The natural history of chronic hepatitis B (CHB) is complex and may run through different immune phases that may overlap. In particulars, the immune-tolerant phase is the most interesting and not as well understood as we thought. The concept of true immune tolerance have been under challenged from immunology points of view. The major international guidelines have not yet reached a consensus on the definition of the immune-tolerant phase. While positive hepatitis B e antigen (HBeAg), high serum hepatitis B virus (HBV) DNA and normal serum alanine aminotransferase (ALT) levels are the three key features of this phase, some guidelines also put age into consideration. A new nomenclature, Phase 1 or HBeAg-positive chronic HBV infection, is given by the latest European Association for the Study of the Liver (EASL) published in April 2017. While current guidelines advise against starting antiviral treatment for immune-tolerant CHB patients, some new data suggest treating such patients may reduce the risk of liver fibrosis progression and hepatocellular carcinoma.
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KASL clinical practice guidelines for management of chronic hepatitis B
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Background/Aims Clinical characteristics of patients with chronic hepatitis B (CHB) who developed genotypic resistance to entecavir (ETV) were compared to those without resistance.
Methods Two hundred fifty eight CHB patients who underwent ETV treatment in our institution from July 2007 to May 2013 were included.
Results Eight (3.1%) patients developed genotypic resistance to ETV during the follow-up period. The patterns of genotypic resistance to ETV were as follows: L180M + M204V + S202G (n=3); M204I + V173M (n=1); I169V + V173M (n=1); L180M + M204V + V173L (n=1); L180M + M204V + V173L + M250V (n=1); M204I + V214A + P237H (n=1). The cumulative occurrence rates of genotypic resistance to ETV were not significantly different between CHB patients with prior nucleos(t)tide analogues (NA) exposure (NA experienced, n=56) and NA naïve patients (n=202, P=0.823 by log rank comparison). Older age, higher baseline log10hepatitis B virus-deoxynucleic acid (log10HBV-DNA), higher log10HBV-DNA at 3, 6, 12 and 24 months after baseline, and complete virologic response (CVR, undetectable serum HBV-DNA by polymerase chain reaction 6 months after ETV treatment) were significant contributors to the development of genotypic resistance to ETV. Multivariate analyses showed higher log10HBV-DNA 6 months after baseline and absence of CVR were independent and significant contributors to the development of ETV resistance.
Conclusions Clinical characteristics of patients who developed ETV resistance were higher log10HBV-DNA 6 months after baseline and absence of CVR during the ETV treatment.
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Jae Kwon Jung, M.D., Chang Hyeong Lee, M.D., Eun Young Kim, M.D.,
Jin Tae Jung, M.D., Joon Hyuck Choi, M.D., Ji Min Han, M.D.,
Myoung In Jin, M.D., Ju Yeon Cho, M.D., Byung Seok Kim, M.D., Im Hee Shin, Ph.D.1
Korean J Hepatol 2007;13(4):513-520. Published online December 20, 2007
Backgroud/Aims: Lamivudine is an effective, safe therapeutic agent for the treatment of chronic hepatitis B. The aim of this study was to investigate whether early suppression of the viral load predicts HBeAg loss within 1 year during lamivudine therapy. Methods: This prospective study encompassed 74 patients (mean age: 37.1 years, male/female: 51/23) who were positive HBeAg, their AST or ALT levels were ≥2 times the upper limit of normal and their HBV DNA was ≥105 copies/mL. The patients received lamivudine 100 mg for 12 months with monitoring their HBV DNA, AST, ALT, HBeAg and anti-HBe, and all these tests were performed at pretreatment and 1, 3, 6, 9 and 12 months after treatment. The serum HBV DNA was measured by HBV branched DNA assay. Results: HBeAg loss was observed in 12 patients (16.2%), and 9 patients achieved anti-HBe seroconversion during up to 1 year of lamivudine therapy. The mean time to HBeAg loss was 5.6 months (range: 1-12 months). The posttreatment HBV DNA (<2,000 copies/mL) after 3 month (P=0.008) and 6 month (P=0.012)) were significant predictors of HBeAg loss after 1 year of lamivudine treatment on univariate analysis. Pretreatment HBV DNA, AST/ALT, gender, age and liver cirrhosis had no impact on HBeAg loss. The six-month posttreatment HBV DNA level <2,000 copies/mL was a significant predictor of HBeAg loss on multivariate analysis (P=0.008, odds ratio=0.108). Conclusion: We suggest that an HBV DNA level <2,000 copies/mL at 6 month after lamivudine therapy is the most important predictor of HBeAg loss during up to 1 year of lamivudine therapy. (Korean J Hepatol 2007;13:513-520)
Kwang Hyub Han, M.D., Jin Suk Kim, M.D., Hyo Young Chung1,
Sang Hoon Ahn, M.D., Yong Han Paik, M.D., Kwan Sik Lee, M.D.,
Chae Yoon Chon, M.D. and Young Myoung Moon, M.D.
Background/Aims : We studied to evaluate the virological and biochemical responses to lamivudine and to detect YMDD mutants in patients who received long-term lamivudine therapy. Methods : We conducted a one-year trial of lamivudine in 45 Korean patients with chronic liver disease due to hepatitis B virus. The patients were treated with a single oral average dose of 100 mg of lamivudine every day for 12 months. Results : The suppression of serum HBV DNA was sustained in 77.8% of the patients and the normalization of serum ALT in 80%. The proportions of patients with HBeAg seroconversion were 25%. YMDD mutants were detected in 4 of 8 patients who showed sustained HBV DNA and serum ALT response (n=31) and in 3 of 8 patients who showed HBV DNA or serum ALT breakthrough (n=9). The response to lamivudine therapy in HBeAg-negative patients was excellent. Conclusion : Lamivudine therapy resulted in a significant virological and biochemical improvements and were well tolerated. But, YMDD mutants were detected during lamivudine therapy. (Korean J Hepatol 1999;5:97－104)
Rock Kwon Kim, M.D., Byung Min Ahn1, M.D., Dong Soo Lee1 , M.D., Kang Moon Lee1, M.D.,
Young Min Park1, M.D., Young Sok Lee1 , M.D., Kyu Won Chung1 , M.D., Won Chul Lee2 , M.D.,
and Kwang Ho Meng2 , M.D.
Background/Aims Before the introduction of the HBV vaccination programs, the positivity of HBsAg among the general population was reported to be around 8% in Korea. Although recent reports revealed somewhat decreased values, a wide range of variation exists according to the authors. Major movements to control HBV infection include the programs such as the introduction of HBV vaccination in 1983, mass inoculation of the elementary school children since 1988 and inclusion of type B hepatitis in 1995 in Class III legal epidemics. The purpose of the present study was to examine the changing trend of the positivities of HBsAg, HBeAg and anti-HCV in army draftees in Korea since we believed that they are an ideal study group with a set of fixed variables such as gender and age. Methods: From January 1, 1993 to December 31, 1999, we evaluated a total of 498,206 male army draftees for serum ALT, HBsAg, HBeAg and anti-HCV antibody. HBsAg (Genedia, Yongin, Korea) and HBeAg (Amrad, Austrailia) were examined by EIA and Immunochromatography, respectively. Anti-HCV antibody was tested by 3rd generation EIA (Genedia, Yongin, Korea). Serum ALT was determined by autoanalyser, Polystat 2000 (Hitachi, Japan). Results: The majority of the draftees were 20 years old (68.8%). The positivity of HBsAg gradually decreased from 5.8% in 1993 to 4.3% in 1999(mean 4.8%). The positivity of HBeAg among the asymptomatic HBsAg carriers ranged from 47.9% to 55.6%(mean 51.8%). The positivity of anti-HCV antibody was seen in the range from 0.09% to 0.29%(mean 0.18%), and 84.5% showed normal ALT. The positivity of HBsAg among the anti-HCV positive subjects was 6.6%. Conclusion: The HBsAg positivity has significantly(p=0.001) decreased for the past 7 years. However, the positivity of anti-HCV antibody showed no significant pattern of change during the same period.
Background/Aims The aim of this study was to evaluate the efficacy of lamivudine in patients with HBeAg-negative and HBV DNA-positive chronic liver disease. Methods: Twenty-four chronic liver disease patients were enrolled whose serology had common characteristics of HBeAg (-), and anti-HBe (+) but HBV DNA (+). All had elevated alanine aminotransferase (ALT) levels. 150mg of lamivudine was given orally once daily for more than 6 months. The goal of this treatment was the elimination of HBV DNA in serum and normalization of ALT level. Once HBV DNA disappearance and ALT normalization were observed, lamivudine was continued for two additional months. HBeAg, anti-HBe, HBV DNA and ALT were followed up every 1-2 month during, and after, treatment. Results: Median duration of treatment was seven months. HBV DNA became undetectable after a median one month of treatment and ALT activity was normalized in all 24 patients within six months. Among the sixteen patients who were followed for more than 12 months after cessation of treatment, six relapsed. The cumulative relapse rate at 12 months was 37.5%. Conclusion: Lamivudine suppresses HBV replication effectively and normalizes serum ALT in patients with HBeAg-negative and HBV DNA-positive chronic liver disease. The relapse rate after cessation of treatment seems to be relatively low.
Background/Aims Lamivudine, an oral nucleoside analogue, effectively suppresses HBV replication and improves liver enzymes as well as liver histology. Long-term lamivudine therapy can induce the emergence of drug resistant HBV strains in some patients. The aim of this study was to evaluate the effects of lamivudine, the breakthrough rate, and the relapse rate of discontinuing therapy after HBeAg loss. Methods: A total of 190 patients with HBeAg and HBV DNA positive showing abnormal serum levels of aminotransferases for at least 6 months received 100 mg of lamivudine once daily. The duration of lamivudine therapy was from 6-36 months (mean 14 months). Responder was defined as the ALT normalization with sustained suppression of HBV DNA and HBeAg loss. Therapy was to be stopped after HBeAg loss. Post-treatment monitoring continued for 1-21 months (mean 6 months). Results: The cumulative HBeAg loss rates at 12 months and 18 months were 35% and 43%, respectively. Pretreatment serum HBeAg quantitation, and the duration of lamivudine therapy were independent predictive factors for HBeAg loss. The cumulative breakthrough rates at 18 and 24 months were 38% and 57%, respectively. Pretreatment HBV DNA level was the only predictable factor for breakthrough. Therapy was discontinued after HBeAg loss in 52 patients. Most episodes of relapse (15/16) occurred within 6 months after cessation of lamivudine. The cumulative relapse rates at 3 months and 6 months were 21% and 50%, respectively. A predictive factor for post-treatment relapse after HBeAg loss was the duration of lamivudine therapy. Conclusions: These results suggested the pretreatment quantitative HBeAg in serum and duration of lamivudine therapy are independent predictive factors for HBeAg loss. The HBeAg response of lamivudine-induced HBeAg loss was not durable after discontinuing therapy.(Korean J Hepatol 2001;7:77-89)
Background / Aims : It has been reported in patients with chronic hepatitis B, that the response rate of lamivudine therapy increases in proportion to the duration of the therapty. What was not well known was the durability of the therapeutic response after the cessation of lamivudine therapy in patients with chronic hepatitis B. Patients and Methods : We retrospectively analyzes 73 patients with chronic hepatitis B who were treated with lamivudine 100 mg orally once daily and followed up for more than 12 months between April 1997 and March 1999. Sixty-three patients were initially hepatitis B e antigen (HBeAg) positive and Hepatitis B virus (HBV) DNA positive(group Ⅰ). Ten patients were HBeAg negative and HBV DNA positive (group Ⅱ). Results : The response rates of group Ⅰ and group Ⅱwere 68.3% and 70.0% at 12 months, respectively(p=NS). In group I, cumulative HBeAg seroconversion rates art 1 year, 2years, and 3 years were 30.2%, 38.8%, and 42.4%, respectively. The cumulative durability of response was higher in group I than in group II (64.6% vs 33.3% at 1 year ; 35.4% vs 22.2% at 22.2% at 2 years p=.079); lamivudine therapy for more than 6 months after HBeAg seroconversion than for less than 6 months (90.0% vs 40.0% at 1 year ; 90.0% vs 20.0% at 2 years ; p=.013). Conclusions : The long-term response to lamivudine therapy showed no difference between HBeAg - negative/HBV DNA-positive and HBeAg - positive patients. The HBeAg serocinversion rate increased in proportion to the duration of lamivudine therapy. The durability of response. (Korean J Hepatol 200 1;7 :423 - 431)
Background /Aim: A significant correlation between HBV DNA and liver damage was found in precore mutant strains but there was no significant association between viral replication and liver damage in HBeAg positive patients. Laboratory tests are often requested to predict hepatitis activity (grade) and fibrosis (stage) in HBeAg positive chronic hepatitis B. We assessed ALT, AST, and HBV-branched DNA to find which is the best for predicting hepatitis activity and fibrosis. Methods: Routine biochemical liver function tests and HBV DNA in sera were assessed in 119 young patients positive with HBsAg and HBeAg. The mean age of patients was 21±2 years. All patients were male. By logistic regression analysis the relationships between laboratory data, hepatitis activity, fibrosis, or risk of chronic active hepatitis were analyzed. Results: There was a significant correlation between aminotransferase (AST, ALT) and hepatitis activity/ fibrosis. A significant inverse relationship between the HBV bDNA and hepatitis activity was demonstrated (Pearson's correlation coefficient: lobular activity,-0.305; porto-periportal activity, -0.410). But HBV bDNA was not correlated with severity of fibrosis. AST and HBV bDNA was the important test for predicting the more severe hepatitis activity (lobular activity and porto-periportal activity: score≥3, respectively) Conclusion: The higher AST, but the lower HBV bDNA, in sera shows the more severe hepatitis activity. AST and HBV bDNA could be helpful for assessing the hepatitis activity in young male patients with HBeAg positive chronic hepatitis B if proper reference values are used.(Korean J Hepatol 2002;8:44-51)
Yun Jung Chang, M.D., Jeong Yoon Yim, M.D., Nam Young Cho, M.D., Chang Won Choi, M.D.,
Soo Jung Baek, M.D., Soo Hyun Ahn, M.D., Do Won Choi, M.D., Yong Dae Kwon, M.D.,
Sun Suk Kim, M.D.**, Oh Sang Kwon, M.D.**, Ju Hyun Kim, M.D.**, Jong Eun Yeon, M.D.,
Jin Won Song, M.D.*, Kwan Soo Byun, M.D. and Chang Hong Lee, M.D.
Background/Aims Long-term efficacy and the rate of viral breakthrough in patients with HBeAg-negative chronic hepatitis B receiving lamivudine therapy is uncertain. This study was conducted to determine the rate of viral breakthrough according to the HBeAg status and the relation of viral breakthrough with YMDD mutants. Methods: Two hundred and five patients with HBeAg-positive and 49 patients with HBeAg-negative chronic hepatitis B, who had received lamivudine for at least 9 months, were included. The mean durations of the lamivudine treatment were 176 months and 155 months in HBeAg-positive and negative patients, respectively. Analysis of HBV genome for YMDD mutations was performed by restriction-fragment-length polymorphism assay and direct sequencing. Results: While the cumulative rates of viral breakthrough at 12th and 24th months of the lamivudine therapy were 0% and 7% in the HBeAg-negative group, they were 12% and 39% in the HBeAg-positive group. The cumulative rate of viral breakthrough in the HBeAg-negative group was significantly lower than in the HBeAg-positive group (p<0.01). In multivariate analysis, the only significant factor related to viral breakthrough was the HBeAg status (p<0.05). The YMDD mutants were detected in all patients with viral breakthrough irrespective of HBeAg status. However, in patients without viral breakthrough, the rate of YMDD mutants was significantly higher in the HBeAg-negative group than in the HBeAg-positive group (13.3% vs 5.1%; p<0.01). Conclusions: Lamivudine is expected to be more persistently effective in HBeAg-negative chronic hepatitis B because of a lower viral breakthrough rate than in HBeAg-positive chronic hepatitis B in spite of the emergence of YMDD mutants. Korean J Hepatol 2002;8:397-404)
Background/Aims Lamivudine therapy is effective in inhibiting HBV replications in patients with HBeAg-negative chronic liver disease. However, the sustained response rate appears to be particularly poor, because the vast majority of patients relapse soon after cessation of therapy. The aim of this study was to evaluate the efficacy of lamivudine, the breakthrough rate, and the relapse rate of discontinuing therapy after response in patients with HBeAg-negative chronic liver disease. Methods: Fifty-nine patients with HBeAg-negative chronic liver disease who have received lamivudine for at least 6 months, were studied. The mean duration of treatment was 14 months. Complete response was defined as undetectable serum HBV DNA by bDNA and normalization of ALT levels. Once HBV DNA disappearance and ALT normalization were observed, lamivudine therapy was continued for at least two additional months. The mean follow-up after cessation of treatment was 6 (1-22) months. Results: Fifty-six patients were undetectable HBV DNA. The cumulative HBV DNA loss rates at 3 months and 5 months were 90% and 95%, respectively. The ALT normalization was observed in 52 patients. The cumulative ALT normalization rates at 6 months and 10 months were 78% and 86%, respectively. The complete response was observed in 52 patients. The cumulative rates of complete response at 10 months and 18 months were 80% and 88%, respectively. A predictive factor for complete response was only the duration of lamivudine treatment. Virological breakthrough was observed in 5 (8.5%). Thirty-four patients stopped taking lamivudine after 7.7 (2-15) months of the additional therapy. Seventeen of those patients (50%) experienced relapse. The cumulative relapse rates at 3 months, 6 months and 10 months were 24%, 47%, and 66%, respectively. The only predictive factor for relapse was the duration of additional lamivudine treatment after response. Conclusions: Lamivudine was an effective treatment of HBeAg negative chronic liver disease. Relapse, however, was usually observed after cessation of lamivudine. Our results showed that long-term lamivudine therapy is required in order to decrease the high relapse rates in patients with HBeAg-negative chronic liver disease.(Korean J Hepatol 2003;9:69-78)
Background/Aims Long-term treatment with lamivudine causes breakthrough, but the clinical course
after lamivudine breakthrough is not well known. The aims of this study were to evaluate the clinical course
in lamivudine after breakthrough, and to identify predictive factors of breakthrough. Methods: 124 patients
with chronic hepatitis B infection, who represented viral breakthrough during lamivudine therapy, were
included. The mean duration of lamivudine therapy and additional lamivudine therapy after breakthrough was
30.5 months and 12.5 months, respectively. Results: The cumulative breakthrough rates at 12, 18, 24 and 36
months were 8, 24, 36 and 52%, respectively. After viral breakthrough, only 4 patients maintained normal ALT
levels. 120 patients showed ALT elevation. The number of patients with ALT levels greater than 5 times, and
greater than 10 times, the upper normal limit were 67 (56%) and 29 (24%), respectively. While still on
lamivudine therapy after breakthrough, 98 patients presented ALT elevation. Only 22 had normalized ALT
levels. Hepatic decompensation developed in 2 patients. HBeAg seroconversion after breakthrough occurred
in 10 patients. The changing pattern of quantitative HBeAg levels during lamivudine therapy was the only
predictive factor associated with viral breakthrough. The mean time of turning points in decrescendo-crescendo
patterns of HBeAg levels during lamivudine therapy was earlier than viral breakthrough (9 months vs. 17
months). Conclusions: These results suggested that deterioration of hepatic function can usually be observed
after breakthrough. The serial monitoring of serum quantitative HBeAg levels may allow an early recognition
of viral breakthrough.(Korean J Hepatol 2003;9:293-303)
Kyung Hwan Kim, M.D., Il Hwan Na, M.D., Jae Moon Cha, M.D.,
Yong Ki Cho, M.D., Se Young Park, M.D., Hyoung Pil Kim, M.D.,
Chul Soo Song, M.D., Jeong Heo, M.D.1 and Mong Cho, M.D.1
Background/Aims HBeAg-negative chronic hepatitis B (CHB) has a poor long-term prognosis. Since
no precise clinically relevant HBV thresholds are known in HBeAg-negative CHB, the decision to treat
is difficult. The aim of this study was to evaluate the levels of serum HBV DNA and transaminase and to
investigate the correlation of these values in patients with HBeAg-negative CHB. Methods: The study
analyzed the sera from 82 patients with HBeAg-negative CHB, 61 men and 21 women. The mean age was
45 years. The patients were divided into two groups according to serum ALT levels: the patients with lower
ALT level (n=52, UNL<ALT<2×UNL) and higher level (n=30, ALT≥ 2×UNL). The level of serum HBV
DNA was determined by the Cobas Amplicor HBV Monitor™ (Roche). Results: The median serum HBV
DNA level was 2.7×105 copies/mL in patients with HBeAg-negative CHB. The median serum HBV DNA
level of patients with a higher ALT level (1.0×106 copies/mL) was significantly higher than that of patients
with a lower ALT level (5.6×104 copies/mL)(p<0.001). The serum ALT level was correlated with serum
HBV DNA levels in patients with HBeAg-negative CHB (r=0.416, p<0.001). The serum level of HBV DNA
in patients with cirrhosis (median 2.0×105 copies/mL) did not differ from patients without cirrhosis (median
4.7×105 copies/mL). Conclusions: The level of serum HBV DNA was higher in patients with higher serum
ALT level than it was in patients with lower serum ALT, and it was closely correlated with serum ALT
levels in HBeAg-negative CHB.(Korean J Hepatol 2003;9:284-292)
Background/Aims Lamivudine is a potent inhibitor of hepatitis B virus replication, but an increased
incidence of YMDD mutation may be associated with its long term use. Thus, the decision to initiate therapy
should be based on variables that are predictive of lamivudine-induced HBeAg loss. The objective of this
analysis was to determine patient-dependent or laboratory variables that predict HBeAg loss. Methods: We
retrospectively analyzed 99 HBeAg-positive patients with chronic hepatitis B who were treated with
lamivudine and followed up for more than 52 weeks. All patients had a liver biopsy before starting
lamivudine therapy. HBeAg loss and HBeAg seroconversion after 52 weeks of treatment were defined as
endpoints. Results: The overall rates of HBeAg loss and HBeAg seroconversion were 41.4% (41/99) and
37.4% (37/99), respectively. The rates of HBeAg loss increased as pretreatment ALT levels increased
(P=0.013) and were highest among patients with pretreatment ALT levels greater than 5 times the upper
limit of normal, occurring in 56.8% of those patients. The rate of HBeAg loss was higher in patients with
more active histologic disease on pretreatment liver biopsy (Grade 1&2 vs. Grade 3&4, 28.3% vs 56.5%,
P=0.004). Similar results were seen with HBeAg seroconversion, though seroconversion occurred less
frequently than HBeAg loss. Multivariate analysis showed that elevated baseline ALT levels (P<0.05) and
histologic activity (P<0.05) were the best independent predictors of HBeAg loss and seroconversion in
response to lamivudine. Conclusions: Pretreatment ALT levels and histologic activity were the most
important predictors for response to lamivudine.(Korean J Hepatol 2002;10:31-41)
Background/Aims Acute exacerbation (AE) of chronic hepatitis B (CHB) can occur spontaneously, and may be followed by HBeAg clearance. HBeAg seroconversion often coincides with the normalization of liver biochemical tests and clinical remission. The purpose of this study was to identify the etiology and the clinical consequence of severe AE in Korean patients with CHB. Methods: The medical records of CHB patients with severe AE (defined by the sudden increase of ALT above 400 IU/L) who were admitted to Kyung Hee University Hospital between January 1992 and December 2001, were reviewed retrospectively. Forty-four patients were included in the severe AE group. Results: The most common etiology of severe AE was spontaneous exacerbation (77%). Drugs (16%), alcohol (5%), and HCV coinfection (2%) were suspected of causing AE in the remaining patients. HBeAg seroconversion at 12, 18, and 24 months following severe spontaneous AE was 18.5%, 40.7%, and 48.1%, respectively. These were significantly higher compared to CHB patients without AE (4.3%, 4.3%, and 10.9%, respectively). Seroconversion within 3 months, however, occurred in only 15% of CHB patients with AE. There was a tendency to progress to liver cirrhosis more frequently in the patients with AE as compared to the patients without AE (17.6% vs. 5.5%, P<0.08). Conclusions: Severe AE in patients with CHB is mainly caused by spontaneous exacerbation. Although HBeAg seroconversion occurs frequently in these patients, the rates are relatively low compared to those reported in other countries and early seroconversion is expected only in a small proportion. Further studies will be warranted to determine the efficacy of the early use of antiviral agents at the time of AE.(Korean J Hepatol 2004;10:99-107)
Chun Kyon Lee, M.D., Kwang-Hyub Han, M.D.1,2, Jeong Hun Suh, M.D.,
Young Suk Cho, M.D., Sun Young Won, M.D., Chae Yoon Chon, M.D.1,
Young Myoung Moon, M.D.1 and In Suh Park, M.D.
Background/Aims Viral suppression of the hepatitis B virus (HBV) can be induced by lamivudine, but the relapse seen in many patients after cessation of lamivudine therapy is troublesome. We thought that the host immune response is important to prevent viral relapse. We compared the frequency of HBV-specific CD8+ T cells in the peripheral blood and their expansion capacity after exposure to viral antigen between the patients showing sustained HBeAg seroconversion after use of lamivudine and those patients without sustained response. Methods: We analyzed HBV-specific CD8+ T cells that were isolated from the blood of 14 patients with HLA-A2 who showed lamivudine induced HBeAg seroconversion (HBV DNA < 0.5 pg/mL, and the cells were negative for HBeAg) at the end of lamivudine therapy. The purified T cells were directly stained ex vivo, after they had been stimulate with synthetic peptide, using the HBV core 18-27-specific HLA tetramer (Tc 18-27) and monoclonal antibody to CD8. The HBV viral load was quantified by the Amplicor HBV Monitor assay. Results: In patients with a sustained HBeAg response (the sustained group) for a duration of 15.5 months of follow-up, the median number of Tc 18-27 cells out of the 5×104 CD8+ T cells was 49.5 (15-135). On the contrary, in patients who experienced relapse (the relapsed group) during a median of 7.5 months of follow-up, the median number of Tc 18-27 cells out of the 5×104 CD8+ T cells was 13.5 (0-95). Especially, among patients with a viral load of HBV DNA < 1×103 copies at the end of treatment, the median number of Tc 18-27 cells out of 5×104 CD8+ T cells was 87 (45-135) in sustained group compared to 12 (6-50) in the relapsed group. All patients in the sustained group demonstrated a vigorous expansion of the core 18-27-specific CD8+ T cells after stimulation with viral peptide, in contrast to only 3 out of 8 patients in the relapsed group. Conclusions: This study demonstrates that the frequency and functional responsiveness of the circulating HBV-specific CD8+ T cells may be important for obtaining a sustained HBeAg response to lamivudine. (Korean J Hepatol 2005;11:34-42)
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