Discontinuation Of Lamivudine Research Articles

Lamivudine prophylaxis prevents hepatitis B virus reactivation in anti-HBc positive patients under rituximab for non-Hodgkin lymphoma

BackgoundA significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non-Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation. AimsWe wanted to assess efficacy and safety of lamivudine (LMV) prophylaxis to prevent this complication. MethodsEighty-five consecutive HBsAg negative/anti-HBc positive NHL patients (71 years, 100% serum HBV DNA undetectable, 74% anti-HBs positive) received LMV coadministered with R-CT and for 18 months after the end of R-CT. Serum ALT, HBsAg, anti-HBs and HBV DNA were assessed every 4 months during and after end of LMV. ResultsDuring 39 (2–108) months of study period, including 21 months of LMV and 27 additional months after LMV discontinuation, one patient (2%) had HBV reactivation, 31 months after stopping LMV and during administration of new immunosuppressive regimens, without LMV prophylaxis, owing to incomplete oncological response. A 50% decline of anti-HBs titers occurred in 22/63 (35%) patients, including 12 who became anti-HBs seronegative. Five (6%) patients had ALT increase during R-CT but none required R-CT discontinuation. Seventeen (20%) patients died, all for tumour progression. ConclusionLMV prophylaxis is safe and effective in preventing HBV reactivation in HBsAg negative/anti-HBc positive NHL patients receiving R-CT.

Comparison of replication competence of wild-type and lamivudine-resistant hepatitis B virus isolates from a chronic hepatitis B patient

In lamivudine-refractory chronic hepatitis B (CHB) patients, discontinuation of lamivudine therapy may lead to loss of lamivudine-resistant hepatitis B virus (HBV) and reappearance of wide-type HBV as dominant strains, yet the underlying mechanism remains unclear. In this study, we cloned wide-type and lamivudine-resistant HBV genomes from the sera of a CHB patient who stopped lamivudine therapy after occurrence of resistant virus and determined the biologic properties of the two isolates in hepatoma cell lines. Sequencing reverse transcriptase region of HBV revealed that the patient developed lamivudine-resistant mutations (rtV173 L, rtL180 M, and rtM204 V) 36 months after the start of lamivudine therapy, and lamivudine-resistant mutants reversed to wild-type after the treatment was stopped for 8 months. Our data showed that the wild-type and mutant isolates had similar transcriptional and translational activity. However, comparison of intracellular and released HBV DNA levels showed that replication efficiency of the mutant virus was approximately 50% of wild-type HBV, while the infectivity of released virus was not affected by the lamivudine-resistant mutations. In conclusion, the reversion of lamivudine-resistant mutants to wild-type HBV after discontinuation of lamivudine in hepatitis B patients may be attributed to better replication fitness of wild-type HBV.

Durability of the virological response after lamivudine discontinuation in lamivudine-resistant patients with a complete virological response after lamivudine and adefovir combination therapy.

We investigated the durability of virological response after lamivudine (LAM) discontinuation in LAM-resistant chronic hepatitis B (CHB) patients with complete virological response after LAM-adefovir (ADV) combination therapy. We enrolled 58 patients switched to ADV monotherapy with undetectable viral loads (<12 IU/ml) and normal alanine aminotransferase levels after ADV add-on combination treatment for at least 6 months in LAM-resistant CHB patients. Virologic relapse was defined as HBV DNA detection at more than 20 IU/ml by quantitative polymerase chain reaction determined on two consecutive measurements. During median 40.9 months of follow-up (range 11.5-79.0 months), seven (12.1%) patients experienced virological relapse. The cumulative rate of virological relapse at 3 and 5 years was 5.5% and 22.4%, respectively. Two patients had elevated alanine aminotransferase during virological relapse. These seven patients with virological relapse had undetectable HBV DNA after switching to tenofovir therapy. In our study, switching to ADV monotherapy resulted in sustained HBV DNA suppression in 87.9% of the patients during median 40.9 months follow-up. This adapting step-down strategy, switching from combination therapy to monotherapy in virologically suppressed CHB patients with stable liver disease, may reduce the cost burden and the risk of potentially harmful effects of combination therapy. J. Med. Virol. 89:85-90, 2017. © 2016 Wiley Periodicals, Inc.

English

The aim of this study was to compare the safety, efficacy, and pharmacoeconomics of the diminishing type antiviral combination of lamivudine and adefovir group (LA group) and entecavir monotherapy group (E group) in HBeAg-positive chronic hepatitis B.&nbsp;One hundred (100)&nbsp;patients were randomized equally to LA group,&nbsp;and&nbsp;E group in a multi-center randomized clinical trial. In the LA group, the earliest time for lamivudine discontinuation was 12 weeks and adefovir monotherapy continued until 96 weeks. Group E received entecavir monotherapy for 96 weeks. At 12 weeks, the&nbsp;hepatitis B virus (HBV)DNA suppression and ALT normalization rates in LA group were both comparable to E group. At weeks 24 and 48 of treatment, the difference in virological response (VR) and HBeAg seroconversion between LA group and E group was not significant, while&nbsp;similar results were observed for the biochemical response (BR). At 96 weeks, HBeAg seroconversion of LA group were higher than that of the E group, but the difference was still not&nbsp;statistically significant, while BR and VR in LA and E group were similar. At the same time, no virological breakthrough or drug resistance occurred in either of the two treatment groups by week 96 of the study. Both treatment strategies were well tolerated, with a low incidence of adverse reaction. The costs of all items related to LA group were lower than those related to E group (RMB&nbsp;ï¿¥14,480.13 vs. RMB&nbsp;ï¿¥28,818.47; t=164.78, p&lt;0.001). This study demonstrates that diminishing type antiviral combination of lamivudine and adefovir is economical, safe, and effective in HBeAg-positive chronic hepatitis B. &nbsp; Key words:&nbsp;Chronic hepatitis B, HBeAg-positive, lamivudine, adefovir dipivoxil, combination treatment, entecavir, monotherapy, pharmacoeconomic.

An optimized antiviral modification strategy for prevention of hepatitis B reactivation in patients undergoing prophylactic lamivudine and chemotherapy: a pilot study

In patients receiving prophylactic lamivudine (LAM) and chemotherapy, hepatitis B virus (HBV) reactivation cannot be eliminated without knowing the latent causes and optimal management. In our previous study, virus breakthrough and relapse were highly suspected as potential virologic causes for HBV reactivation. Therefore, we reviewed 24 previous studies and 447 patients who underwent chemotherapy and prophylactic LAM, with an incidence of 7.2 % HBV reactivation. Virus breakthrough and relapse were seldom investigated in these studies. In addition, 72 patients that underwent prophylactic LAM and chemotherapy at our centers were also analyzed. Among them, eight patients developed virus breakthrough, with another nine developing virus relapse after discontinuation of LAM. Eight patients received antiviral modification, which included administration of adefovir for patients with virus breakthrough or resumption of LAM for patients with virus relapse and none of them developed HBV reactivation. In contrast, of the nine patients who did not receive antiviral modification, six developed HBV reactivation and two died. In conclusion, this study demonstrated that virus breakthrough and relapse were the critical causative factors of HBV reactivation in patients receiving chemotherapy and prophylactic LAM. An optimized antiviral modification strategy could effectively prevent HBV reactivation in patients with virus breakthrough or relapse.

Low-Level Persistence of Drug Resistance Mutations in Hepatitis B Virus-Infected Subjects with a Past History of Lamivudine Treatment

We sought to determine the prevalence of hepatitis B virus (HBV) lamivudine (LAM)-resistant minority variants in subjects who once received LAM but had discontinued it prior to virus sampling. We performed direct PCR Sanger sequencing and ultradeep pyrosequencing (UDPS) of HBV reverse transcriptase (RT) of plasma viruses from 45 LAM-naive subjects and 46 LAM-experienced subjects who had discontinued LAM a median of 24 months earlier. UDPS was performed to a depth of ∼3,000 reads per nucleotide. Minority variants were defined as differences from the Sanger sequence present in ≥0.5% of UDPS reads in a sample. Sanger sequencing identified ≥1 LAM resistance mutations (rtL80I/V, rtM204I, and rtA181T) in samples from 5 (11%) of 46 LAM-experienced and none of 45 LAM-naive subjects (0%; P = 0.06). UDPS detected ≥1 LAM resistance mutations (rtL80I/V, rtV173L, rtL180M, rtA181T, and rtM204I/V) in 10 (22%) of the 46 LAM-experienced subjects, including 5 in whom LAM resistance mutations were not identified by Sanger sequencing. Overall, LAM resistance mutations were more likely to be present in LAM-experienced (10/46, 22%) than LAM-naive subjects (0/45, 0%; P = 0.001). The median time since LAM discontinuation was 12.8 months in the 10 subjects with a LAM resistance mutation compared to 30.5 months in the 36 LAM-experienced subjects without a LAM resistance mutation (P < 0.001). The likelihood of detecting a LAM resistance mutation was significantly increased using UDPS compared to Sanger sequencing and was inversely associated with the time since LAM discontinuation.

Randomized trial of lamivudine, adefovir, and the combination in HBeAg-positive chronic hepatitis B

The aim of this study was to compare the efficacy of lamivudine or adefovir alone for 96 weeks versus initial treatment with the combination of lamivudine and adefovir for 12 to 24 weeks followed by adefovir alone. One hundred and fifty patients with HBeAg-positive chronic hepatitis B were randomized equally to lamivudine and adefovir diprivoxil combination therapy (LA), lamivudine alone (L), or adefovir dipivoxil alone (A) in a multicenter randomized clinical trial. In the LA group, the earliest time for lamivudine discontinuation was 12 weeks and adefovir monotherapy was continued until 96 weeks. Groups L and A received monotherapies for 96 weeks. At 12 weeks, the decrease in HBV DNA, percentage of patients with negative HBV DNA, and ALT normalization rate for the LA group were comparable to those of group L, but superior to those of group A. At 24 weeks, the rates of negative HBV DNA and HBeAg seroconversion of group LA were significantly higher than the monotherapy groups. This superiority was subsequently preserved during the maintenance phase with adefovir monotherapy. Starting at 48 weeks, the mean HBV DNA level of group L increased over the 24-week level. In contrast, the A group's rates of virological response, biochemical response, and HBeAg seroconversion continued to improve. At week 96, the percentage of patients with undetectable DNA and HBe seroconversion of LA group (100%, 51%) was higher than that of L (66%, 21%) and A group (49%, 33%), while no significant difference was observed between the L and A groups. During the course of therapy, no lamivudine- or adefovir-resistance mutations were discovered in the LA group. Rates of adverse reactions were comparable between the three groups. Combination therapy with lamivudine and adefovir for 12 to 24 weeks followed by adefovir monotherapy significantly improved antiviral efficacy and reduced drug resistance without compromising safety and tolerability compared to either drug alone in HBeAg-positive chronic hepatitis B.

6.0 HIV and hepatitis virus coinfections

6.0 <scp>HIV</scp> and hepatitis virus coinfections

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

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

The therapeutic response of antiviral therapy in HBsAg-positive renal transplant recipients and a long-term follow-up

Early prediction of lamivudine (LAM) response by individualized monitoring of serum HBV DNA like roadmap concept, and investigation of the outcome after LAM discontinuation in renal transplant recipients (RTRs) with chronic hepatitis B (CHB). We conducted a study on 19 RTRs with HBV infection receiving LAM treatment for 2years from 2004 to 2007. HBV DNA level was assessed at baseline, 12, 24, 52, and 104weeks after treatment. Risk factors of tyrosine-methionine-aspartate-aspartate (YMDD) mutation on treatment and relapse rate of HBV after LAM discontinuation were analyzed. HBV DNA levels became undetectable in 32, 37, 63, and 53% of patients after 12, 24, 52, and 104weeks of LAM treatment, respectively. Overall, three (16%) and five (33%) patients were detected with YMDD mutations at week 52 and 104, respectively. In the concept of roadmap, of the seven patients with inadequate virologic response (IAVR) at week 24, five had YMDD mutations. There was no significant association of YMDD mutations with age, gender, genotype, cirrhosis, HBeAg status, baseline HBV DNA, precore/core promoter mutations, and primary response, except IAVR at week 24 (P=0.001). The relapse rate of HBV after LAM discontinuation was high (75%) during a median follow-up of 65weeks. The rate of LAM resistance in RTRs is similar to immunocompetent CHB patients in a 2-year therapy. By roadmap concept, RTRs with IAVR require a change in therapy to prevent viral resistance. Relapse after LAM withdrawal is frequent. Long-term antiviral therapy is crucial for immunosuppressed patients.

Evaluation of distant results after lamivudine discontinuation in children with chronic hepatitis B.

The aim of this study was to estimate distant results after discontinuation of long term lamivudine treatment in children with chronic hepatitis B. Furthermore, the emergence of HBV polymerase gene variants in YMDD motif during therapy was examined. Additionally, the most commonly occurring type of mutation in the polymerase YMDD region were investigated. The study involved 27 HBeAg positive children with chronic hepatitis B. Children included to lamivudine therapy were previously treated without effects with interferon alpha.

Patients with hematologic malignancies may be at higher risk of hepatitis B reactivation in spite of lamivudine prophylaxis

Abstract Abstract 1389 Poster Board I-411 Introduction: Although lamivudine (LMV) prophylaxis is recommended for chronic hepatitis B (HBV) patients undergoing cytotoxic chemotherapy for their malignant disease, viral reactivation sometimes occurs during or after LMV administration. Patients with solid tumors and hematologic malignancies may have different risk of HBV reactivation because hematologic malignancies require more intensive and immunosuppressive treatment. The aims of this study are to determine predictors of LMV prophylaxis failure and to evaluate the relative risk of failure in patients with hematologic malignancies. Patients and Methods: Cancer patients were routinely screened about serum hepatitis B surface antigen (HBsAg) before the initiations of chemotherapy. HBsAg-positive patients received LMV prophylaxis (100mg/day po) during the chemotherapy and for 1 to 6 months after the completion of chemotherapy. Serum HBV titer and alanine aminotransferase (ALT) level were followed at least every 3 months. Viral breakthrough during chemotherapy was defined as 10-fold or more elevation in serum HBV DNA titer above nadir regardless of serum ALT. Withdrawal hepatitis was defined as an increase of serum ALT more than upper normal limit accompanied by an elevation in serum HBV DNA titer more than that of the pre-exacerbation baseline. Either of viral breakthrough or withdrawal hepatitis was regarded as prophylaxis failure. Time to viral breakthrough was measured from the start of LMV, whereas time to withdrawal hepatitis was measured from the discontinuation of LMV. Time to prophylaxis failure was measured from the LMV initiation to either of viral breakthrough or withdrawal hepatitis. Kaplan-Meier method was used to generate survival curves of each event and log-rank test was employed to compare them. Patients were censored at death without viral reactivation or last follow-up. Cox proportional model was used to estimate the relative hazards ratio of each event in various subgroups. Death without HBV reactivation was regarded as a competing risk event and Fine and Gray model was used to adjust it. Results: One hundred eleven patients were enrolled and 28 patients had hematologic malignancies (non-Hodgkin lymphoma: 20, acute leukemia: 8). Remaining 83 patients had solid tumors such as gastric cancer, colorectal cancer, and lung cancer. Median follow-up duration was 22 (range 1.2-83.6) months and 30 patients experienced the prophylaxis failure (viral breakthrough: 15, withdrawal hepatitis: 15 patients). Log-rank test showed that liver cirrhosis, rituximab treatment, high serum HBV DNA titer (°A20,000 IU/ml), and hematologic malignancies were significant predictors (p Conclusions: Patients with hematologic malignancies or high serum HBV DNA titer are at greater risk of prophylaxis failure and need more intensive anti-viral prophylaxis. Prophylaxis failure Viral breakthrough Withdrawal hepatitis Cox model Fine and Gray Cox model Fine and Gray Cox model HR p-value HR p-value HR p-value HR p-value HR p-value Liver cirrhosis 1.193 0.72 1.132 0.76 0.722 0.630 0.692 0.54 7.39 0.0026 Rituximab 0.700 0.62 2.086 0.35 0.824 0.840 1.895 0.43 2.32 0.42 High serum HBV DNA titer 15.671 8.119 0.0001 14.179 0.003 5.509 0.018 7.16 0.0012 Hematologic malignancies 4.554 0.014 1.425 0.61 4.659 0.055 1.840 0.41 0.89 0.89 Disclosures: No relevant conflicts of interest to declare.

Patients with Hematologic Malignancies May Be at Higher Risk of Hepatitis B Reactivation in Spite of Lamivudine Prophylaxis.

Abstract 1389Poster Board I-411 Introduction:Although lamivudine (LMV) prophylaxis is recommended for chronic hepatitis B (HBV) patients undergoing cytotoxic chemotherapy for their malignant disease, viral reactivation sometimes occurs during or after LMV administration. Patients with solid tumors and hematologic malignancies may have different risk of HBV reactivation because hematologic malignancies require more intensive and immunosuppressive treatment. The aims of this study are to determine predictors of LMV prophylaxis failure and to evaluate the relative risk of failure in patients with hematologic malignancies. Patients and Methods:Cancer patients were routinely screened about serum hepatitis B surface antigen (HBsAg) before the initiations of chemotherapy. HBsAg-positive patients received LMV prophylaxis (100mg/day po) during the chemotherapy and for 1 to 6 months after the completion of chemotherapy. Serum HBV titer and alanine aminotransferase (ALT) level were followed at least every 3 months. Viral breakthrough during chemotherapy was defined as 10-fold or more elevation in serum HBV DNA titer above nadir regardless of serum ALT. Withdrawal hepatitis was defined as an increase of serum ALT more than upper normal limit accompanied by an elevation in serum HBV DNA titer more than that of the pre-exacerbation baseline. Either of viral breakthrough or withdrawal hepatitis was regarded as prophylaxis failure. Time to viral breakthrough was measured from the start of LMV, whereas time to withdrawal hepatitis was measured from the discontinuation of LMV. Time to prophylaxis failure was measured from the LMV initiation to either of viral breakthrough or withdrawal hepatitis. Kaplan-Meier method was used to generate survival curves of each event and log-rank test was employed to compare them. Patients were censored at death without viral reactivation or last follow-up. Cox proportional model was used to estimate the relative hazards ratio of each event in various subgroups. Death without HBV reactivation was regarded as a competing risk event and Fine and Gray model was used to adjust it. Results:One hundred eleven patients were enrolled and 28 patients had hematologic malignancies (non-Hodgkin lymphoma: 20, acute leukemia: 8). Remaining 83 patients had solid tumors such as gastric cancer, colorectal cancer, and lung cancer. Median follow-up duration was 22 (range 1.2-83.6) months and 30 patients experienced the prophylaxis failure (viral breakthrough: 15, withdrawal hepatitis: 15 patients). Log-rank test showed that liver cirrhosis, rituximab treatment, high serum HBV DNA titer (°Ã20,000 IU/ml), and hematologic malignancies were significant predictors (p <0.05), so that Cox proportional model was constructed using them. This model satisfied the assumption of proportional hazards and didn't constitute the mulicolinearity. In these models, high serum HBV DNA titer and hematologic malignancies were significant predictors of prophylaxis failure. High serum HBV DNA titer was also a significant predictor of viral breakthrough and hematologic malignancies were marginally significant. However, only high serum HBV DNA titer remained significant after Fine and Gray adjustment of a competing risk factor. Liver cirrhosis and high serum HBV DNA titer were significant predictors of withdrawal hepatitis. The model of withdrawal hepatitis didn't require Fine and Gray adjustment, because there was no death without viral reactivation after the discontinuation of LMV. Conclusions:Patients with hematologic malignancies or high serum HBV DNA titer are at greater risk of prophylaxis failure and need more intensive anti-viral prophylaxis.Prophylaxis failureViral breakthroughWithdrawal hepatitisCox modelFine and GrayCox modelFine and GrayCox modelHRp-valueHRp-valueHRp-valueHRp-valueHRp-valueLiver cirrhosis1.1930.721.1320.760.7220.6300.6920.547.390.0026Rituximab0.7000.622.0860.350.8240.8401.8950.432.320.42High serum HBV DNA titer15.671<0.00018.1190.000114.1790.0035.5090.0187.160.0012Hematologic malignancies4.5540.0141.4250.614.6590.0551.8400.410.890.89 Disclosures:No relevant conflicts of interest to declare.

Lamivudine Maintenance Beyond One Year After Hbeag Seroconversion Is A Major Factor for Sustained Virologic Response in Hbeag-Positive Chronic Hepatitis B

The reported durability of virologic response after successful lamivudine monotherapy is variable, and the question remains as to whether virologic responses can be maintained over an extended follow-up period. The aim of this study was to investigate posttreatment durability, the optimal duration of additional treatment after HBeAg clearance or seroconversion, and determinants for sustained virologic response (SVR) following lamivudine monotherapy in patients with HBeAg-positive chronic hepatitis B (CHB). From January 1999 to August 2004, 178 Korean patients with HBeAg-positive CHB were treated with lamivudine and achieved complete responses, defined as a loss of serum HBeAg and hepatitis B virus DNA, and alanine aminotransferase normalization. The mean duration of lamivudine monotherapy was 26 months (range, 12-77). SVR was maintained in 138 patients (77.5%). Host and viral factors were compared between 138 patients with SVR and 40 patients whose response was not sustained. The cumulative relapse rates increased from 15.9% at 1 year to 30.2% at 5 years, with a mean time to relapse after cessation of lamivudine of 12 months (range, 7-42). Most relapses occurred within 2 years after discontinuation of lamivudine (33/40, 82.5%). On multivariate analysis, age <or=40 years and additional treatment for more than 12 months after HBeAg clearance or seroconversion were independent factors for SVR. The lamivudine-induced virologic response was durable in patients under 40 years old and those receiving lamivudine for more than 12 months after HBeAg clearance or seroconversion. Age and additional treatment were major predictive factors for SVR.

Durability of Antiviral Response in HBeAg-Positive Chronic Hepatitis B Patients Who Maintained Virologic Response for One Year After Lamivudine Discontinuation

The purpose of this study is to determine the long-term relapse rate and associated risk factors in HBeAg-positive chronic hepatitis B (CHB) patients who had maintained virologic response (VR) for 1 year after lamivudine (LMV) discontinuation. We enrolled 55 treatment-naive HBeAg-positive CHB patients who achieved and maintained VR until 1 year after LMV discontinuation. Delayed relapse was defined as an elevation of HBV DNA after sustained VR for 1 year. During follow-up, 16 of 55 patients (29%) showed delayed relapse. Beginning 1 year after LMV discontinuation, the cumulative rates of relapse after 2 and 4 years were 29 and 44%, respectively. In multivariate analysis, age (P = 0.029) and >2,000 copies/ml HBV DNA 3 months after LMV discontinuation (P = 0.047) were significant predictors of delayed relapse. Delayed relapse is not infrequent, even in patients who maintain VR for 1 year after LMV discontinuation. Therefore, LMV maintenance therapy might be considered in HBeAg-positive CHB patients who achieve VR.

Long-Term follow-up of Lamivudine Treatment in Patients with Severe Acute Exacerbation of Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B

The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown. Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospectively recruited from 1999 to 2004 and treated with lamivudine. All patients had alanine aminotransferase (ALT) and serum bilirubin levels 10x and 3x above the upper limit of normal, respectively. HBeAg-positive patients without severe acute exacerbation served as controls. Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine for a median of 2.8 (range 1.0-7.1) years and 3.8 (range 3.5-8.4) years, respectively. Compared with controls, patients with severe acute exacerbation had higher HBeAg seroconversion rates (78% versus 52%; P=0.02) and lower risk of virological breakthrough. However, 33% of patients with severe acute exacerbation still developed lamivudine resistance and virological breakthrough by year 5. HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough. All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response. Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for > or =6 months, 11 (73%) had virological relapse at a median of 1.4 (0.2-3.9) years. ALT increased beyond 10x the upper limit of normal in six (38%) patients who stopped lamivudine and two (7%) patients on maintained lamivudine treatment (P=0.02). Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine, virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion. Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine.

Risk of Hepatitis B and Efficacy of Treatment with Lamivudine in Patients Undergoing Allogeneic Stem Cell Transplant.

Hepatitis B virus (HBV) positive patients undergoing allogeneic stem cell transplantation (allo-SCT) and recipients of allo-SCT from HBV positive donors are at risk of hepatitis reactivation and fatal liver failure. Prophylaxis with lamivudine (LAM) in this setting is still unclear. Since 2005 patients undergoing allo-SCT at risk of HBV reactivation at our Center were treated with LAM prophylaxis to prevent hepatitis B reactivation. Ninety-seven patients undergoing allo-SCT between 1999 and 2007 entered the study. Only 84 patients with a follow-up longer than 3 months (median 17 months, range 3–87) were analysed. Patients, median age of 51 years (21–66), were transplanted for multiple myeloma (50), acute myeloid leukemia (14), chronic lymphatic leukemia (8), lymphoma (7), chronic myeloproliferative disease (4) and aplastic anemia (1). The conditioning regimens consisted of busulfan-cyclophosphamide (7), thiothepa-cyclophosphamide (11), and 2 Gy total body irradiation +/− fludarabine (64); 2 patients received 2 allo-SCT from the same donor for disease progression. Stem cell source was peripheral blood in 83 patients and bone marrow in 1. Sixty-five patients had a HLA-matched sibling donor and 19 an unrelated donor. Sixty subjects were not considered at risk of HBV reactivation (recipients hepatitis B surface antigen -HBsAg- and anti-hepatitis B core antigen antibodies -antiHBc- negative, with donors HBsAg-negative). Of note, 4 donors were antiHBc-positive. None of them experienced HBV related hepatitis during follow-up. The other 24 patients were considered at risk and divided in 3 groups: Group A: 2 HBsAg-negative recipients from HBsAg-positive donors; Group B: 1 HBsAg-positive recipient from negative donor; Group C: 21 antiHBc-positive recipients from 5 positive and 16 negative donors. Group A: Recipients were treated with LAM. None of them developed hepatitis B at a follow up of 24 and 18 months, respectively, and serum HBV-DNA remained undetectable. Group B: One patient with pre-transplant HBV-DNA of 19500 UI/mL received LAM. HBV-DNA became negative 3 months after allo-SCT and the patient did not develop acute hepatitis after a follow-up of 10 months. Group C: Twelve patients were not treated and 9 received prophylactic LAM for a median time of 11 months (range 6–29). Of these, one discontinued LAM after 8 months due to intolerance. Hepatitis developed in 3 untreated patients (2 patients undergoing allo-SCT before 2005 and 7 months after LAM discontinuation in the subject who stopped prophylactic LAM) and in none of the patients on prophylaxis. No detectable serum HBV-DNA was observed in patients on LAM prophylaxis. Two/3 patients with hepatitis received allo-SCT from antiHBc-negative donors. In conclusions, this retrospective study confirms:1.a null risk of hepatitis B in HBsAg and antiHBc-negative recipients, transplanted with HBsAg-negative donors, regardless of donor's antiHBc serology;2.a significant (23%) risk of hepatitis B in antiHBc-positive recipients from negative donors, untreated with prophylactic LAM;3.the efficacy of prophylactic LAM in HBsAg-negative and antiHBc-positive recipients;4.the efficacy of LAM in controlling HBV replication and hepatitis B reactivation in both HBsAg-positive recipients from negative donors and in HBsAg-positive donors used in negative recipients.

Efficacy of adefovir dipivoxil in the treatment of lamivudine‐resistant hepatitis B virus genotype C infection

Adefovir dipivoxil (ADV) is a nucleotide analogue that is known to be effective for lamivudine-resistant hepatitis B virus (HBV) mutants as well as wild-type HBV. The aim of this study is to assess the efficacy of ADV against lamivudine-resistant genotype C HBV mutants. Thirty-five patients with breakthrough hepatitis due to lamivudine-resistant HBV received ADV 10 mg daily with discontinuation of lamivudine. Quantitative HBV DNA, HBeAg, liver function test including alanine aminotransferase (ALT) was checked every 4-12 weeks to evaluate the efficacy of ADV. ADV was administered for a median of 48 weeks (range: 24-120 weeks). The rate of serum HBV DNA loss was 68.6%, 80.0%, 84.0%, and 88.2% at weeks 12, 24, 36, and 48, respectively. The rate of serum HBeAg seroconversion was 8.3% and 14.3% at weeks 24 and 48, respectively. The rate of serum ALT normalization at week 48 was 70.6%. Within 32 weeks after stopping ADV therapy, serum HBV DNA levels increased to a median of 378.9 pg/ml in 88.9% of patients, who were treated for a median of 40 weeks. Moreover, in some patients, the ALT level increased to more than five times the upper limit of normal. Administration of ADV is an effective option for the treatment of patients with lamivudine-resistant genotype C HBV infection.

A prophylactic approach for bone marrow transplantation from a hepatitis B surface antigen-positive donor

It has been accepted that bone marrow transplantation (BMT) is the only curative therapeutic option for certain hematologic malignancies. The southeast Asia region is an endemic area of hepatitis B virus (HBV) infection; thus, BMT using a hepatitis B surface antigen (HBsAg)-positive donor is occasionally unavoidable. Organ transplantation using a HBsAg-positive donor can lead to post-transplantation de novo HBV infection and severe HBV-related hepatitis if no effective prophylactic measures are taken prior to and after transplantation. In this report, a four-level approach was designed for a patient with chronic myeloid leukemia, beginning with a booster HBV vaccination before performing BMT with a HBsAg-positive donor. Prior to BMT, the HBV viral load of the donor was reduced to an undetectable level by antiviral therapy. After BMT, hepatitis B immunoglobulin was administered intramuscularly for 1 wk together with a long-term antiviral drug, lamivudine. One year after discontinuation of lamivudine, the patient is still free of HBV infection.

Discontinuation of lamivudine treatment for hepatitis flare after kidney or heart transplantation in hepatitis B surface antigen-positive patients: A retrospective case series

Background: Limited data are available on the clinical course of hepatitis B virus (HBV) infection after discontinuation of lamivudine prescribed for kidney or heart posttransplantation hepatitis flare Objective: The purpose of this study was to investigate the reasons for discontinuation, subsequent reappearance of HBV DNA, and mortality in heart and kidney transplant recipients who discontinued lamivudine treatment. Methods: This retrospective case series followed up male and female hepatitis B surface antigen (HBsAg)-positive Taiwanese transplant recipients from the National Taiwan University Hospital, Taipei, Taiwan, between July 1989 and January 1999. Biochemical, virologic, and serologic parameters and liver-related mortality of patients who discontinued lamivudine 100 mg QD prescribed for posttransplantation hepatitis flare were compared with those in a group of patients who continued use of lamivudine administered for the same indication over the same period of time. Serum HBV DNA levels were checked in all patients before and after discontinuation of lamivudine, and after resumption of lamivudine treatment and in patients with breakthrough hepatitis flare. Results: A total of 39 HBsAg-positive transplant recipients (mean [SD] age, 45 [10.0] years) were identified during regular follow-up visits. Nine patients discontinued lamivudine use; 11 patients who continued it were selected as a control group. No significant between-group differences were observed in mean (SD) age (46 [14.0] vs 45 [6.9] years), sex (men/women,vs 1), type of transplant received (heart/kidney,vs ), or pretransplantation liver function test results. The reasons for discontinuation were informed patient decision (4 patients); YMDD mutation (2); self-discontinuation without physician consultation (2); and pregnancy (1). Of those who discontinued lamivudine, serum HBV DNA was undetectable at a mean of 30 (range, 9–47) months' follow-up in 6 (66.7%) of 9 patients. Lamivudine treatment was resumed in 3 patients on reappearance of HBV DNA, and a subsequent rapid decline in the serum HBV DNA was observed. The liver-related mortality rate was not significantly higher in patients who discontinued treatment compared with continuously treated patients (both, 0%). The between-group difference in overall mortality rates was not significant (22.2% and 18.2%, respectively). Conclusions: This case series illustrated a variety of clinical situations in which discontinuation of lamivudine treatment prescribed for posttransplantation hepatitis flare may occur. However, liver-related mor tality was not increased in these patients compared with those who continued lamivudine treatment.