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Keywords:

  • chronic hepatitis B;
  • HBeAg seroconversion;
  • hepatitis B virus (HBV);
  • lamivudine;
  • YMDD variant

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

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.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Hepatitis B virus (HBV) infection is a serious global public health issue.1 Following the recent success of national HBV vaccination programs, the chronic hepatitis B surface antigen (HBsAg) carrier rate decreased from 9.75% in 1992 to 7.18% in 2006.2,3 However, there are approximately 90 million individuals in China who are already infected with HBV, of whom at least 20–30% require safe and effective treatment to reverse their existing liver disease and prevent future disease progression. Lamivudine was the first oral anti-HBV nucleoside analog licensed for the treatment of chronic hepatitis B worldwide including China. Its efficacy and safety have been well documented.4–7 It is well tolerated with a good safety profile, and therefore long-term lamivudine therapy is a feasible management option.8,9 Data from up to 5 years of lamivudine treatment in a cohort of 58 Chinese patients showed that HBeAg seroconversion continues to increase with the duration of therapy.10 The long-term benefits of lamivudine may be reduced in some patients due to emergence of YMDD variants after extended therapy.11 In view of the high prevalence of chronic hepatitis B infections in China, and in an effort to confirm the long-term safety and efficacy data of lamivudine, a 7-year an efficacy and safety study (5 years of lamivudine treatment and 2 years of post-treatment follow up) was undertaken in 429 Chinese patients with chronic hepatitis B.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Study design

This was a randomized, multicenter, double-blind, placebo-controlled trial conducted for 12 weeks, followed by open-label treatment with 100 mg lamivudine daily for a further 248 weeks. From week 156 on, patients who had achieved hepatitis B virus e antigen (HBeAg) seroconversion and had undetectable HBV DNA on two consecutive occasions 3 months apart (by branched DNA [bDNA] assay) were offered maintenance lamivudine for 3 years or more. Patients who did not achieve HBeAg seroconversion and had detectable HBV DNA by bDNA assay received lamivudine for up to 5 years. Patients who subsequently relapsed (defined as a redetection of serum HBV DNA on two successive occasions, in association with a positive serum HBeAg) resumed open-label treatment (Fig. 1).

image

Figure 1.  Study design.

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This study was approved by the Chinese Ministry of Health and State Drug Administration and the Ethics Committee of Medical Center of Fudan University (formerly Shanghai Medical University). The trial was conducted in accordance with good clinical practice (GCP) and all patients gave their written informed consent before enrollment.

Patients

Patients, who were aged 16–65, were HBsAg positive, HBeAg and HBV DNA-positive in the 6 months before screening, and had alanine aminotransferase (ALT) levels less than tenfold the upper limit of normal (ULN) for the previous 3 months were eligible for inclusion in the study. Patients were excluded if they had hepatitis C, hepatitis D, human immunodeficiency virus infection, decompensated liver disease, bone marrow depression, an antinuclear antibody titer > 1:20, elevated creatinine concentrations (>1.5 × ULN), or had received antiviral agents or immunomodulators in the previous 6 months.

Efficacy parameters and assay methods

The efficacy parameters evaluated were HBV DNA suppression, loss of HBeAg and HBsAg, development of an antibody to HBeAg (anti-HBe) and HBsAg (anti-HBs), and ALT normalization. After week 52 the serum HBV DNA assay was switched from Abbott Genostics liquid hybridization (with a lower limit of detection [LLOD] of <1.6 pg/mL, Abbott Laboratories, Abbott Park, IL, USA) to a more sensitive Bayer Quantiplex branched DNA assay with a LLOD of 0.7 mEq/mL (Bayer Diagnostics, Walpole, MA, USA). All HBV DNA values measured using the Abbott Genostics assay were converted to values corresponding to the branched DNA assay in mEq/mL using the multimeasurement method described by Krajden et al.12 HBeAg and anti-HBe, HBsAg and anti-HBs antibodies were detected by a qualitative HBeAg/anti-HBe, HBsAg/anti-HBs Abbott IMAX enzyme immunoassay (Abbott Laboratories, Abbott Park, IL, USA). HBV DNA, HBeAg/anti-HBe and ALT were assessed every 4 weeks in the first year and every 12 weeks thereafter until week 260. HBsAg/anti-HBs were assessed at weeks 104, 156, 208 and 260 only.

Resistance surveillance

Serum samples were collected and assayed at weeks 24, 48, 104, 156, 208 and 260 at GlaxoSmithKline's virology laboratory in North Carolina, USA.13 Genotypic analysis was performed by using PCR and restriction fragmented length polymorphism assay. The LLOD for differentiating between the two viral genotypes had been determined to be 5% of the viral population. The assay used had a 95% probability at HBV DNA levels of 104 genomes/mL and an 80% probability at 103 genomes/mL.

Safety evaluation

Identification of all adverse events (AE) and abnormal changes in clinical biochemistry and hematology profiles were evaluated until week 260. The severity of AE was scored according to World Health Organization classifications.

Statistical evaluation

Efficacy analyses were based on the modified intent-to-treat population (mITT) (defined as all patients with confirmed chronic hepatitis B infection randomized to treatment, regardless of whether the study drug was actually taken or if the patient completed the planned duration of the study). Safety and YMDD analyses were based on all patients for whom there was no clear evidence of failure to take study medication (the treated population). All analyses were performed using SAS software, version 8 (SAS Institute, Cary, NC, USA).

No adjustment was made for missing data for any post-baseline visit including data collected after withdrawal from the study and data collected after a patient entered the observational period for HBV DNA, ALT, HBeAg/HBsAg loss and seroconversion. Percentages presented for each scheduled visit were based on those patients with available data.

The number (%) of patients with loss of HBeAg/HBeAg seroconversion, HBV DNA suppression and ALT normalization was calculated at annual time points throughout the study. Descriptive data were presented for patients’ socio-demographic and baseline characteristics. Safety data were summarized by tabulating the number (%) of patients with any adverse event (AE), the number (%) of patients experiencing a serious adverse event (SAE) at any time during the study and the number of patients with ALT elevations (≥2× baseline value) at any time during treatment. The number (%) of patients with YMDD variant HBV at any time during the study was tabulated for those patients with evaluable serum samples. Analyses of all the efficacy parameters described above were also tabulated for the YMDD variant and non-variant subgroups to provide an assessment of the impact of the YMDD variant HBV on long-term efficacy.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Patient population

A total of 440 patients were enrolled, among whom one patient did not receive treatment. Of the 439 treated patients, 10 patients did not fulfill the inclusion criteria. Included in the mITT population were 429 patients randomized in a ratio of 3:1 to receive lamivudine 100 mg (n = 322) or a placebo (n = 107) once daily for 12 weeks. The baseline characteristics were similar in both groups (Table 1). A total of 227 (51%) patients completed 5 years of open-label treatment.

Table 1.  Baseline characteristics: as treated population
 Treatment group
Placebo/lamivudineLamivudine/lamivudineTotal
  • Bayer-Chiron Quantiplex. ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, upper limits of normal.

Patients (no.)110329439
Median age (years)303030
Male (%)707473
Median HBV DNA (mEq/mL)1326 (4–19 548)1455 (4–16 447)1437 (4–19 548)
Median ALT (×ULN)1.0 (0.3–6.7)1.0 (0.2–17.3)1.0 (0.2–17.3)
Median albumin (g/dL)4.9 (3.9–6.4)4.8 (3.3–6.3)4.8 (3.3–6.4)
Median bilirubin (mg/dL)1.0 (0.2–2.3)1.0 (0.2–3.4)1.0 (0.2–3.4)

Serum HBV DNA level

Following lamivudine treatment, serum HBV DNA levels decreased rapidly (Fig. 2), while there was little change in the placebo group. By week 12 overall 92% (269/293) of patients in the lamivudine group had undetectable serum HBV DNA (<1.6 pg/mL by liquid hybridization assay) compared with 14% (14/99) of patients in the placebo group (P < 0.001). At week 12 all patients were given open-labeled lamivudine. After 52 weeks overall 82% (283/346) of patients had serum HBV DNA below the level of detection. At the end of 5 years median HBV DNA levels had dropped from a baseline of 1437 mEq/mL to 0.4, 1.9, 43.9, 84.0 and 100.5 mEq/mL at the end of 1, 2, 3, 4 and 5 years, respectively.

image

Figure 2. Median hepatitis B virus (HBV) DNA (mEq/mL). (inline image) pacebo plus lamivudine, 107 patients; (inline image) lamivudine plus lamivudine, 322 patients.

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HBeAg loss and HBeAg seroconversion

HBeAg loss increased with baseline ALT concentration and the duration of therapy. For patients with baseline ALT > 2 × ULN, HBeAg loss at the end of years 1–5 was 19%, 45%, 52%, 54% and 54%, respectively, (Fig. 3). The total proportion of patients with HBeAg loss remained essentially constant after 3 years of treatment. HBeAg seroconversion also correlated with the baseline ALT concentration and duration of therapy. For example, in patients with baseline ALT > 2 × ULN, seroconversion after 1–5 years of treatment was 16% (13/83), 28% (19/67), 40% (26/65), 54% (34/63) and 50% (29/58), respectively (Fig. 3). Three patients experienced HBsAg loss; no patients achieved HBsAg seroconversion.

image

Figure 3. HbeAg seroconversion is increased in patients with elevated baseline ALT (total patients) at (inline image) Year 1, (inline image) year 2, (inline image) year 3, (inline image) year 4, (inline image) year 5.M, missing data; O, entered observation. (inline image) poatients entering observation at year 4 and (inline image) year 5.

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Serum ALT level

There were 202 patients with elevated ALT at baseline. At the end of years 1–5 of lamivudine treatment, 76% (144/189), 66% (100/152) 59% (90/153), 52% (71/136), and 58% (66/114) of patients had normalized ALT levels. Of the 224 patients who did not have elevated ALT at baseline, 67% (62/92) had normal values at week 260.

YMDD variant HBV

Of the 227 patients who completed 5 years of lamivudine treatment, 226 had serum samples for YMDD variant HBV analysis. YMDD variant HBV incidence increased with the duration of therapy to approximately 70% at the end of week 156, with no further increase during the following 2 years (Table 2). Sixty-six of 226 patients (29.2%) had no evidence of YMDD variant HBV by week 260. Among these, 20.8% (47/226) had wild-type HBV and 8.4% (19/226) had undetectable HBV DNA by PCR analysis. YMDD variant HBV was detected in 160 patients at the end of the study. Of these, 96 patients had a mixed YMDD variant and wild-type, while 64 patients had the YMDD variant alone (Table 2).

Table 2.  Emergence of YMDD mutants in 5 years
 1 year (n = 369)2 years (n = 336)3 years (n = 278)4 years (n = 273)5 years (n = 226)
Undetected PCR (%)36 (9.1)37 (11.0)21(7.6)30 (11.0)19 (8.4)
Wild type (%)312 (78.8)132 (39.3)61 (21.9)59 (21.6)47 (20.8)
YMDD variants (%)48 (12.1)167 (49.7)196 (70.5)184 (67.4)160 (70.8)

Impact of YMDD variant HBV on efficacy parameters

At week 260, 84% (135/160) patients with YMDD variant HBV had HBV DNA levels less than baseline. A slight increase in HBV DNA median levels was observed in the YMDD variant group (to 107.5 mEq/mL after 5 years), but levels were lower than that of pretreatment median baseline levels (1318.7 mEq/mL) at all times.

After the emergence of the YMDD variant, HBeAg loss and HBeAg seroconversion were less frequent than in the non-YMDD variant patients. In patients with baseline ALT ≥ 2 × ULN who developed the YMDD variant HBV, HBeAg loss and HBeAg seroconversion increased with duration of therapy. HBeAg loss occurred in 5% (two out of 38), 24% (seen out of 29), 30% (11/37), 36% (14/39) and 32% (12/38) of patients with YMDD variant HBV at years 1–5, respectively, compared to 45% (10/22), 77% (17/22), 86% (19/22), 86% (18/21) and 91% (20/22) for patients with a non-YMDD variant. Similarly, HBeAg seroconversion occurred in 3% (one out of 38), 17% (five out of 29), 19% (seven out of 36), 36% (14/39) and 29% (11/38) of patients with YMDD variant HBV, compared to 41% (nine out of 22), 50% (11/22), 73% (16/22), 87% (18/21) and 86% (18/21) in non-YMDD variant patients at years 1–5, respectively.

Influence on serum ALT levels

Median ALT levels remained below baseline throughout the study period for patients with YMDD variant HBV but ranges were greater than in patients with a non-YMDD variant. In patients with YMDD variant HBV and an elevated ALT at baseline, 92% (78/85), 84% (61/72), 74% (64/86), 72% (60/83) and 77% (63/82) had ALT levels below baseline at years 1–5, respectively, compared to 95% (38/40), 100% (38/38), 92% (37/40), 90% (35/39) and 90% (38/42) in patients with a non-YMDD variant HBV. Among patients with normal ALT at baseline who developed YMDD variant HBV, 63% (46/73) sustained normal values after 5 years, compared to 76% (16/21) for patients with a non-YMDD variant.

Durability of HBeAg seroconversion

At the end of year 5 the HBeAg/anti-HBe seroconversion rate was 21.7% (58/267 cases). A total of 177 patients continued to receive lamivudine treatment for up to 6 years. When HBeAg seroconversion occurred more than twice (3 months apart), those patients continued treatment for 12 months or more, then stopped lamivudine and were followed up for at least 1 year. Forty-five patients achieved seroconversion. Nine of 45 patients developed reactivation with the reappearance of HBeAg and the re-elevation of HBV DNA after 1 or more years of follow up. The 1-year durability of HBeAg seroconversion after discontinuing lamivudine therapy was 80% (36/45).

The χ2 test and single- and multivariant logistic analysis data show that the HBeAg seroconversion and durability rate were correlated with baseline HBV DNA (bDNA) and ALT levels. They were not correlated with age, sex, disease course or HBV genotype.

Safety

Lamivudine was well tolerated during the 5 years of therapy. There was no increase in the frequency of AE up to 3 years of therapy or in SAE up to 5 years. Each year, approximately 1% of patients were withdrawn from the study due to an AE. The main reason for withdrawal was failure to return to the clinic due to relocation, immigration, pregnancy, etc. (Table 3). The yearly withdrawal rates due to failure to return for follow up were 6.1%, 3.9%, 7.7%, 3.0% and 7.5%. The rate of AE was from 58.8% to approximately 67.5% during years 1 to 5. Most AE were mild to moderate and subsided spontaneously during treatment. According to the evaluation by investigators, 24.8% of SAE could have been caused by the study drug. Over the course of the study, SAE were reported in 45 patients. Of these, 21 incidents were irrelevant to liver disease and the study drug treatment, including acute appendicitis (three), traumatic fracture (three), myocardial infarction (three), gallbladder disease (three) and one of the following: lymphoma, atopic pregnancy, thyroid adenoma, acute hepatitis A, acute Epstein-Barr virus (EBV) infection, rectal cancer, influenza, irritable bowel syndrome and severe fatigue. A total of 22 patients were diagnosed with hepatitis B reactivation (ALT > 5 × ULN, with or without hyperbilirubinemia). Two patients developed liver cancer and portal hypertension during the study. Overall 16 SAE were reported in patients with the YMDD variant HBV. Six patients had at least one SAE that was considered to be related to the drug under investigation.

Table 3.  Patients and reasons for withdrawal
ReasonYear 1Years 2Years 3Years 4Years 5Total
Adverse events34935 24
No return2617331332121
No efficacy09664 25
Other813821 32
Total (%)37 (8.6)43 (10.0)56 (13.1)24 (5.6)42 (9.8)202 (47.1)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

This study represents the largest long-term lamivudine clinical trial to date in mainland China among Chinese patients with chronic hepatitis B. Five years of open-label treatment with lamivudine resulted in the continued suppression of serum HBV DNA and the normalization of ALT in most patients. The number of HBeAg losses and HBeAg seroconversions increased with the duration of therapy, and was greater in patients with an elevated ALT baseline. Approximately half (39/74) of patients with ALT > 2 × ULN at baseline had achieved an HBeAg loss and HBeAg seroconversion at the end of the 5-year study. These data are consistent with a recent analysis of lamivudine phase IV studies which showed that elevated pretreatment ALT levels and/or active liver histological disease were the most important predictors of lamivudine-induced HBeAg loss.14 This study suggested that both Asians and Caucasians had similar rates of response to lamivudine at comparable ALT levels.15

Our results are comparable to those from a previous extended-therapy trial in a cohort of 58 HBeAg-positive Chinese patients outside mainland China treated with lamivudine 100 mg/day for up to 5 years.10 For patients with baseline serum ALT > 2 × ULN, HBeAg seroconversion rates continued to increase with the duration of lamivudine therapy, such that by the end of years 3 and 5, 65% and 77% of patients, respectively, had achieved HBeAg seroconversion.

In the current study, 45 patients who achieved HBeAg/anti-HBe seroconversion entered a non-treatment observation period. During the following 2 years of observation after stopping treatment, nine (20%) relapsed, showing a sustained HBeAg response of 80% (36/45). Three of these nine patients showed evidence of YMDD variant HBV. This is consistent with other prospective studies that showed the durability of the HBeAg response in most patients following lamivudine therapy, if treatment was continued for at least 12 months.16 Even patients who did not achieve HBeAg seroconversion experienced benefits in terms of reduced HBV DNA levels and low or normal ALT levels, which have been shown to be generally associated with less progressive disease and better outcomes. At the end of this 5-year study 91% (178/196) of patients had serum HBV DNA levels below the baseline and 58% (66/144) of patients with an elevated ALT at baseline had normal ALT.

Quality-of-life was evaluated in our phase III and IV trials before and after treatment. The Medical Outcome Study short form 36 (MDS SF 36) instrument was used for evaluation in 44 and 244 cases, respectively. The patients’ physical and social function, mental health, general health perception and disease-specific dimensions significantly improved over the 1- and 2-year treatment periods.17,18 It is suggested that long-term lamivudine therapy could improve patients’ health and performance.

Long-term lamivudine treatment is associated with the emergence of resistant viral variants, which may compromise the initial clinical benefit of the treatment. Once a resistant variant occurs, it could be regarded as a viral breakthrough and clinical flare up during the course of treatment. Guan et al. reported that the YMDD variant HBV was detected in 69% (40/58) of Chinese patients during 5 years of lamivudine therapy. This was similar to the 70% (160/226) observed in our study (Table 2). Patients without the YMDD variant experienced the greatest clinical benefit from lamivudine therapy. However, our study demonstrated that the emergence of the YMDD variant could result in a rebound of the viral load and serum ALT level, reduce the HBeAg/anti-HBe seroconversion rate and worsen the patient's clinical condition.

Despite this unfavorable impact in YMDD variant patients, the findings showed that some patients with YMDD variants still maintained HBV DNA and ALT concentrations below baseline levels and derived clinical benefit with continued therapy. But these benefits did not last long in patients with serum ALT levels > 2 × ULN at baseline. On the other hand, HBeAg seroconversion occurred in 29% (11/38) of patients. Guan et al. reported a 38% (15/38) HBeAg seroconversion in patients with the YMDD variant over a similar 5-year period.10 These results suggest that an HBeAg loss and HBeAg/anti-HBe seroconversion are still possible in patients who develop the YMDD variant if lamivudine treatment is continued.

A long-term lamivudine treatment was well tolerated. The frequency of SAE in patients with a YMDD variant HBV was similar to those reported in patients with a non-YMDD mutant HBV. Slightly more patients with a YMDD variant HBV had ALT elevations during therapy than among patients who remained free of the variant, but these were within acceptable levels in compensated patients. Clinically significant hepatitis occurred in 8% (12/160) of patients with YMDD, compared to 3% (two out of 66) of patients with non-mutant HBV. Alternative treatment strategies might be needed for patients with YMDD variant HBV who experience progressive disease activity.

At present, four nucleosides (nucleotide) are approved in China. Lamivudine remains the mainstay for long-term treatment in many Asian regions, including China, because it is effective, well tolerated and economical.19

A major concern with long-term lamivudine is the selection of resistant variants. This could be prevented or overcome by early and regular monitoring of serum HBV DNA levels and salvage therapy.20,21 Recent studies demonstrated that rescue therapy is more effective if it is initiated early at the time of virological breakthrough and in most instance, rescue therapy should be added to the original therapy. At present, the addition of adefovir dipivoxil in lamivudine therapy is the recommended choice for lamivudine resistance.22,23

ACKNOWLEDGMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

This study was sponsored by Glaxo-Smith Kline Pharmaceutical Corporation (UK and China).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES
  • 1
    Hepatitis B fact sheet WHO/2004. Hepatitis B. Geneva: World Health Organization, October 2004. Available from URL: http://www.who.int medicentres /facsheets/fs204/en
  • 2
    Sero-epidemiology survey of hepatifis B infection in China. http://www.chinaccdc.net.cn/n272442/n3246177/23316.html 2008-4-23.
  • 3
    Dai ZC, Qi GM. The Epidemiology Characteristics of Viral Hepatitis B in China: Sero-epidemiological Survey in Chinese Population (Part One) 1992–1995. Beijing: Sci Tech Pub. 1997 (in Chinese).
  • 4
    Dienstag JL, Schiff ER, Wright TL et al . Lamivudine as initial treatment for chronic hepatitis B virus in the United States. N Engl J Med 1999; 341: 125663.
  • 5
    Lai CL, Chien R, Leung N et al . for the Asian Hepatitis Lamivudine Study Group. A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998; 339: 618.
  • 6
    Yao GB, Wang BE, Cui ZY, Yao JL, Zeng MD. Long term efficacy of lamivudine in the treatment of hepatitis B patients. Chinese J Hepatol 1999; 7: 803 (in Chinese).
  • 7
    Yao GB. Management of hepatitis B in China. J Med Virol 2000; 61: 3927.
  • 8
    Yao GB, Wang BE, Cui ZY, Yao JL, Zeng MD. Three year clinical trial of lamivudine in the treatment of patients with chronic hepatitis B. Hepatobiliary Pancreat Dis Int 2004; 3: 18893.
  • 9
    Lok ASF, Lai CL, Leung N et al . Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterol 2003; 125: 171422.
  • 10
    Guan R, Lai CL, Liaw YF, Lim SG, Lee CM. Efficacy and safety of 5 years lamivudine treatment of Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol 2001; 16 (Suppl.): A60.
  • 11
    Yao GB, Wang BE, Cui ZY, Yao JL, Zeng MD. Four-year long term efficacy of lamivudine in the treatment of hepatitis B patients. Chinese J New Drug Clin Rem 2003; 22: 58792 (in Chinese).
  • 12
    Krajden M, Minor J, Cor KL, Comanor L. Multi-measurement method comparison of three commercial hepatitis B virus DNA quantification assays. J Viral Hepatitis 1998; 5: 41222.
  • 13
    Allen M, Gauther J, Des Lauries M et al . Two sensitive PCR-based methods for the detection of hepatitis B virus mutants associated with reduced susceptibility in lamivudine. J Clin Microbiol 1999; 37: 333847.
  • 14
    Yao GB, Cui ZY, Yao JL et al . Chronic hepatitis B treated with domestic manufactured lamivudine in 2200 patients: a phase IV study. Chin J Hepatol 2003; 11: 1039 (in Chinese).
  • 15
    Perrillo RP, Lai CL, Liaw YF et al . Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatol 2002; 36: 18694.
  • 16
    Dienstag JL, Cianciara J, Karayalcin S et al . Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatol 2003; 37: 74855.
  • 17
    Yang MY, Yao GB. The effect of the health related quality of life after 2 years treatment of lamivudine in chronic hepatitis B. Chinese J Current Pract Medicine 2002; 1: 479. (in Chinese)
  • 18
    Yao GB, Alison TM, Huang Y, Jian NX, Yang L. Evaluation of health related quality of life with treatment of lamivudine in chronic hepatitis B. Chinese Hepatol 2003; 8: 35. (in Chinese)
  • 19
    Liaw YF, Leung N, Kao JH et al . Asia-Pacific Consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008; 2: 26383.
  • 20
    Yuen MF, Fong DYT, Wong DKH et al . Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5 year ideal response. Hepatology 2007; 46: 1695703.
  • 21
    Lok ASF. Navigating the maze of hepatitis B treatments. Gastroenterol 2007; 132: 158694.
  • 22
    Lampertico P, Viganno M, Meneti E et al . Low resistance to adefovir combined with lamivudine: a 3-year study of lamivudine-resistant hepatitis B patients. Gastroenterol 2007; 133: 144551.
  • 23
    Fung SK, Chae HB, Fontana RJ et al . Virologic response and resistant to adefovir in patients with chronic hepatitis B. J Hepatol 2006; 44: 28390.