multicenter prospective study.

AIM: To observe the effect of response-guided add-on therapy with adefovir (ADV) and lamivudine (LAM) in cirrhotic hepatitis B (CHB) patients. METHODS: A total of 100 patients with CHB and cirrhosis were divided into three arms according to hepatitis B virus (HBV) DNA level after 24 wk LAM monotherapy: Arm A (complete response, HBV DNA ≤ 60 IU/mL, n = 49), Arm B (partial response, HBV DNA: 60-2000 IU/mL, n = 31) and Arm C (inadequate response, HBV DNA > 2000 IU/mL, n = 20). ADV was added to LAM at week 48 in Arms A and B, but at week 24 in Arm C. Virological response, YMDD mutations, biochemical response, and liver function were evaluated. RESULTS: Comparison of the three arms demonstrated that early complete virologic response at week 24 was associated with maintained viral suppression (undetectable rate of HBV DNA at week 144 was 95.96%, 66.67% and 35.29%, respectively, P = 0.000) and reduced YMDD mutations (mutation rate at week 144 was 0%, 3.23% and 15%, respectively, P = 0.015) after 144 wk treatment. For patients who failed to achieve complete virological response at week 24, switching to combination therapy further decreased HBV DNA level by 1 log10 IU/mL. All three arms obtained biochemical benefits including decline of alanine aminotransferase and elevation of albumin. In patients who developed HBV DNA breakthrough for YMDD mutations, ADV add-on therapy did not induce further multiple drug resistance to LAM or ADV. CONCLUSION: Optimized response-guided add-on therapy of ADV and LAM maintains long-term suppression of HBV DNA and improves liver function in CHB patients with compensated liver cirrhosis.

[The clinical characteristics of primary biliary cirrhosis in China: a systematic review].

OBJECTIVE: To summarize the clinical features, diagnosis and treatment of patients with primary biliary cirrhosis (PBC) in China. METHODS: Systematic analysis of clinical characteristics by searching the Chinese literatures. RESULTS: From 1955 to 2007, 2740 PBC patients were reported in 103 papers (duplicated reports were deleted). The detailed information of 985 patients from 16 papers were collected. Female : male was 6.82:1. The age range was 42 to 56.2-year-old. The time from onset to diagnosis was 12 to 98.4 months. The most common symptoms were fatigue (72.40%), jaundice (67.41%), anorexia (68.58%) and pruritus (45.60%). 20% patients were asymptomatic at onset. The most frequent physical signs were splenomegaly (57.53%), hepatomegaly (43.56%) and ascites (18.45%). Serum alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT) levels were markedly elevated in most of these patients. The immunological marks of AMA and M2 were positive in 88.98% and 82.65% patients, respectively. The most common comorbidity were Sjögren syndrome (9.14%), rheumatoid arthritis (3.95%) and diabetes type II (2.54%). Of the 507 patients treated with ursodeoxycholic acid (UDCA), 345 patients got complete or partial clinical biochemical response. The common complications were gastrointestinal bleeding (41.67%) and liver failure (41.67%). Liver transplantation was the only effective way for the treatment of the end-stage liver disease. CONCLUSION: The clinical feature of primary biliary cirrhosis in China was similar to the overseas literatures. Further research should focus on epidemic investigation, early diagnosis, long term follow up of asymptomatic patients, immunological mechanism and the efficacy of liver transplantation.

[Results of 3 years of continuous entecavir treatment in nucleos(t)ide-naive chronic hepatitis B patients].

OBJECTIVE: To evaluate the virological, serological and biochemical outcomes of 3 years of entecavir (ETV) treatment in nucleoside-naive chronic hepatitis B patients. METHODS: This study was divided into two stages: Patients receiving either ETV 0.5 mg/d (n = 258) or lamivudine (LAM) 100 mg/d (n = 261) entered the initial 96-week randomized, double blind, controlled efficacy study. Patients not achieving a consolidated response (HBV DNA less than 0.7 MEq/ml, ALT less than 1.25 times*ULN, and if HBeAg-positive at baseline, loss of HBeAg for >or= 24 weeks), or those experienced viral breakthrough or relapse, entered a 48-week entecavir rollover study. RESULTS: 96 weeks after the treatment, 79% of ETV treated and 46% of LAM treated patients had HBV DNA less than 300 copies/ml (P < 0.0001), 96% of ETV treated and 92% of LAM treated patients had normalized ALT (P = 0.06). 21% of ETV treated and 23% of LAM treated patients achieved HBeAg seroconversion. Among the 160 patients received continuous ETV for 144 weeks, 89% had undetectable serum HBV DNA, 86% showed ALT normalization, and 27% achieved HBeAg seroconversion. ETV resistance was rare: only 3 patients showed ETV resistance 96 weeks after the treatment, and additional 2 patients developed ETV resistance during the following 48 weeks, genotyping indicated the ETV resistance was caused by gene mutation. Adverse event rates in ETV-treated patients were similar to those in LAM-treated patients, but fewer ALT flares were observed in ETV-treated patients. CONCLUSIONS: This study demonstrates that ETV treatment results in long-term HBV suppression and ALT normalization in Chinese CHB patients, and is associated with low rate of drug resistance.

Virologic, serologic, and biochemical outcomes through 2 years of treatment with entecavir and lamivudine in nucleoside-naïve Chinese patients with chronic hepatitis B: a randomized, multicenter study.

PURPOSE: Entecavir demonstrated superior virologic and biochemical benefits over lamivudine at 48 weeks in nucleoside-naïve Chinese patients with chronic hepatitis B (CHB). We evaluated the effect of continued entecavir and lamivudine treatment in patients who continued treatment in year 2 and the off-treatment durability of patients who achieved a protocol-defined consolidated response at week 48. METHODS: Chinese adults (n = 519) with CHB were randomized to a minimum of 52 weeks of treatment with entecavir 0.5 mg/day or lamivudine 100 mg/day. Patients with a consolidated response at week 48 (HBV DNA <0.7 MEq/ml for >/=24 weeks, ALT <1.25 times ULN, and, if HBeAg(+) at baseline, loss of HBeAg for at least 24 weeks) stopped treatment at week 52 and were followed off-treatment. Patients with a partial response at week 48 (HBV DNA <0.7 MEq/ml in the absence of other criteria for a consolidated response) could continue blinded treatment for up to 96 weeks. Patients were assessed for HBV DNA, ALT normalization, safety, and, if HBeAg(+) at baseline, for HBe seroconversion. Cumulative proportions of all treated patients who ever achieved these responses were also analyzed. RESULTS: Among patients treated during year 2 (entecavir: n = 193; lamivudine: n = 145), 74% of entecavir-treated and 41% of lamivudine-treated patients had HBV DNA <300 copies/ml by PCR at end of dosing and 96% of entecavir-treated and 82% of lamivudine-treated patients normalized ALT. Eleven percent of entecavir-treated versus 19% of lamivudine-treated patients underwent HBe seroconversion during year 2. Cumulative confirmed analysis for all treated patients through 96 weeks showed that 79% of entecavir-treated versus 46% of lamivudine-treated patients (p < 0.0001) achieved HBV DNA <300 copies/ml by PCR. Similar proportions of entecavir- and lamivudine-treated patients achieved confirmed ALT normalization and HBe seroconversion. Safety profile was comparable for both treatment groups. CONCLUSIONS: Through 96 weeks of treatment, entecavir resulted in continued clinical benefit in nucleoside-naïve Chinese patients with CHB, with a safety profile comparable with lamivudine.

Entecavir is a potent anti-HBV drug superior to lamivudine: experience from clinical trials in China.

Infection with the hepatitis B virus (HBV) can result in chronic hepatitis B (CHB) in many patients. Patients with CHB require regular screening and monitoring to facilitate disease surveillance and to determine if/when treatment is indicated. The current goal of CHB treatment is sustained viral suppression with the aim of reducing or preventing hepatic injury and disease progression. Effective anti-HBV therapy is now available that can suppress, but not eradicate, HBV replication. Among the currently licensed and approved anti-HBV nucleos(t)ides, entecavir demonstrates a potent anti-HBV activity and a low rate of emergence of drug resistance, with good safety and tolerability profiles. These excellent pharmacological characteristics were assessed both in large international clinical trials and in separate studies in China. This article presents results from Phase II and Phase III trials involving 876 Chinese patients with CHB. The results of these studies suggest that entecavir should be recommended as a first-line choice among the currently available anti-HBV nucleos(t)ides.

Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China.

PURPOSE: This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and safety of entecavir in Chinese patients with lamivudine-refractory chronic hepatitis B. METHODS: One hundred forty-five lamivudine-refractory patients with chronic hepatitis B were randomized to double-blind treatment with oral entecavir 1 mg (n = 116) or placebo (n = 29) daily for 12 weeks, followed by 36 weeks of open-label entecavir treatment. The primary efficacy endpoint was the mean change from baseline in serum hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR) assay at week 12. RESULTS: At week 12, the mean change from baseline in serum HBV DNA by PCR assay was -4.30 log(10) copies/ml for patients on entecavir compared to -0.15 log(10 )copies/ml for patients on placebo (P < .0001). Among patients with baseline serum alanine aminotransferase (ALT) >1 x upper limit of normal (ULN), a higher proportion of entecavir than placebo patients (68% vs. 6%, respectively) achieved ALT normalization by week 12 (P < .0001). After 48 weeks of entecavir treatment, the mean change in HBV DNA by PCR assay was -5.08 log(10) copies/ml, and 85% of patients with baseline ALT >1 x ULN had achieved ALT normalization. The safety profile of entecavir was similar to that of placebo during the first 12 weeks of blinded dosing. Entecavir was also well tolerated during 36 weeks of open-label treatment. CONCLUSIONS: Lamivudine-refractory chronic hepatitis B patients treated with entecavir demonstrated marked HBV DNA reduction and normalization of ALT in most cases. Entecavir treatment for 48 weeks was well tolerated.

Efficacy and safety of entecavir compared to lamivudine in nucleoside-naïve patients with chronic hepatitis B: a randomized double-blind trial in China.

BACKGROUND/AIMS: Chronic hepatitis B has a high prevalence (>8%) in China. We compared the safety and efficacy of entecavir with that of lamivudine for the treatment of patients with chronic hepatitis B in China. METHODS: A total of 519 nucleoside-naive Chinese patients with chronic hepatitis B were randomized (1:1) and treated with entecavir 0.5 mg/d or lamivudine 100 mg/d. The primary endpoint was serum HBV DNA <0.7 MEq/ml by bDNA assay and alanine aminotransferase <1.25 x upper limit of normal (ULN) at week 48. Patients with missing week 48 measurements were considered non-responders. RESULTS: About 90% (231/258) of entecavir-treated versus 67% (174/261) of lamivudine-treated patients achieved the primary endpoint (P < 0.0001). The mean reduction from baseline in HBV DNA was greater with entecavir than lamivudine (5.90 vs. 4.33 log(10) copies/ml, P < 0.0001). Greater proportions of entecavir-treated patients achieved undetectable HBV DNA (<300 copies/ml) by polymerase chain reaction assay (76% vs. 43%, P < 0.0001) and alanine aminotransferase normalization (

A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B.

Four hundred and eighty Chinese subjects with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were enrolled in a multicenter, double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) 10 mg once daily. There was a significant difference in reduction of serum hepatitis B virus (HBV) DNA after 12 weeks between subjects who received ADV and those who received the placebo (3.4 and 0.1 log10 copies/mL, respectively, P < .001). Further reductions in serum HBV DNA and increases in the proportion of subjects with an HBV DNA level of at most 10(5) copies/mL, with HBV DNA undetectable, and with ALT normalization were observed in ADV-treated subjects at week 52 (median HBV DNA reduction of 4.5 log(10) copies/mL, 67% with HBV DNA

[A double-blind, double-dummy, randomized, controlled study of entecavir versus lamivudine for treatment of chronic hepatitis B].

OBJECTIVE: This study was to evaluate the antiviral efficacy and safety in nucleoside naive Chinese patients with chronic hepatitis B (CHB) treated with entecavir (ETV) or lamivadine (LVD). METHODS: The trial was a randomized, double-blind, double-dummy and control design. 519 nucleoside naive CHB patients were treated with daily dose of ETV 0.5 mg (258 patients) or LVD 100 mg (261 patients) for at least 52 weeks. The primary endpoint was a composite endpoint of HBV DNA < 0.7 MEq/ml by bDNA assay and ALT < 1.25 x ULN at week 48. HBV DNA levels were also measured by the Roche Cobas Amplicor(TM) PCR assay at weeks 12, 24, 36 and 48. Clinical and laboratory adverse events were recorded every 4 weeks. RESULTS: Baseline characteristics were well balanced between treatment groups. The primary end point were achieved in 90% of ETV treated patients versus 69% of LVD treated patients (P < 0.0001). The mean HBV DNA level decreased 5.9 lg copies/ml (by PCR assay) from baseline in ETV group versus 4.3 lg copies/ml in LVD group (P < 0.0001). The serum HBV DNA become undetectable (< 300 copies/ml by PCR) in 76% of ETV group versus 43% of LVD group (P < 0.0001). The normalization of ALT were 90% in ETV group versus 78% in LVD group (P = 0.0003). The difference of HBeAg seroconversion rates between this 2 groups (15% vs 18%) at week 48 was no statistically significant. The overall incidence of adverse events (AEs) was comparable: 60% of ETV patients and 56% of LVD patients reported AEs; and 3% of ETV patients and 5% of LVD patients reported serious AEs. CONCLUSIONS: ETV achieves better virologic and biochemical improvements in nucleoside-naive patients with CHB while the safety profile is comparable to LVD.

[A study of the dosage and efficacy of entecavir for treating hepatitis B virus].

OBJECTIVE: To evaluate the antiviral activity and safety of entecavir in patients with chronic HBV infection as a preliminarily step in selecting 0.1 mg or 0.5 mg as a better dosage for a further large scale clinical trial. METHODS: This was a randomized, double-blinded, placebo-controlled and dose-ranging trial of entecavir usage in 212 patients with chronic HBV infection. The patients were randomly assigned to 3 groups: 0.1 mg entecavir (69), 0.5 mg entecavir (72) and, placebo (71) groups and treated for 28 days. The patients were then followed for 56 days without treatment. RESULTS: The proportion of subjects who achieved the primary endpoint at day 28, with their HBV DNA level decreased >2 log or undetectable, was significantly greater in the entecavir 0.1 mg and 0.5 mg dose groups compared with the placebo group (P < 0.01 for both comparisons). The mean change from baseline in HBV DNA levels at day 28 was greater for entecavir 0.1mg and 0.5 mg groups compared with the placebo group (both P < 0.01). The mean change from baseline in HBV DNA levels at day 28 for entecavir 0.5 mg group was greater than that of the entecavir 0.1 mg group (P < 0.01). During the 56-day post-dosing follow-up phase, the entecavir 0.5 mg group was associated with greater and more sustained suppression of viral replication than the entecavir 0.1 mg group (P < 0.01). There were no clinically meaningful differences in the incidence of any adverse events between the entecavir dosing and the placebo groups. CONCLUSION: Entecavir at both 0.1 mg and 0.5 mg doses demonstrated superior antiviral activity compared with a placebo. Since the entecavir 0.5 mg dose appears to have greater antiviral activity than the 0.1 mg dose and with a comparable safety and tolerability profile, the 0.5 mg entecavir dose could be used in further trials.

[Durability of HBeAg seroconversion in lamivudine treatment of chronic hepatitis B patients].

OBJECTIVE: To investigate the factors which may affect the rate of HBeAg seroconversion and its durability after long-term lamivudine therapy in chronic hepatitis B patients. METHODS: 81 patients were treated in a phase III clinical trial with lamivudine 100 mg daily for up to 5 years. The mean period of treatment was (48.84+/-10.52) months (range: 16 approximately 60 months). When HBeAg seroconversion occurred in the patients, which was defined as loss of HBeAg and detection of anti-HBe antibody, HBV DNA level less than 10 mEq/ml more than two times (once every 3 months), the lamivudine treatment was stopped and they were followed-up for another 6 approximately 12 months. The HBV DNA level was detected using Branched DNA assay (Chiron). The HBV markers were detected using IMX assay (Abbott). HBV genotyping was performed using type-specific PCR. The data were analyzed using logistic multivariant analysis. RESULTS: (1) The distribution of HBV genotypes was as follows: type B, 17 (20.97%), type C, 62 (76.54%), and type B+C, 2 (2.47%). (2) 26 patients achieved HBeAg seroconversion (32.10%). The annual seroconversion rates were 16.05% (13/81) in the 1st year, 19.75% (16/81) in the 2nd, 27.16 % (22/81) in the 3rd, 28.40% (23/81) in the 4th and 32.10% (26/81) in the 5th year. Four patients had a reappearance of HBeAg and an elevation of HBV DNA. Therefore the stability ratio was 84.62% (22/26). The mean baseline ALT and HBV DNA levels in those who were seroconvered were (104.8+/-86.3) U/L and (940.1+/-1123.7) mEq/ml, respectively. Mean baseline ALT and HBV DNA of non-seroconverters were (48.3+/-46.9) U/L and (2152.3+/-3063.5) mEq/ml. There was a significant difference between the two groups shown by Kruskal-Wallis Test (P < 0.05). Analysis by logistic multivariate analysis showed that the rate of HBeAg seroconversion and its durability rate correlated with a high baseline ALT. In contrast, a relatively low seroconversion rate and durability rate was observed in patients with high baseline HBV DNA. The durability rate also correlated with additional lamivudine treatment after HBeAg seroconversion. CONCLUSION: Continuation of lamivudine therapy for more than 6 months after HBeAg seroconversion might increase the durability of response.

[Efficacy and safety in chronic hepatitis B adolescent patients with lamivudine therapy].

OBJECTIVE: To analysis the efficacy and safety of lamivudine (made in China) therapy for 52 weeks in adolescent patients with chronic hepatitis B (CHB). METHODS: One hundred and five teenage CHB patients were treated with lamivudine 100 mg once daily for 52 weeks. Patients with elevated ALT at baseline were in group 1 and those with normal ALT were in group 2. The changes of HBV DNA, HBV seromarkers and ALT at the end of 12, 24 and 52 weeks after lamivudine therapy were compared with those at baseline. Adverse events were recorded and evaluated. RESULTS: At the end of 52 weeks of lamivudine therapy, HBV DNA-ve, HBeAg loss and anti-HBe seroconversion were observed in 92.0%, 24.4% and 22.0% in group 1 patients and 76.1%, 14.2% and 14.2% in group 2 patients respectively. No significant differences were found between two groups. At 12, 24 and 52 weeks, normalization rates of ALT were 59.0%, 66.7% and 76.0%, normal ALT with undetectable HBV DNA were 44.9%, 64.1% and 70.7% at the same time. During 52 weeks lamivudine treatment 26 mild adverse events were observed in 18 patients. CONCLUSION: Lamivudine can inhibit HBV replication rapidly and normalize ALT in majority adolescent CHB patients. HBeAg loss or seroconversion of anti-HBe was observed in some of these patients. All patients in this study were safety and well tolerated.

A 3-year clinical trial of lamivudine in treatment of patients with chronic hepatitis B.

BACKGROUND: Lamivudine was approved for the treatment of chronic hepatitis B in China in 1999; however the long-term result has not yet been reported in detail. This clinical trial was to evaluate the long-term efficacy and safety of 3-year lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: This multi-center, randomized, double-blind, placebo controlled trial began from 1996 to 1999. A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily (322 patients) or placebo (107) for the first 12 weeks. All patients were given subsequently open labelled lamivudine 100 mg/d for a total of 156 weeks. RESULTS: After 12-week lamivudine therapy, the levels of serum HBV DNA decreased rapidly. The negativity of HBV DNA (<1.6 pg/ml) at week 12 was 92.2% in the lamivudine group, whereas it was only 14.1% in the placebo group (P<0.01). After 1-year lamivudine treatment, 72.7% of the patients showed undetectable serum HBV DNA (<1.6 pg/ml). At the end of 3 years, serum HBV DNA continued to be substantially suppressed with a median level below a detectable level in patients with non-YMDD variant HBV, which was increased to 86 mEq/ml (bDNA method, equivalent hybridization method 10 pg/ml) in patients with YMDD mutation. At the end of 1, 2 and 3 years, the rates of HBeAg loss were 9.5%, 16.8% and 20.0% respectively and the rates of HBeAg/anti-HBe seroconversion were 8.3%, 11.5% and 17.3%. The rates of HBeAg loss and seroconversion were correlated with the baseline level of ALT. In patients with a baseline level of alanine transaminase (ALT)>2 x upper limit of normal (ULN) and ALT >5xULN, the rates of HBeAg loss were 42.2% and 66.7%, and the rates of seroconversion were 34.4% and 61.1% respectively (P<0.01) at the end of year 3. The levels of ALT at year 3 remained normal in 58.8% of patients whose baseline level of ALT was elevated, and in 79.1% of patients whose level of ALT was normal before treatment. YMDD mutations occurred in 12.1%, 49.7% and 70.5% of patients respectively at year 1, 2 and 3. In patients with YMDD mutation, the levels of HBV DNA were increased slightly with mild to moderate elevation of ALT level. HBeAg loss and seroconversion were 20.0% and 15.1% in patients with YMDD mutation at the end of year 3, which were lower than those in non-variant patients (P<0.01). Adverse drug reactions or events varied generally from mild to moderate. In 2 patients serious adverse events (fatigue and abdominal distension) were related to medication. ALT flares (ALT>5xULN) occurred in 17 patients: 10 were YMDD mutants and 7 were non-mutants; all of them were relieved. No death occurred in the period of 3 years. CONCLUSION: Sustained inhibition of HBV replication and clinical improvement could be obtained after 3-year lamivudine therapy of good tolerance and safety.

[Liver histological changes after lamivudine treating in chronic hepatitis B patients with HBeAg positive].

OBJECTIVES: To investigate the histological changes in liver biopsy tissues taken from chronic hepatitis B patients with HBsAg and HBeAg positive and ALT abnormal after lamivudine therapy for one year. METHODS: Lamivudine was given orally at the dose of 100 mg once a day for one year. 101 patients were enrolled into this open-label study. Paired liver biopsies from patients with hepatitis B before and after therapy with lamivudine were studied. Blinded biopsies were evaluated by a histopathologist and scored according to Knodell's histology activity index(HAI). RESULTS: 53.5% (54/101), 51.5% (52/101) and 31.7% (32/101) patients had a reduction of their total hepatic HAI score, necroinflammation and fibrosis scores by >or=2 points or 1 points at the end of one year of lamivudine therapy, compared with their pretreatment values, respectively. There were significant reduction of HAI score, necroinflammation and fibrosis scores from 8.0+/-4.7 to 5.2+/-3.3 (t=7.358, P<0.01), from 5.9+/-3.8 to 3.6+/-2.5 (t=7.298, P<0.01), and from 2.1+/-1.2 to 1.6+/-1.2 (t=3.827, P<0.01), respectively. The histological improvement was independent on the HBeAg seroconvertion during the therapy. CONCLUSION: Significant improvement in liver histology, both necroinflammation and fibrosis, can be obtained in the majority of patients treated with lamivudine for one year.

[The long-term efficacy of lamivudine in chronic hepatitis B: interim analysis of 3-year's clinical course].

OBJECTIVE: To evaluate the long-term efficacy and safety of 3-year lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: This multi-center, randomized, double-blind, placebo-controlled trial began in 1996. A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily (n = 322) or placebo (n = 107) in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were offered open label lamivudine 100 mg/d for a total of 156 weeks. RESULTS: After 12 weeks of lamivudine treatment, serum HBV DNA levels decreased rapidly; at week 12 the negativity of HBV DNA (< 1.6 pg/ml) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. After 1 year of lamivudine treatment, in 72.7% of the patients serum HBV DNA was undetectable (< 1.6 pg/ml). At the end of 3 years, serum HBV DNA continued to be substantially suppressed; the median level was below detectable level in non-YMDD variant patients and was increased to 10 pg/ml in YMDD variant patients. At the end of 1, 2 and 3 years, the HBeAg loss rates were 9.5%, 16.8% and 20.0% respectively; and the HBeAg/anti-HBe sero-conversion rates were 8.3%, 11.5% and 17.3% respectively. The rates of HBeAg loss and seroconversion correlated with baseline ALT levels, in patients with baseline ALT > 2ULN and ALT > 5ULN, the loss of HBeAg was 42.2% and 66.7%, sero-conversion rates were 34.4% and 61.1% respectively (P < 0.01) at the end of year 3. ALT levels at year 3 remained normal in 58.8%, and below baseline in 79.1% of the patients whose ALT were abnormal before treatment. YMDD mutations developed in 12.1%, 49.7% and 70.5% of the patients respectively at year 1, 2 and 3. HBV DNA levels were increased slightly or moderately and accompanied with elevation of ALT. HBeAg loss and sero-conversion could be achieved in YMDD variant patients to 20.0% and 15.1% at the end of year 3, but lower than that in non-variant patients (P < 0.01). The adverse drug reactions or events were generally mild to moderate, 2 patients were reported to have serious events related to the study medication. ALT flares (ALT > 5ULN) occurred in 17 patients, 10 with YMDD variants and 7 with non-variants, but all resolved. No deaths were reported in the 3 year treatment period. CONCLUSION: Sustained HBV replication and clinical improvement could be obtained by 3-year long-term Lamivudine therapy with good tolerance.

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.