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W1799 Preemptive Adefovir Dipivoxil in Chronic Hepatitis B Patients Undergoing Chemotherapy Is Associated with Fewer Hepatitis B Virological Resistance Mutations Compared with the Use of Lamivudine
any known liver disease such as hepatitis virus infection, autoimmune liver disease, alcohol abuse, hemochromatosis or NASH. They were distributed into three groups by age: the <70 y.o. group (n=22), the 70-79 y.o. group (n=24), and the ≧80 y.o. group (n=10). Results: Women accounted for 27% of patients in <70 y.o. group, 13% in 71-79 y.o., and 10% in the ≧80 y.o.. The rate of obesity (body mass index>25) was 41, 38, and 10% (p<0.05) respectively; that of DM was 68, 67, and 40% (p<0.05), for dyslipidemia it was 14, 26, and 0%, for hypertension it was 32, 50, and 40%, respectively; the ratio of patients investigated for the presence of liver disease prior to the diagnosis of HCC was 55, 42, and 0% (p<0.05); and 55, 38, and 0% (p<0.05) of the patients were diagnosed as having cirrhosis. Laboratory tests showed no differences among the three groups in total bilirubin level (0.9, 0.6, and 0.4 mg/dL), γGPT (67, 37, and 30 IU/L), ALT (40, 24, and 17 IU/L), alphafetoprotein increase (45, 54, and 60%), or des-γ-carboxyl prothrombin increase (50, 63, and 50%). The albumin level was 3.4, 3.4, and 4.0 g/dL (p<0.05) and platelet count was 13, 16 and 24 x10000/μL (p<0.05). Seropositivity for HbcAb was 27, 21, and 38% and that for ANA was 9, 8 and 25%. The ratio of patients with a single nodule at the initial diagnosis of HCC was 64, 75, and 80%; the main tumor diameter (median) was 30, 40 and 60 mm in median. Non-cancerous liver tissue was investigated in 64, 58 and 40% of the cases; and cirrhosis was detected in 64, 50 and 0% (p<0.05) of them. Conclusions: The frequency of DM, obesity and cirrhosis was significantly low in the ≧80 y.o group of patients. Given the lack of risk factors in this age group, age may be the most important risk factor for HCCs in elderly subjects.
log-rank). Of these patients with virological breakthrough, 8 of 13 (53.8%) on LAM compared with 0 of 10 (0%) on ADV had drug resistance mutations (p=0.012 by log-rank). There was no difference in HBV related hepatitis between the LAM and ADV [1/35 (2.9%) vs. 2/ 35 (5.7%), p=0.805 by log-rank]. Mortality was similar between the two groups [11/35 (31.4%) vs. 11/35 (31.4%) respectively, p=0.523 by log-rank]. Both drugs were well tolerated and no patients in the ADV group developed a 10% increase in serum creatinine. Conclusion: The use of ADV is of similar efficacy and safety as LAM as preemptive therapy for HBsAg positive patients treated with chemotherapy. However, significantly fewer virological breakthrough due to resistance mutations developed in patients treated with ADV. W1800 Association Between HBV Replication and Serum ALT Changes Is Not Dependent On HBV Genotype and Mutants Hwai-I Yang, Uchenna H. Iloeje, Jun Su, Chin-Lan Jen, San-Lin You, Chien-Jen Chen Background and aims: We previously showed that elevated serum HBV DNA predicts future changes in serum ALT level, which in turn is associated with CHB disease progression. We explore the impact of the HBV genotype and specific gene mutations on this association. Methods: This analysis used a sub-group of the REVEAL-HBV study participants who had normal serum ALT level at baseline (<45 U/L), and had at least 3 ALT tests during followup. Serum ALT elevation (≧45 U/L) during follow-up was the outcome of interest. Multiple logistic regression was used to derive multivariate-adjusted odds ratio (ORadj) and 95% confidence interval (CI) for risk factors associated with the outcome. Baseline ALT was categorized as <15 and 15-44. The model was adjusted for HBV genotypes B, C or B+C, and precore 1896 and basal core promoter 1762/1764 mutations. Results: There were 1986 subjects in the cohort with normal baseline ALT level and ≧ 3 ALT measurements during follow-up. Of these, 854 subjects (43%) contributed 10,354 PYFU, and had enough DNA sample for complete description of the genotype and the mutations of interest. 320/854 subjects (37.5%) had at least one ALT elevation documented during follow-up. Male gender, baseline HBV DNA level, and baseline serum ALT level were significantly associated with future ALT elevation. The ORadj (95% CI) were: Male gender 2.63 (1.67-4.14); baseline ALT level 15-44 1.39 (1.01-1.91); serum HBV DNA level 300-9,999, 10,000-99,999, 100,000999,999 and ≧1 million copies/mL, 0.77 (0.34-1.75), 2.27 (1.05-4.92), 4.56 (2.10-9.89), and 5.53 (2.36-12.94), respectively compared to <300 copies/mL. Test of trend for HBV DNA level was highly significant (P<0.0001). HBV genotype, precore G1896A, and basal core promoter A1762T/G1764A mutants did not predict serum ALT elevation. Conclusions: The association between serum HBV DNA viral load and elevation of ALT level remains the same even after adjusting for HBV genotype or the presence of specific gene mutations in this cohort. Abstract submitted on behalf of The R.E.V.E.A.L.-HBV Study Group.
AASLD Abstracts
W1798 A Phase III Safety and Efficacy Study to Compare Immune Responses Following Either Two Doses of Hepatitis B Surface Antigen Combined with Immunostimulatory Phosphorotioate Oligonucleotide (HBsAg-Iss) or Three Doses of Conventional Hepatitis B Vaccine Scott A. Halperin, Francisco Diaz-Mitoma, Maria Lucia Pecoraro Background: The current licensed Hepatitis B virus (HBV) vaccines contain HBsAg adjuvanted with aluminum hydroxide. Their use is hindered by the requirement for three doses usually over a six-month period. HBsAg-ISS, a vaccine that contains a new class of adjuvant (1018 ISS), a Toll-like Receptor 9 (TLR-9) agonist, has demonstrated 100% seroprotection after a short regimen of only 2 injections in young adults 18-55 years of age. Objective: To compare the proportion of subjects who exhibit seroprotective immune response (SPR - anti-HBsAg antibodies ≥ 10 mIU/mL by Ortho ECi) after 2 doses of HBsAg-ISS administered at 0 and 1 month to the proportion of subjects who exhibit SPRs after 3 doses of licensed HBV vaccine administered at 0, 1 and 6 months among adults 18 to 55 years of age. Methods: This was a randomized, observer-blind study where healthy adults received two injections of HBsAg-ISS, at 0 and 1 month or three injections of licensed HBV vaccine at 0,1 and 6 months. The primary immunogenicity endpoint was the SPR rate 2 months after the last dose of HBsAg-ISS and 1 month after the last dose of licensed HBV vaccine. These endpoints represent the overall seroprotective effect for each group. Geometric mean antibody concentrations were a secondary immunogenicity outcome. The primary hypothesis was that the HBsAg-ISS vaccine was non-inferior to the licensed vaccine as defined as the lower bound of the 95% CI on the difference in SPR exceeding 0.1. Results: 2427 subjects enrolled in this study. Subjects were randomized in a ratio of 3:1 to HBsAg-ISS (n=1819) and licensed HBV vaccine (n=608). Approximately 43% of the subjects were between the ages of 18 and 40 while 57% were greater than 40. The distribution of subjects across these two categories was similar for the two vaccination groups. The number of subjects excluded from the per protocol analysis was similar for the two vaccination groups (14% for HBsAg-ISS and 12% for the licensed HBV vaccine group); most exclusions from both groups were the result of having primary serology sample outside visit window. The percentage of subjects exhibiting a seroprotective immune response at the primary timepoint was 95.1% for HBsAg-ISS and 81.1% for subjects receiving licensed HBV vaccine; the difference in SPR between the two groups was 13.8 %( 95% CI, 10.5% and 17.5%) indicating non-inferiority of the HBsAGISS vaccine. Geometric mean antibody concentrations were 138.2 for the HBsAg-ISS vaccine at week 12 and 347.8 for the licensed vaccine at week 28. Conclusions: This study successfully demonstrated that a short, two-dose regimen of HBsAg-ISS is non inferior to the current three-dose regimen.
W1801 Prevalence of HBsAg in Peru: A Population Based Survey in Urban and Amazonian Communities Cesar P. Carcamo, Carlos Appiani, Patricia J. Garcia, Raul Gutierrez, Nancy Cure-Bolt, Marina Chiappe, Antonio Bernabe, Armando Cotrina, Roberto Orellana, Isaac Alva, Marco A. Gonzales, Geoff P. Garnett, King K. Holmes Background: Hepatitis B is a preventable infection that can lead to severe liver complications and death. Few studies have determined the prevalence of Hepatitis B Virus (HBV) infection based on population surveys.In Peru, a wide prevalence of positive hepatitis B surface antigen (HBsAg) has been described (0.7% - 26%)in many small reports. We conducted a study to determine the prevalence of HBsAg in 31 Peruvian cities and 27 native communities in the Amazon jungle. Methods: The Andes determine three regions in Peru. Cities on the coastal lowlands, west of the Andes are in general more modern than Andean cities, where colonial traditions are maintained. East of the Andes, in the Amazonian basin, cities tend to be more liberal. The study includes 16 coastal, 9 Andean, and 6 Amazonian cities. As part of a large community randomized trial of STD prevention, the PREVEN study, men and women 18 to 29 years old were randomly selected for participation by means of multistage cluster sampling. Questionnaire data and blood specimens were collected from each consenting participant at their households. For the determination of HBV infection, serum was screened by HBsAg II Test (Roche®), with confirmation by neutralization using the HbsAg (Roche®). Results: Serum was obtained from 12,516 participants, including 4,897 (39%) males and 7,619 (61%) females. Serum from rural communities represented 5% (638) of the sample. Mean age was 23 years, but on average men in the sample were 0.8 years older than females. HBsAg test was indeterminate in one sample and reactive in 50 for an overall prevalence of 0.4%. Prevalence of HBV infection was higher in men (0.59%) than in women (0.28%, p=0.008), but did not vary significantly with age. Across cities, prevalence ranged from 0% to 1.55% in the 31 urban settings, with an overall prevalence of 0.28% (33/11,877). A higher prevalence was found in Amazonian cities, as compared to Andean and coastal cities. In the rural native communities HBsAg prevalence was 2.66% (17/638), almost 10 times higher than in urban settings. Conclusion: Our study shows that although the overall prevalence among young adults (0.42%) was less than that expected from earlier studies, it is higher in the Amazonian communities (2.66%). The study was not designed to explore known risk factors for hepatitis B transmission, but we believe that this difference may in part reflect the lack of access to proper medical services for prevention in these communities.
W1799 Preemptive Adefovir Dipivoxil in Chronic Hepatitis B Patients Undergoing Chemotherapy Is Associated with Fewer Hepatitis B Virological Resistance Mutations Compared with the Use of Lamivudine Edith Y. Ho, Lei Lu, April Wong, Thomas Yau, Franck Rousseau, Jenny Heathcote, George K. Lau Background: Hepatitis B virus (HBV) reactivation is a serious cause of morbidity and mortality in hepatitis B surface antigen (HBsAg) positive patients treated with chemotherapy. Although the use of preemptive lamivudine (LAM) may reduce chemotherapy induced HBV reactivation, the use of LAM is associated with a risk of developing LAM resistance mutation. (Lau, Hepatology 2002) Aim: To compare the efficacy of LAM vs. adefovir dipivoxil (ADV) in preventing HBV reactivation in chronic HBV patients treated with chemotherapy for malignancy. Methods: Seventy HBsAg positive cancer patients (19 lower GI solid tumours, 18 head and neck tumours, 13 lymphoma, 7 lung, 4 breast, 4 upper GI solid tumours, 3 leukemia, 2 others) were randomized 1:1 to receive LAM 100 mg daily or ADV 10 mg daily one week before initiating chemotherapy which continued for at least six months postchemotherapy. Serum HBV DNA was measured with the Abbott HBV DNA assay every four weeks. All patients with viral breakthrough (≥1 log increase in serum HBV DNA) were screened for drug resistance mutations by direct sequencing. HBV related hepatitis was defined as serum alanine aminotransaminase ≥2 times upper limit of normal with ≥1 log increase in HBV DNA. Results: The median (range) baseline HBV DNA was 3.36 (1.4910.96) on LAM and 3.16 (1.49-8.59) log10 copies/mL on ADV (p=0.475). The median (range) of duration on LAM and ADV respectively was 9.0 (0.1-20.0) vs. 11.6 (0.6-23.6) months respectively (p=0.512). At the time of analysis, 13 of the 35 patients (37.1%) on LAM compared with 10 of 35 (28.6%) on ADV had virological breakthrough (p=0.037 by
AASLD Abstracts
A-864
log-rank). Of these patients with virological breakthrough, 8 of 13 (53.8%) on LAM compared with 0 of 10 (0%) on ADV had drug resistance mutations (p=0.012 by log-rank). There was no difference in HBV related hepatitis between the LAM and ADV [1/35 (2.9%) vs. 2/ 35 (5.7%), p=0.805 by log-rank]. Mortality was similar between the two groups [11/35 (31.4%) vs. 11/35 (31.4%) respectively, p=0.523 by log-rank]. Both drugs were well tolerated and no patients in the ADV group developed a 10% increase in serum creatinine. Conclusion: The use of ADV is of similar efficacy and safety as LAM as preemptive therapy for HBsAg positive patients treated with chemotherapy. However, significantly fewer virological breakthrough due to resistance mutations developed in patients treated with ADV. W1800 Association Between HBV Replication and Serum ALT Changes Is Not Dependent On HBV Genotype and Mutants Hwai-I Yang, Uchenna H. Iloeje, Jun Su, Chin-Lan Jen, San-Lin You, Chien-Jen Chen Background and aims: We previously showed that elevated serum HBV DNA predicts future changes in serum ALT level, which in turn is associated with CHB disease progression. We explore the impact of the HBV genotype and specific gene mutations on this association. Methods: This analysis used a sub-group of the REVEAL-HBV study participants who had normal serum ALT level at baseline (<45 U/L), and had at least 3 ALT tests during followup. Serum ALT elevation (≧45 U/L) during follow-up was the outcome of interest. Multiple logistic regression was used to derive multivariate-adjusted odds ratio (ORadj) and 95% confidence interval (CI) for risk factors associated with the outcome. Baseline ALT was categorized as <15 and 15-44. The model was adjusted for HBV genotypes B, C or B+C, and precore 1896 and basal core promoter 1762/1764 mutations. Results: There were 1986 subjects in the cohort with normal baseline ALT level and ≧ 3 ALT measurements during follow-up. Of these, 854 subjects (43%) contributed 10,354 PYFU, and had enough DNA sample for complete description of the genotype and the mutations of interest. 320/854 subjects (37.5%) had at least one ALT elevation documented during follow-up. Male gender, baseline HBV DNA level, and baseline serum ALT level were significantly associated with future ALT elevation. The ORadj (95% CI) were: Male gender 2.63 (1.67-4.14); baseline ALT level 15-44 1.39 (1.01-1.91); serum HBV DNA level 300-9,999, 10,000-99,999, 100,000999,999 and ≧1 million copies/mL, 0.77 (0.34-1.75), 2.27 (1.05-4.92), 4.56 (2.10-9.89), and 5.53 (2.36-12.94), respectively compared to <300 copies/mL. Test of trend for HBV DNA level was highly significant (P<0.0001). HBV genotype, precore G1896A, and basal core promoter A1762T/G1764A mutants did not predict serum ALT elevation. Conclusions: The association between serum HBV DNA viral load and elevation of ALT level remains the same even after adjusting for HBV genotype or the presence of specific gene mutations in this cohort. Abstract submitted on behalf of The R.E.V.E.A.L.-HBV Study Group.
AASLD Abstracts
W1798 A Phase III Safety and Efficacy Study to Compare Immune Responses Following Either Two Doses of Hepatitis B Surface Antigen Combined with Immunostimulatory Phosphorotioate Oligonucleotide (HBsAg-Iss) or Three Doses of Conventional Hepatitis B Vaccine Scott A. Halperin, Francisco Diaz-Mitoma, Maria Lucia Pecoraro Background: The current licensed Hepatitis B virus (HBV) vaccines contain HBsAg adjuvanted with aluminum hydroxide. Their use is hindered by the requirement for three doses usually over a six-month period. HBsAg-ISS, a vaccine that contains a new class of adjuvant (1018 ISS), a Toll-like Receptor 9 (TLR-9) agonist, has demonstrated 100% seroprotection after a short regimen of only 2 injections in young adults 18-55 years of age. Objective: To compare the proportion of subjects who exhibit seroprotective immune response (SPR - anti-HBsAg antibodies ≥ 10 mIU/mL by Ortho ECi) after 2 doses of HBsAg-ISS administered at 0 and 1 month to the proportion of subjects who exhibit SPRs after 3 doses of licensed HBV vaccine administered at 0, 1 and 6 months among adults 18 to 55 years of age. Methods: This was a randomized, observer-blind study where healthy adults received two injections of HBsAg-ISS, at 0 and 1 month or three injections of licensed HBV vaccine at 0,1 and 6 months. The primary immunogenicity endpoint was the SPR rate 2 months after the last dose of HBsAg-ISS and 1 month after the last dose of licensed HBV vaccine. These endpoints represent the overall seroprotective effect for each group. Geometric mean antibody concentrations were a secondary immunogenicity outcome. The primary hypothesis was that the HBsAg-ISS vaccine was non-inferior to the licensed vaccine as defined as the lower bound of the 95% CI on the difference in SPR exceeding 0.1. Results: 2427 subjects enrolled in this study. Subjects were randomized in a ratio of 3:1 to HBsAg-ISS (n=1819) and licensed HBV vaccine (n=608). Approximately 43% of the subjects were between the ages of 18 and 40 while 57% were greater than 40. The distribution of subjects across these two categories was similar for the two vaccination groups. The number of subjects excluded from the per protocol analysis was similar for the two vaccination groups (14% for HBsAg-ISS and 12% for the licensed HBV vaccine group); most exclusions from both groups were the result of having primary serology sample outside visit window. The percentage of subjects exhibiting a seroprotective immune response at the primary timepoint was 95.1% for HBsAg-ISS and 81.1% for subjects receiving licensed HBV vaccine; the difference in SPR between the two groups was 13.8 %( 95% CI, 10.5% and 17.5%) indicating non-inferiority of the HBsAGISS vaccine. Geometric mean antibody concentrations were 138.2 for the HBsAg-ISS vaccine at week 12 and 347.8 for the licensed vaccine at week 28. Conclusions: This study successfully demonstrated that a short, two-dose regimen of HBsAg-ISS is non inferior to the current three-dose regimen.
W1801 Prevalence of HBsAg in Peru: A Population Based Survey in Urban and Amazonian Communities Cesar P. Carcamo, Carlos Appiani, Patricia J. Garcia, Raul Gutierrez, Nancy Cure-Bolt, Marina Chiappe, Antonio Bernabe, Armando Cotrina, Roberto Orellana, Isaac Alva, Marco A. Gonzales, Geoff P. Garnett, King K. Holmes Background: Hepatitis B is a preventable infection that can lead to severe liver complications and death. Few studies have determined the prevalence of Hepatitis B Virus (HBV) infection based on population surveys.In Peru, a wide prevalence of positive hepatitis B surface antigen (HBsAg) has been described (0.7% - 26%)in many small reports. We conducted a study to determine the prevalence of HBsAg in 31 Peruvian cities and 27 native communities in the Amazon jungle. Methods: The Andes determine three regions in Peru. Cities on the coastal lowlands, west of the Andes are in general more modern than Andean cities, where colonial traditions are maintained. East of the Andes, in the Amazonian basin, cities tend to be more liberal. The study includes 16 coastal, 9 Andean, and 6 Amazonian cities. As part of a large community randomized trial of STD prevention, the PREVEN study, men and women 18 to 29 years old were randomly selected for participation by means of multistage cluster sampling. Questionnaire data and blood specimens were collected from each consenting participant at their households. For the determination of HBV infection, serum was screened by HBsAg II Test (Roche®), with confirmation by neutralization using the HbsAg (Roche®). Results: Serum was obtained from 12,516 participants, including 4,897 (39%) males and 7,619 (61%) females. Serum from rural communities represented 5% (638) of the sample. Mean age was 23 years, but on average men in the sample were 0.8 years older than females. HBsAg test was indeterminate in one sample and reactive in 50 for an overall prevalence of 0.4%. Prevalence of HBV infection was higher in men (0.59%) than in women (0.28%, p=0.008), but did not vary significantly with age. Across cities, prevalence ranged from 0% to 1.55% in the 31 urban settings, with an overall prevalence of 0.28% (33/11,877). A higher prevalence was found in Amazonian cities, as compared to Andean and coastal cities. In the rural native communities HBsAg prevalence was 2.66% (17/638), almost 10 times higher than in urban settings. Conclusion: Our study shows that although the overall prevalence among young adults (0.42%) was less than that expected from earlier studies, it is higher in the Amazonian communities (2.66%). The study was not designed to explore known risk factors for hepatitis B transmission, but we believe that this difference may in part reflect the lack of access to proper medical services for prevention in these communities.
W1799 Preemptive Adefovir Dipivoxil in Chronic Hepatitis B Patients Undergoing Chemotherapy Is Associated with Fewer Hepatitis B Virological Resistance Mutations Compared with the Use of Lamivudine Edith Y. Ho, Lei Lu, April Wong, Thomas Yau, Franck Rousseau, Jenny Heathcote, George K. Lau Background: Hepatitis B virus (HBV) reactivation is a serious cause of morbidity and mortality in hepatitis B surface antigen (HBsAg) positive patients treated with chemotherapy. Although the use of preemptive lamivudine (LAM) may reduce chemotherapy induced HBV reactivation, the use of LAM is associated with a risk of developing LAM resistance mutation. (Lau, Hepatology 2002) Aim: To compare the efficacy of LAM vs. adefovir dipivoxil (ADV) in preventing HBV reactivation in chronic HBV patients treated with chemotherapy for malignancy. Methods: Seventy HBsAg positive cancer patients (19 lower GI solid tumours, 18 head and neck tumours, 13 lymphoma, 7 lung, 4 breast, 4 upper GI solid tumours, 3 leukemia, 2 others) were randomized 1:1 to receive LAM 100 mg daily or ADV 10 mg daily one week before initiating chemotherapy which continued for at least six months postchemotherapy. Serum HBV DNA was measured with the Abbott HBV DNA assay every four weeks. All patients with viral breakthrough (≥1 log increase in serum HBV DNA) were screened for drug resistance mutations by direct sequencing. HBV related hepatitis was defined as serum alanine aminotransaminase ≥2 times upper limit of normal with ≥1 log increase in HBV DNA. Results: The median (range) baseline HBV DNA was 3.36 (1.4910.96) on LAM and 3.16 (1.49-8.59) log10 copies/mL on ADV (p=0.475). The median (range) of duration on LAM and ADV respectively was 9.0 (0.1-20.0) vs. 11.6 (0.6-23.6) months respectively (p=0.512). At the time of analysis, 13 of the 35 patients (37.1%) on LAM compared with 10 of 35 (28.6%) on ADV had virological breakthrough (p=0.037 by
AASLD Abstracts
A-864