Lamivudine Therapy In Patients Research Articles

Meta-analysis of prophylactic entecavir or lamivudine against hepatitis B virus reactivation

Introduction and aim. Studies suggest that entecavir and lamivudine are useful as prophylactics against hepatitis B virus (HBV) reactivation in patients undergoing chemotherapy or immunosuppressive therapy, but which drug is more effective is unclear. Here we meta-analyzed available evidence on relative efficacy of prophylactic entecavir or lamivudine therapy in patients with chronic or resolved hepatitis B infection who were undergoing chemotherapy or immunosuppressive therapy.Material and methods. Two reviewers searched PubMed, EMBASE and Google Scholar as well as reference lists in relevant articles to find studies published between January 2005 and May 2015 that met inclusion and exclusion criteria. Data on HBV reactivation, HBV-related hepatitis and all-cause mortality were extracted from the studies and meta-analyzed.Results. A total of eight studies involving 593 patients were included in the meta-analysis, which was performed using a fixed-effect model since no significant heterogeneity was found. Entecavir was associated with significantly lower risk of HBV reactivation than lamivudine (RR 0.29, 95% CI 0.17 to 0.52) as well as lower risk of HBV-related hepatitis (RR 0.11, 95% CI 0.03 to 0.40). The two drugs were associated with similar risk of all-cause mortality (RR 1.12, 95% CI 0.54 to 2.35). Egger’s test suggested no significant publication bias in the meta-analysis.Conclusions. The available evidence suggests that entecavir is more effective than lamivudine for preventing HBV reactivation and HBV-related hepatitis in patients with chronic or resolved HBV infection who are undergoing chemotherapy or immunosuppressive therapy.

Abstract IA37: Prevention of Hepatocellular Carcinoma (HCC) with antiviral therapy

Abstract On a world-wide basis, chronic viral hepatitis accounts for nearly 75% of all cases of HCC. One of the important implications of this is that HCC may be more readily preventable either by vaccination or with anti-viral therapy. Antiviral therapy against hepatitis B has largely evolved away from using alpha interferon to nucleoside analogues. Lamivudine is the nucleoside analogue agent that has been best studied in preventing HCC. In a large prospective, randomized placebo-controlled trial of lamivudine therapy in patients with advanced liver disease associated with HBV infection, 3.9% of patients receiving lamivudine developed HCC compared to 7.4% on placebo (p=0.047) (1). More recently entecavir and tenofovir have become widely used as the main antiviral agents to control HBV infection. Both agents appear to be very effective in controlling HBV infection but data on their ability to reduce the risk of HCC are controversial. At least two meta-analyses have been done of the anti-cancer benefits of antiviral therapy. Chronic HCV infection appears to be associated with about 30% of HCCs worldwide but in some regions including Europe and the United States it is the leading underlying cause of HCC. The evidence is substantial that effective treatment of hepatitis C can reduce the risk of HCC. The HALT-C Trial was a large randomized controlled trial carried out at multiple sites within the United States, enrolling more than 1,000 patients and randomized patients with HCV infection and advanced fibrosis (bridging hepatic fibrosis or cirrhosis) to receive long-term maintenance therapy with a low dose of peginterferon alfa or to remain untreated for a period of 4 years (2). The initial report from this study showed that antiviral therapy did not reduce the rate of either hepatic decompensation or HCC but an analysis of liver related outcomes after 7 to 8 years of follow up among patients who did not respond to therapy colleagues found that patients who achieved viral cure had significantly lower rates of hepatic decompensation, liver transplantation, or HCC than patients with remained non-responders to interferon (3). This was confirmed in other large cohort studies from several countries in Europe and Canada and meta-analyses. In summary, antiviral treatment for viral hepatitis appears to have benefits in decreasing the risk of HCC in chronically infected patients. This benefit is most pronounced in patients with chronic hepatitis C and advanced hepatic fibrosis or cirrhosis in patients achieving viral clearance and seems much more marginal in patients with chronic hepatitis B where antiviral therapy usually results in viral suppression rather than elimination.

Entecavir and lamivudine therapy for severe acute chronic hepatitis B

Severe acute exacerbation in patients with chronic hepatitis B is a unique clinical presentation that results in high mortality. To compare the efficacy of 4 weeks of entecavir or lamivudine therapy in patients with severe acute exacerbation caused by chronic hepatitis B, 65 patients were retrospectively analyzed. The groups received 0.5 mg entecavir (group A) or 100 mg lamivudine (group B) daily. After 4 weeks of treatment, virological and biochemical responses and the deterioration rates were determined. The average age and alanine aminotransferase (ALT), bilirubin, albumin, creatinine (Cr), and HBV DNA levels were similar in groups A and B prior to treatment, but the prothrombin time (PT) was shorter in group A. Following treatment, ALT and bilirubin levels were improved while there were no significant changes in PT, albumin or Cr levels at week 4 in group B. Only ALT was markedly upregulated following treatment in group A. There were no significant differences between the virological and biochemical responses or the deterioration rates of the two groups. These results suggested that short-term treatment with lamivudine markedly alleviated the increased bilirubin (TB) levels in patients with severe acute exacerbation of chronic hepatitis B and that there was no significant difference in the deterioration rate between patients treated by the two types of medication.

HLA-DRB1*010101 Allele Is Closely Associated with Poor Virological Response to Lamivudine Therapy in Patients with Chronic Hepatitis B

Background/Aims: We intended to evaluate the association between specific human leukocyte antigen (HLA)-DRB1 gene polymorphism and antiviral response to lamivudine (LAM) therapy in chronic hepatitis B (CHB) patients. Methods: Six-digit HLA-DRB1 genotypes were determined using sequence-based typing in 334 CHB patients initially treated with LAM for at least 12 months. Antiviral response was evaluated every 3–6 months during LAM therapy. Results: Median age of the subjects was 43 years (range, 16–72). Median duration of LAM therapy was 69 months (range, 13–140). Median baseline serum hepatitis B virus (HBV DNA) level was 7.0 log₁₀ copies/ml (range, 5.5–9.1). At 12 months of LAM therapy, serum HBV DNA was undetectable by solution hybridization method in 308 (88%) patients. Among 25 HLA-DRB1 alleles identified, HLA-DRB1*090102, *080302, and *070101 were the most frequent alleles (>10%). HLA-DRB1*010101 was identified in 5.4% (18/334). The frequency of the HLA-DRB1*010101 allele was significantly lower in patients with virological response at 12 months of LAM therapy than in patients without it (4.2 vs. 19.2%, p = 0.025). The other HLA-DRB1 alleles were not associated with virological response. HBeAg loss/seroconversion and alanine aminotransferase normalization were not associated with HLA-DRB1 alleles. Conclusion: The HLA-DRB1*010101 allele is closely associated with poor virological response to initial LAM therapy in CHB patients.

Adefovir‐based combination therapy with entecavir or lamivudine for patients with entecavir‐refractory chronic hepatitis B

This study evaluated the efficacy of adefovir (ADV) plus lamivudine (LAM) or ADV add-on therapy for patients with entecavir (ETV)-refractory hepatitis B infection. Twenty-nine ETV-resistant and 8 patients with suboptimal response to ETV were enrolled. Twenty-seven patients received ADV + LAM therapy and 10 patients received ADV + ETV therapy for >24 weeks. In 29 patients who were ETV-resistant, the mean reduction in HBV DNA levels at 24 weeks was not different between the ADV + LAM and ADV + ETV groups (-1.98 log(10) IU/ml vs. -2.16 log(10) IU/ml; P = 0.792). Primary non-response was observed in 52.2% (12/23) of ADV + LAM group and 33.3% (2/6) of ADV + ETV group (P = 0.651). Initial virologic response (IVR) was observed in 17.4% (4/23) of ADV + LAM group and 33.3% (2/6) of ETV + ADV group (P = 0.362). In eight patients with suboptimal response to ETV, the ADV + ETV group had a greater reduction in HBV DNA at 24 and 48 weeks than the ADV + LAM group (-2.29 log(10) IU/ml vs. -0.09 log(10) IU/ml and -2.04 log(10) IU/ml vs. -0.72 log(10) IU/ml; P = 0.020 and P = 0.012, respectively). Primary non-response and IVR did not significantly differ between the two groups [100% (4/4) vs. 50% (2/4) and 0% (0/4) vs. 50% (2/4); P = 0.429 and P = 0.429, respectively]. The antiviral efficacies of ADV-based therapy with ETV or LAM for patients with ETV-resistant hepatitis B were limited and did not differ between the two groups. However, adding ADV to ETV may be more effective than ADV + LAM therapy in patients with suboptimal virologic response to ETV.

Risk assessment for the development of hepatocellular carcinoma: According to on-treatment viral response during long-term lamivudine therapy in hepatitis B virus-related liver disease

To assess the risk for the development of hepatocellular carcinoma (HCC) according to the underlying liver status and on-treatment viral response during long-term lamivudine therapy in patients with hepatitis B virus-related liver disease. Between March 1997 and February 2005, a total of 872 patients were treated with lamivudine for more than one year. Between 1983 and 1998, a total of 699 patients were enrolled as historical controls. For patients with compensated cirrhosis, HCC occurred in 4.9% (5/103) of cases with sustained viral suppression (persistently <141,500 copies/ml), 11.8% (20/170) in cases with viral breakthrough, and 19.4% (7/36) in cases with a suboptimal response (persistently 141,500 copies/ml): the mean follow-up was 5.1+/-2.7, 5.4+/-2.3, and 3.7+/-1.8 years, respectively. For the control group, HCC developed in 25.0% (37/148) of the cases during a mean follow-up of 6.1+/-4.3 years. Thus, the annual incidence of HCC was 0.95%, 2.18%, 5.26%, and 4.10% in patients with sustained viral suppression, viral breakthrough, suboptimal response, and the control group, respectively. The cumulative incidence of HCC in patients with sustained viral suppression was significantly lower than in patients with a suboptimal response and the controls (p=0.002 and p=0.005, respectively). In patients without cirrhosis and with decompensated cirrhosis, the preventive effects of lamivudine on the development of HCC were not observed (p=0.446 and p=0.123, respectively). Lamivudine therapy reduced the incidence of HCC in patients with compensated cirrhosis when the viral suppression was sustained.

Clinical Efficacy of a 24-months Course of Lamivudine Therapy in Patients with HBeAg Negative Chronic Hepatitis B: A Long-term Prospective Study

The optimal duration of oral nucleos(t)ide analogue therapy for HBeAg negative chronic hepatitis B (CHB) has not been defined. The aim of this study was to investigate the clinical efficacy of 24-months course of lamivudine therapy in patients with HBeAg negative CHB in Korea. A total of 50 Korean patients with HBeAg negative CHB were prospectively enrolled. The patients received 100 mg/day of lamivudine orally for 24 months. Patients who showed complete response at 24 months to lamivudine therapy stopped treatment, and regular follow-up was done thereafter. The mean follow-up duration after cessation of therapy was 40.8±22.7 (range 12-96) months. The complete response rate at months 12 and 24 were 86.0% (43/50) and 86.0% (43/50), respectively, and the clinical breakthrough at months 12 and 24 were 4.0% (2/50) and 14.0% (7/50), respectively. The expected durability of responses at months 12, 24, and 36 after cessation of lamivudine therapy in 43 complete responders was 79.1%, 64.0%, and 56.9%, respectively. In conclusion, a 24-months course of lamivudine therapy shows high end-treatment response rate and substantial durability of initial response after cessation of therapy in HBeAg negative CHB patients in Korea.

Comparison of ligase detection reaction and real-time PCR for detection of low abundant YMDD mutants in patients with chronic hepatitis B

To compare the ligase detection reaction (LDR) and real-time PCR for detection of low abundant YMDD mutants in patients with chronic hepatitis B infection. Mixtures of plasmids and serum samples from 52 chronic hepatitis B patients with low abundant lamivudine-resistant mutations were tested with LDR and real-time PCR. Time required and reagent cost for both assays were evaluated. Real-time PCR detected 100, 50, 10, 1 and 0.1% of YIDD plasmid, whereas LDR detected 100, 50, 10, 1, 0.1, and 0.01% of YIDD plasmid, in mixtures with YMDD plasmid of 10(6) copies/mL. Among the 52 clinical serum samples, completely concordant results were obtained for all samples by both assays, and 39 YIDD, 9 YVDD, and 4 YIDD/YVDD were detected. Cost and time required for LDR and real-time PCR are 60/80 CNY (8/10.7 US dollars) and 4.5/2.5 h, respectively. LDR and real-time PCR are both sensitive and inexpensive methods for monitoring low abundant YMDD mutants during lamivudine therapy in patients with chronic hepatitis B. LDR is more sensitive and less expensive, while real-time PCR is more rapid.

Efficacy of lamivudine therapy in elderly patients with chronic hepatitis B infection

The aim of this study was to evaluate the efficacy of lamivudine therapy in elderly patients with chronic HBV infection. Patients aged >or=60 years (n = 40) received lamivudine monotherapy between February 1995 and September 2005 at Toranomon Hospital. We compared the efficacy of lamivudine therapy in these patients and in 639 patients aged <60 years, including 80 patients aged <60 years matched for sex, hepatitis B e antigen (HBeAg) status, and hepatitis B virus (HBV) DNA level. The rates of normalization of alanine aminotransferase (ALT) level in 40 patients aged >or=60 years and 639 patients aged <60 years were 85% versus 76%, and 86% versus 73% at 1 and 3 years, respectively. The respective rates of loss of HBV-DNA were 74% versus 74%, and 76% versus 68% at 1 and 3 years. The respective cumulative emergence rates of the YMDD mutant were 16% and 17% at 1 year, and 46% and 49% at 3 years. In 80 patients <60 years old matched for sex, HBeAg status, and HBV-DNA level, the rates of normalization of the ALT level and loss of HBV-DNA were similar to those in the 639 patients aged <60 years. The emergence rate of YMDD mutants in patients aged >or=60 years were similar to those in matched patients aged <60 years. Multivariate analyses identified low serum bilirubin (<1 mg/dl) as an independent factor associated with the emergence of the YMDD motif mutation in patients aged >or=60 years. Our results suggest that treatment with lamivudine is both well tolerated and efficacious in elderly patients with chronic HBV infection.

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

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

Characterization of Naturally Occurring and Lamivudine-Induced Surface Gene Mutants of Hepatitis B Virus in Patients with Chronic Hepatitis B in India

Background: Besides vaccine escape or immune escape hepatitis B virus (HBV) mutants, naturally occurring and drug-induced mutations have been reported in the surface gene (S-gene) of HBV. Aim: To investigate the frequency and profile of naturally occurring S-gene mutants and the influence of long-term lamivudine therapy in patients with chronic hepatitis B (CHB). Materials and Methods: 57 patients with histologically proven CHB, on lamivudine 100 mg/day for more than 24 months, were included. Viral DNA was extracted at baseline and from on-therapy serum samples. The region encoding the complete major hydrophilic region (MHR) and flanking regions (nucleotides 425–840) of major S-gene that overlapped with the viral polymerase was PCR amplified and sequenced. End-of-therapy response (ETR) was assessed. Results: Two (3.5%) patients had naturally occurring HBV mutants, sP127S and sS143L seen in the ‘a’ determinant of the S-gene. Following lamivudine therapy, 14 of 57 (24.5%) patients developed 16 types of S-gene mutations (sP120S, sA128V, sS143L, sW182St., sT189I, sV190A, sS193L, sI195M, sW196L, sW196St., sS207R, sI208T, sS210E, sF219S, sF220L and sC221G). Thirteen (81.2%) of these mutations emerged downstream to the MHR. Nine of 16 types of S-gene mutations observed with lamivudine therapy were also associated with the corresponding changes in the polymerase gene. Baseline viral DNA was significantly higher (2,093 vs. 336 pg/ml; p < 0.05) among patients developing S-gene mutants and the ETR in them was significantly lower [3 of 16 (18.8%) vs. 17 of 41 (41.5%); p < 0.05]. Conclusions: Naturally occurring S-gene mutations are uncommon and are restricted to the ‘a’ determinant region. Mutations develop in about a quarter of the patients on lamivudine therapy, mostly downstream to the MHR. They may contribute to non-response to the antiviral therapy.

Determinants of early mortality and benefits of lamivudine therapy in patients with hepatitis B virus‐related decompensated liver cirrhosis

Chronic hepatitis B infection (HBV) is a major health problem worldwide. The prognosis is grave for patients with HBV-related decompensated liver cirrhosis (LC). We evaluated the effectiveness and the determinants of early mortality of lamivudine treatment in patients with HBV-related decompensated LC. Thirty patients with HBV-related decompensated LC and active viral replication were treated with lamivudine 100 mg daily for a median duration of 9 months. Among these patients, five patients died within 3 months. Two patients were lost to follow-up at week 8 and 9. One patient was treated for <6 months. Twenty-two patients were treated over 6 months. Univariate analysis revealed that the total bilirubin (P = 0.008), prothrombin time (P = 0.004), Child-Turcotte-Pugh score (P = 0.005), the model of efd-stage liver disease score (P = 0.004) and stage III hepatic encephalopathy (P = 0.001) were predictive factors of early mortality. Multivariate analysis revealed that the independent factor associated with early mortality was stage III encephalopathy. Among 22 patients, liver function improved markedly after lamivudine therapy. Of the nine hepatitis B e antigen (HBeAg)-positive patients, three had HBeAg seroconversion. Two patients had YMDD mutant and virological breakthrough at 41 and 46 weeks. One of the two had hepatocellular carcinoma and died of hepatic failure at week 125; the other received adefovir and is doing well. Lamivudine appeared to have benefits in viral suppression and significant improvement in liver function in patients with HBV-related decompensated LC. As noted in prior studies, poor baseline liver function is associated with a poor prognosis in Asian patients with decompensated HBV cirrhosis treated with lamivudine.

The Clinical Impact of Early Detection of the Ymdd Mutant on the Outcomes of Long-Term Lamivudine Therapy in Patients with Chronic Hepatitis B

The early emergence of lamivudine (3TC)-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutants has been reported during 3TC therapy in patients with chronic hepatitis B (CHB) in hepatitis B virus (HBV)-endemic areas; however, its clinical impact during long-term 3TC therapy is unknown. This study was performed to investigate the impact of the early emergence of YMDD mutants 3 months after the initiation of treatment on the outcomes of long-term 3TC therapy in HBV e antigen (HBeAg)-positive CHB. We analysed YMDD genotypes in consecutive samples from 30 patients with HBeAg positive CHB throughout 3TC treatment using both restriction fragment length polymorphism and mass spectrometric assays. Long-term outcome was compared between patients who had YMDD mutations detected at 3 months and those who had no mutations. YMDD mutation was detected in 16 (53.3%) out of 30 patients at 3 months and only the rtM2041 mutation was found. Cumulative HBeAg loss rates at 3 years was 12.5% and 57.4% in patients who had the rtM2041 mutant and wild-type virus at 3 months, respectively (P=0.010). Cumulative viral breakthrough rates at 3 years was 75.0% and 14.3% in patients who had the rtM204I mutant and wild-type virus at 3 months, respectively (P=0.002). Logistic regression revealed that YMDD mutation at 3 months was significantly related to viral breakthrough within 24 months (P=0.003). In conclusion, early detection for HBV YMDD mutation at 3 months may be useful to predict the long-term outcomes of 3TC therapy in patients with HBeAg-positive CHB in HBV-endemic areas.

Favorable efficacy of long‐term lamivudine therapy in patients with chronic hepatitis B: An 8‐year follow‐up study

The long-term efficacy of lamivudine therapy in patients with hepatitis B virus (HBV) infection is still not clear. In this study, 20 non-cirrhotic Japanese patients infected with HBV received lamivudine therapy for more than 1 year and were followed for a median period of 8.5 years (range, 6.7-8.7 years). The rates of HBe antigen (HbeAg) negative, HBV-DNA undetectable, and alanine aminotransferase (ALT) normal level at the start of lamivudine were 55%, 25%, and 20% and 85%, 80%, and were 80%, respectively, at the last visit, including patients who received additional treatment. The values at the last visit tended to and were significantly higher than those at the start. The values improved at the last visit regardless of the emergence of YMDD motif mutant and continuation of lamivudine. YMDD mutant and biochemical relapse with mutant virus (breakthrough hepatitis) appeared in 65% and 45% during follow-up, respectively, but severe breakthrough hepatitis occurred in only 5%. Furthermore, 80% of patients who received additional treatment for breakthrough hepatitis, regardless of continuation of lamivudine, were ALT normal level at the last visit, in contrast to 25% untreated. HBsAg clearance occurred in two patients of the discontinuous lamivudine group with non-vertical transmission, who were relatively young. One was infected with HBV genotype C with breakthrough hepatitis and the other had no YMDD mutant and was infected with genotype D, a rare type in Japan. None developed cirrhosis or hepatocellular carcinoma (HCC) during follow-up. Our results suggest that long-term lamivudine therapy improves long-term prognosis, especially when additional treatment for breakthrough hepatitis is used.

Efficiency and safety of lamivudine therapy in patients with chronic HBV infection, dialysis or after kidney transplantation

To analyze the effectiveness and safety of lamivudine treatment in patients with chronic HBV infection undergoing hemodialysis or after kidney transplantation, and to study the frequency of tyrosine-methionine-aspartate-aspartate (YMDD) mutation occurrence after lamivudine treatment. We analyzed 91 patients with chronic hepatitis B, among whom, 16 patients underwent hemodialysis, 7 patients had kidney transplantation and 68 patients had normal function of kidney. The hemodialysis patients were treated by lamivudine 300 mg/wk. Patients after kidney transplantation and patients with normal function of kidney were treated with lamivudine 100 mg/d. Therapy lasted for 12 mo. HBV-DNA, HBsAg, HBeAg and anti-HBe, and anti-HCV antibodies were assessed in sera of patients. The analysis was performed before and 6 mo after the end of lamivudine treatment. Before, during and after the lamivudine therapy, the number of erythrocytes, leukocytes, platelets and hemoglobin concentration, ALT and AST activity, as well as bilirubin, urea and creatinine concentrations were analyzed in sera from patients. After the 12-mo lamivudine treatment, elimination of HBV-DNA was observed in 56% patients undergoing hemodialysis and in 53% patients with normal kidney function. Only 1 from 7 (14%) kidney-transplanted patients eliminated HBV-DNA. Furthermore, HBeAg elimination was observed in 36% hemodialysis patients, in 51% patients with normal function of kidneys and in 43% kidney-transplanted patients. Among the patients undergoing dialysis, no YMDD mutation was found after 12 mo of therapy, while it was detected in 9 patients (13%) with normal function of kidney and in 2 kidney-transplanted patients (29%, P<0.006). We did not observe significant side effects of lamivudine treatment in studied patients. Effectiveness of lamivudine therapy in dialysis patients is comparable with that in patients with normal function of kidney. Lamivudine treatment is well tolerated and safe in patients with renal insufficiency undergoing hemodialysis and kidney-transplantation. However, in the latter group, high incidence of YMDD mutation after lamivudine treatment was observed.

Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine

The effect of lamivudine treatment on the outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis is unclear. In a retrospective multicenter study, we have analyzed the virological events observed during lamivudine therapy in patients with HBeAg-negative chronic hepatitis and evaluated the correlation between virological response and clinical outcomes. Among 656 patients (mean age 49.1 years) included in the database, 54% had chronic hepatitis, 30% had Child-Turcotte-Pugh (CTP) A cirrhosis, and 16% had CTP B/C cirrhosis. On therapy (median 22 months, range 1-66), a virological response was obtained in 616 patients (93.9%). The rate of maintained virological response was 39% after 4 years. During follow-up, 47 (7.2%) patients underwent liver transplantation, liver disease worsened in 31 (4.7%), hepatocellular carcinoma (HCC) developed in 31 (4.7%), and 24 patients (3.6%) died of liver-related causes. Patients who had cirrhosis and who maintained virological response were less likely than those with viral breakthrough to develop HCC (P &lt; .001) and disease worsening (P &lt; .001). Survival was better in CTP A patients with cirrhosis and maintained virological response (P = .01 by rank test). Multivariate analysis revealed that presence of cirrhosis and viral breakthrough were independently related to mortality and development of HCC. In conclusion, lamivudine is highly effective in reducing viral load in HBeAg-negative patients. After 4 years of therapy, 39% of patients maintain a virological and biochemical response. Loss of virological response may lead to clinical deterioration in patients with cirrhosis. (Hepatology 2004;40:883-891).

Recovery of functional cytotoxic T lymphocytes during lamivudine therapy by acquiring multi-specificity.

To characterize cytotoxic T lymphocytes (CTLs) that appeared in circulation during lamivudine therapy, we analyzed HBV-specific CTLs using HLA-A24 tetramer and HBcAg-specific Th1 cells in patients receiving lamivudine therapy. Six patients (HLA-A24(+)) with chronic hepatitis B, six patients (HLA-A24(-)) with chronic hepatitis B, and six patients (HLA-A24(+)) with chronic hepatitis C were studied. In addition to known CTL epitopes (C117 and P756), three epitopes were confirmed as CTL epitopes (C23, S89, S226) by chromium release assay and by staining intracellular perforin. CTLs specific for P756 were most frequently found at pre-treatment. During lamivudine therapy, increase in the frequencies of HLA-tetramer(+) cells was found for C117, S89, and S226. Recovery of CTLs was observed earlier in patients with HBeAg(-)/anti-HBe(+) compared with those with HBeAg(+)/anti-HBe(-). HBcAg-specific Th1 cells did not increase significantly up to 8 weeks. T cell lines from patients with chronic hepatitis B had a lower level of proliferation (0- to 24.9-fold expansion by in vitro stimulation) and a higher ability to produce interferon-gamma (0-84% except for S89), while perforin-positive cells showed low frequencies (0-50% except for S89). In conclusion, these results suggest that lamivudine therapy induces mainly CTLs that were less frequent before the therapy. Since recovered CTLs maintained the ability to produce interferon-gamma in response to peptides, these CTLs apparently contribute to the efficacy of lamivudine therapy in patients with hepatitis B.

Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine.

The effect of lamivudine treatment on the outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis is unclear. In a retrospective multicenter study, we have analyzed the virological events observed during lamivudine therapy in patients with HBeAg-negative chronic hepatitis and evaluated the correlation between virological response and clinical outcomes. Among 656 patients (mean age 49.1 years) included in the database, 54% had chronic hepatitis, 30% had Child-Turcotte-Pugh (CTP) A cirrhosis, and 16% had CTP B/C cirrhosis. On therapy (median 22 months, range 1-66), a virological response was obtained in 616 patients (93.9%). The rate of maintained virological response was 39% after 4 years. During follow-up, 47 (7.2%) patients underwent liver transplantation, liver disease worsened in 31 (4.7%), hepatocellular carcinoma (HCC) developed in 31 (4.7%), and 24 patients (3.6%) died of liver-related causes. Patients who had cirrhosis and who maintained virological response were less likely than those with viral breakthrough to develop HCC (P <.001) and disease worsening (P <.001). Survival was better in CTP A patients with cirrhosis and maintained virological response (P =.01 by rank test). Multivariate analysis revealed that presence of cirrhosis and viral breakthrough were independently related to mortality and development of HCC. In conclusion, lamivudine is highly effective in reducing viral load in HBeAg-negative patients. After 4 years of therapy, 39% of patients maintain a virological and biochemical response. Loss of virological response may lead to clinical deterioration in patients with cirrhosis.

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

Background & Aims: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). Methods: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level ≥1.2 times the upper limit of normal, and serum HBV DNA level ≥6 log10 copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. Results: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG16 was −0.07 in the lamivudine group compared with −2.45 and −2.46 log10 copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, −3.59, and −4.04 log10 copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. Conclusions: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.

Effect of SEN virus coinfection on outcome of lamivudine therapy in patients with hepatitis B.

Interactions between hepatitis B virus (HBV) and other viral hepatitis infections are well known, whether the newly discovered SEN virus (SENV) has any effect on lamivudine antiHBV activity is unclear. Our aim was to clarify the effect on treatment outcome of coinfection with SEN virus in patients with hepatitis B during lamivudine therapy. Nested polymerase chain reaction (PCR) amplification was used to detect SENV-D and SENV-H strains in serum from 45 patients with chronic hepatitis B treated with lamivudine 100 mg daily for 12 mo. HBV DNA load was detected with fluorescence quantitative PCR (FQ-PCR) and YMDD (tyrosine, methionine, aspartate, aspartate) motif mutation of HBV DNA was investigated with cDNA microarray. SENV DNA was detected in 5 of 45(11.1%) cases after 12 mo they received lamivudine treatment. SENV-D and SENV-H were 4.4% and 6.7% respectively. HBV DNA failed to respond to lamivudine therapy in 4 of 5 SENV coinfected patients while only 10 of 40 patients became SENV positive and the difference was statistically significant. Response of ALT and HBeAg to lamivudine had no significant difference between coinfection patients and single HBV infection ones. Coinfection with SEN virus in chronic hepatitis B patients may adversely affect the outcome of lamivudine treatment.