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M1910 Tenofovir Disoproxil Fumarate (TDF) Is Highly Active for Treatment of Chronic Hepatitis B in Subjects with Cirrhosis
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One hundred and twelve subjects originally randomized to ADV initiated TDF at WK48; 35 subjects had HBV DNA > 400 c/mL just prior to switching to TDF. At WK72 after 24 weeks of TDF, 108/112 subjects had HBV DNA < 400 c/mL; 33 of the 35 viremic subjects and 75 of 77 subjects with HBV DNA <400 c/mL at week 48. Two subjects had HBV DNA >400 c/mL and 2 subjects were missing data at WK72. For subjects treated with TDF during the first 48 weeks, 235 subjects continued TDF and 15 did not (10/15 subjects had HBV DNA <400 c/mL at their last visit): 6 discontinued (DC) prior to WK48 and 9 did not enter the study extension (5 refused WK48 biopsy, 2 withdrew consent, 2 subjects were at sites that did not participate in the study extension). At WK72, 222 subjects had HBV DNA <400 c/mL, 4 subjects had HBV DNA >400 c/mL and HBV DNA data were missing for 9 subjects (8 of whom had HBV DNA <400 c/mL at their last visit). TDF was well tolerated through WK72. Conclusion: Continuous therapy with TDF past 48 weeks produced additional viral suppression. A switch to TDF after 48 weeks of ADV treatment produced significant additional viral suppression. Tolerability of TDF for 72 weeks was good.
AASLD Abstracts
Analysis of Factors Affecting HBeAg Early Seroconversion to anti-HBe in Acute Exacerbation of HBeAg Positive Chronic Hepatitis B with Genotype C; a Prospective Study Hyoung Su Kim, Ji Won Park, Ji Sun Jang, Woon Geon Shin, Kyung Ho Kim, Jin Heon Lee, Hak Yang Kim, Myoung Kuk Jang Background/aims: Acute exacerbation (AE), abruptly elevated alanine aminotransferase (ALT) levels, were associated with a high chance of HBeAg seroconversion in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (HBeAg+ CHB), but seroconversion rates were lower in genotype C. To date, there were no studies about the predictors for HBeAg early seroconversion among only patients under AE with genotype C HBV infection. This study was performed to identify the predictive factors for HBeAg early seroconversion during AE of HBeAg+ CHB with genotype C. Methods: A total of 124 patients who experienced AE during follow-up of HBeAg+ CHB were prospectively enrolled. AE and severe AE (SAE) were defined as elevations of ALT to more than 5 times the upper limit of normal (ULN) and 10 times ULN with more than twice the patients' baseline values, respectively. HBeAg early seroconversion was defined as “HBeAg loss and anti-HBe appearance within 6 months after AE”. Clinical and laboratory data such as age, gender, transmission modes, the existence of cirrhosis, serum HBV DNA levels, and other biochemistry were analyzed. HBV was genotyped by RFLP. Various parameters were compared between early seroconversion group and nonseroconversion group using univariate and multivariate analyses. Results: After excluding 33 patients who were not followed up for at least 6 months or took anti-viral therapy before AE, remained 91 patients were analyzed. All HBVs were genotype C. Early seroconversion occurred in 35% (32/91). On univariate analysis, transmission mode (P=0.03), the existence of cirrhosis (P=0.04) and serum HBV DNA levels (P=0.001) and anti-viral therapy after AE (P=0.03) were significantly associated with early seroconversion. Age (P=0.1), gender (P= 0.8) and serum ALT levels (AE vs. SAE, P=0.08) during AE were not associated with early seroconversion. On multivariate analysis, transmission mode (non-vertical vs. vertical; RR= 3.696, 95% CI; 1.019-13.398, P=0.047) and serum HBV DNA levels (<5x7Log vs. ≥5x7Log copies/ml; RR=4.294, 95% CI; 1.500-12.294, P=0.007) were significant independent factors for predicting early seroconversion. Conclusions: Non-vertical transmission and low serum HBV DNA levels (less than 5x7Log copies/ml) were independent factors favoring for HBeAg early seroconversion. Therefore, we should take into account the transmission modes and HBV DNA levels to select the managing strategies such antiviral therapies in AE of HBeAg + CHB with genotype C.
M1909 Will Interferon and Anti-Viral Therapy Reduce Risk of HBV-Related Liver Cancer? Joseph J. Sung, Kelvin K. Tsoi, Kevin C. Li, Vincent W. Wong, Henry Lik-Yuen Chan Background: Chronic hepatitis B infection (CHB) increases the risk of hepatocellular carcinoma by nearly 100 fold. Objective: We studied effects of interferon (IFN) or nucleoside/ tide analog (NA) on the risk of developing HCC in CHB patients Method: Full publications and abstracts from MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects, and the International Pharmaceutical Abstracts were retrieved. Abstracts published in international conferences over the past 10 years were also manually searched. Both randomized controlled trials and case-control studies were included. Subgroup analysis were conducted to investigate the effects of cirrhosis, HBeAg status and drug resistance on HCC risk reduction. Result: 12 studies enrolling patients treated by IFN (n=1,292) versus control (n=1,450) showed that the overall risk of HCC after treatment was reduced by 34% (RR 0.66, 95%CI 0.48-0.89). Benefit is more significant among patients with early cirrhosis (RR 0.53, 95%CI 0.36-0.78) than those without (RR 0.72, 95%CI 0.16-3.15, p=0.66). Four studies compared the risk of HCC development after using NA (n=1,125) versus control (n=898). The overall risk of HCC after treatment was reduced by 78% (RR 0.22, 95%CI 0.09-0.53). HBeAg positive patients showed more significant reduced HCC risk with treatment (RR 0.20, 95%CI 0.09-0.45). Patients with no cirrhosis benefited more from the treatment (RR 0.21, 95%CI 0.10-0.47) than those with early cirrhosis. Resistance to NA has obviated the benefit of the treatment. Conclusion: Long term follow up shows IFN and NA treatment significantly reduce the risk of HCC.
M1907 Efficacy of Entecavir in Nucleoside-NaïVe Patients with Mildly Elevated ALT Stuart C. Gordon, Steven-Huy B. Han, Ting-Tsung Chang, Ching Lung Lai, Kwang-Hyub Han, You Chen Chao, Chee-Kiat Tan, William Sievert, Tawesak Tanwandee, B. L. Neo Background: International guidelines for the management of chronic hepatitis B (CHB) use HBV DNA and ALT to identify candidates for treatment: ALT > 2 x upper limit of normal (ULN) is a key requirement. Previous analysis of nucleoside-naïve patients enrolled in entecavir phase III studies showed that up to 75% of patients with elevated HBV DNA had clinically significant necroinflammation (Knodell necroinflammatory score ≥ 7) even when ALT is < 2 x ULN. This analysis examines responses at 48 weeks in nucleoside-naïve patients with mildly elevated ALT who were treated with entecavir or lamivudine. Methods: Phase III studies ETV-022 (HBeAg-positive) and ETV-027 (HBeAg-negative) enrolled patients with CHB who had ALT > 1.3 - 10 x ULN. Efficacy outcomes in patients with ALT < 2 x ULN were evaluated. Results: More than 35% of entecavir and lamivudine patients enrolled had ALT < 2 x ULN. Efficacy among these patients is reported below. Conclusions: Entecavir treatment of nucleoside-naïve patients with mildly elevated ALT (< 2 x ULN) results in large observed proportions of patients achieving histologic improvement, undetectable HBV DNA and ALT normalization.
M1910 Tenofovir Disoproxil Fumarate (TDF) Is Highly Active for Treatment of Chronic Hepatitis B in Subjects with Cirrhosis Chia Wang, Maria Buti, Stephanos J. Hadziyannis, Philipe Mathurin, Morris Sherman, Simone I. Strasser, Joerg Petersen, Myron J. Tong, Jeff Sorbel, Elsa Mondou, Jane Anderson, Franck Rousseau Background: TDF is a nucleotide analogue and obligate HBV DNA chain terminator with potent activity against HBV. A subset analysis of efficacy and safety was performed of cirrhotics with chronic hepatitis B (CHB) enrolled in two Phase 3 registration trials, GS174-0102 and GS-174-0103. Methods: In study 0102 (HBeAg- CHB) and 0103 (HBeAg+ CHB) subjects with compensated cirrhosis (Knodell fibrosis score=4) and non-cirrhotic liver disease were randomized 2:1 to double-blind TDF 300 mg or adefovir dipivoxil (ADV) 10 mg once daily for 48 weeks. Eligibility criteria required abnormal ALT and viremia HBV DNA >100,000 copies/mL with Roche COBAS TaqMan assay (LLOQ=169 copies/mL). Virologic (HBV DNA <400 copies/mL) and histologic response (≥2-point decrease in the Knodell necroinflammation without worsening fibrosis) were prospectively evaluated. Results: Onehundred-twenty-three subjects with cirrhosis (81 TDF; 42 ADV), 72 HBeAg- and 51 HBeAg+ enrolled (19% of all participants across studies). Mean age among cirrhotics was 47 (TDF) and 44 years (ADV), most were Caucasian (59%) and male (80%), with mean baseline HBV DNA of 7.49 (TDF) and 7.64 log copies/mL (ADV). Baseline characteristics were similar to noncirrhotics (n=511), although cirrhotic subjects were older with a higher mean Knodell necroinflammatory score (9.2 TDF; 8.7 ADV). TDF produced efficacy responses in a high proportion in the cirrhotic subset: histologic response in 79%, suppression of HBV DNA <400 copies/mL in 85%, and normal ALT in 69%, consistent with the results for the overall studies. TDF also provided significantly greater HBV DNA suppression (proportion <400 copies/mL) than ADV (48%), p<0.001, and comparable histologic and ALT response. TDF
* Patients with evaluable histology: > 5 portal areas available (to assess inflammation) and ≥ 2 cm (to assess fibrosis) M1908 Tenofovir Disoproxil Fumarate (TDF) for the Treatment of HBeAg-Negative Chronic Hepatitis B: Week 72 TDF Data and Week 24 Adefovir Dipivoxil Switch Data (Study 102) Patrick Marcellin, Ira M. Jacobson, Naoky Tsai, Natalie Bzowej, François Habersetzer, Hakan Senturk, Christopher D. Moyes, Gerlinde Teuber, Jeff Sorbel, Jane Anderson, Elsa Mondou, Joe Quinn, Franck Rousseau Background: TDF, a nucleotide analogue and obligate chain terminator has potent activity against hepatitis B virus (HBV). Methods: Subjects with HBeAg- CHB mono-infection were randomized 2:1 to double-blind TDF (N=250) or ADV (N=125) for the first 48 weeks. After 48 weeks eligible subjects with week (WK) 48 biopsy were switched to TDF for up to an additional 4 years. HBV DNA was measured using the Roche COBAS TaqMan assay. Results:
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had a safety profile in cirrhotics that was comparable to non-cirrhotic subjects, good renal tolerability, and numerically fewer serious adverse events than ADV among cirrhotic subjects. Conclusions: TDF demonstrated high efficacy, good tolerability, and superior HBV DNA suppression compared with ADV in subjects with compensated cirrhosis due to CHB.
within the TDF treatment group were observed for LAM-experienced subjects versus LAMnaïve subjects, respectively: 88% versus 86% with HBV DNA <400 c/mL (69 IU/mL); 80% versus 72% with histologic improvement; 78% versus 74% with normal ALT. Consistent with the overall findings of the pivotal studies, a greater antiviral response and a similar histologic response was observed for TDF versus ADV in both the LAM-experienced and LAM-naïve groups. The safety and tolerability were comparable between LAM-experienced and LAM-naïve TDF-treated subjects and between TDF and ADV treatment groups. Renal safety was excellent; no TDF treated subject had a confirmed 0.5 mg/dL creatinine increase or creatinine clearance value < 50 mL/min. Conclusion: The potent antiviral effect of TDF was the same at 48 weeks in the LAM naïve and experienced subgroup.
M1911 Cost-Effectiveness of Screening for Hepatitis B Infection Among AsianAmericans Undergoing Chemotherapy Walter G. Park, Maureen E. Morgan, Ahmad Kamal BACKGROUND: Although the cost-effectiveness of prophylactic lamivudine for patients with known hepatitis B virus (HBV) infection undergoing lymphoma treatment is well established, the cost effectiveness of screening persons with unknown HBV status prior to starting chemotherapy is unknown. Recent studies have shown that most cancer centers do not routinely perform such screening. We hypothesized that screening all high-risk patients for HBV prior to starting chemotherapy would be cost-effective. METHODS: For our base case, we considered a hypothetical cohort of 60 year old Asian-American males with Stage IIIV non-Hodgkin's lymphoma in whom chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) was planned. We used a decision analysis model to compare three competing strategies prior to initiation of chemotherapy: (1) no HBV prophylaxis, (2) prophylaxis with lamivudine only among patients with previously known HBV infection, and (3) screening all patients for HBV infection and giving prophylaxis to those found to be infected. We examined the cost effectiveness of each strategy over a time horizon of 1 year with no discounting. Sensitivity analysis was carried out on all variables, most notably prevalence of HBV infection and risk of reactivation. RESULTS: The universal screening strategy was associated with both a lower cost and higher effectiveness than the other two strategies. It remained the dominant strategy even if the prevalence of HBV infection fell to 1% (base case = 9%) or the risk of reactivation fell to 22% (base case = 43%). It also remained the preferred strategy over a wide range of costs for anti-viral medication, suggesting that newer agents such as entecavir and adefovir would be also be appropriate in this setting. CONCLUSION: Screening all Asian American patients for HBV infection prior to initiation of cytotoxic chemotherapy for lymphoma is highly cost-effective. The fact that it remains a preferred strategy even with a 1% prevalence of HBV infection suggests that screening might be advisable in lower-risk populations as well. Probabilities and Costs Used in Model
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Background and Aims: To evaluate the influence of baseline (BL) viral genotype (A-H) on antiviral response among HBeAg + and HBeAg- subjects with chronic hepatitis B (CHB) virus receiving tenofovir DF (TDF) 300 mg QD. Methods: Subjects were enrolled in one of two double-blind, randomized studies [GS-US-174-0102 (HBeAg-) or GS-US-174-0103 (HBeAg+)]. At week 48, subjects were evaluated for biochemical, virological, serological and histological response. Viremia was assessed using the Roche Cobas TaqMan assay, with a lower limit of quantification (LOQ) of 169 copies/mL [cp/mL]. Viral genotypes were determined by phylogenetic mapping of the HBsAg nucleotide sequence. Fisher's exact test was used in a pairwise fashion to compare response between genotypes using a significance level of 0.05. Results: 426 subjects were randomized to receive TDF 300 mg QD for 48 weeks [GS-0102 n=250; GS-0103 n=176]. At baseline 69 (16%), 47 (11%), 72 (17%) and 211 (50%) subjects harbored genotype A, B, C and D HBV, respectively. Genotypes E, F, and H were rare (< 8 subjects each) and data were missing/un-evaluable for 10 subjects. Genotypes A and D were predominant among European subjects, 68% and 82%, respectively. Genotypes B and C were predominant among Australian/New Zealand and North American subjects, 30% and 56%, respectively. Asian subjects almost exclusively harbored HBV genotype B and C (94% and 89%, respectively) whereas Caucasian subjects harbored predominantly A and D (75% and 88%, respectively). At week 48, there were no significant differences in the proportion of subjects achieving normal ALT levels (74% A, 83% B, 73% C and 82% D) or those achieving HBV DNA < 400 cp/mL (95% A, 91% B, 91% C and 90% D). HBe and HBs antigen loss were observed in several different genotypes and were not limited to genotype A. Conclusions: Treatment with tenofovir DF 300 mg QD produced a potent virologic, serological and biochemical response associated with histological improvement across genotypes A-D. M1914 HBV Prevention Strategies Using anti-HBc Positive Liver Donors Robert P. Perrillo Background: The best prophylactic regimen for anti-HBc positive liver donation is unclear. It is not known how long nucleoside analog therapy needs to be given and what benefit, if any, HBIg has in this situation. Methods: To understand what is currently being done, a questionnaire was sent to 81 hepatologists, representing 76 transplant centers in the US Asia, and Europe. The following questions were asked about institutional policy: (1.) Is LAM used to prevent reactived infection (always, sometimes, never)? (2.) If not, what is (ADV, EC, Ldt, other)? (3) How long is nucleoside analog given (6 or 12 months, indefinitely, other)? (4) Is HBIg used (always, sometimes, never)? (5) If so, how is it given (anhepatic only; anhepatic + one week; monthly x 6 months; monthly x 12 months or other). The route of HBIg administration was also asked . Results: Responses were obtained from 76 sites: 50 US, 19 European, 5 Canadian, and 2 Asian/Australian centers. All use nucleoside analog therapy. Sixty (79%) always use LAM, an additional 11 (14%) use it sometimes and 5 (7%) never use it. Twenty eight (37%) always use HBIg, an additional 16 (21%) use it sometimes, and 32 (42%) never use HBIg. The majority of programs reported long term use of nucleoside analog therapy but wide disparity was observed in regard to HBIg usage patterns. More US centers reported use of HBIg than did non US centers (64 % vs 46 %, respectively, P =0.15). Use policy for nucleosides (n = 76 sites) were as follows: Given indefinitely, 78%; given x 6 mos, 8%; given x 12 mos, 9%; unclear, 5%. Use policy for HBIg (n = 44 sites): anhepatic only, 18%; anhepatic and wk 1, 7%; IV or IM x 6 mo, 20%; IV or IM x 12 mo, 23%; indefinitely, 7%; other, 25%. Conclusions: (1.) While use of nucleoside analog therapy is universal, not all centers use LAM and approximately 20% do not use it long term. (2.) A large number of centers routinely use HBIg but there is substantial variation in the duration of treatment, and it is more commonly used in the US (3.) These data support the need for a multinational study of nucleoside analog therapy, with and without HBIg. Such a study would be particularly relevant in countries with high prevalence for anti-HBc.
M1912 The Antiviral Response to Tenofovir Disoproxil Fumarate (TDF) Is Comparable in Lamivudine (LAM)-NaïVe and LAM-Experienced Subjects Treated for Chronic Hepatitis B (CHB) Nezam Afdhal, Michael P. Manns, Lennox J. Jeffers, Tuan Nguyen, Thomas Berg, Georgios N. Dalekos, Christian Trepo, Stuart K. Roberts, Martin Prieto, Jeff Sorbel, Jane Anderson, Elsa Mondou, Franck Rousseau Background: TDF, an obligate chain terminator and a nucleotide analogue, approved for the treatment of HIV-1 also has activity against hepatitis B virus (HBV). Treatment response for a subset of subjects from Studies 102 and 103 previously treated with LAM) was compared to subjects naïve to LAM in these two pivotal studies. Methods: These double-blind studies randomized mono-infected subjects with HBeAg positive (+) or HBeAg negative (-) chronic hepatitis B (CHB) in a 2:1 ratio to TDF or ADV. Entry criteria included 18-69 years of age, compensated liver disease, a Knodell necroinflammatory score≥3, ALT >2xULN (HBeAg+) or >ULN (HBeAg-), HBV DNA>106c/mL (HBeAg+) or > 105 c/mL (HBeAg-). Biopsies were performed pre-treatment and between Weeks 44 and 48. HBV DNA was measured using the Roche COBAS TaqMan assay (LLOQ=169c/mL or 29 IU/mL). Results: Seventy LAMexperienced (>12 weeks) subjects (49 TDF: 21ADV) and 571 LAM-naïve subjects (377 TDF: 194 ADV) were randomized and treated for 48 weeks. The majority of LAM-experienced subjects were HBeAg- (N=61). Baseline demographics, mean baseline HBV DNA, prior LAM exposure and ALT were comparable between both treatment groups. Similar responses
M1915 Hepatitis B Virus Variation Discovery in Patients Under Long-Term Lamivudine Treatment Using Base-Specific RNA Cleavage and Maldi-Tof Mass Spectrometry Ju Luan, Henry LY Chan, Joseph JY Sung, Chunming Ding Aim: Nucleoside analogs, such as Lamivudine, are widely used for treating hepatitis B virus (HBV) infection. A number of variations in the polymerase sequence of the HBV genome have been observed during antiviral treatment. Some of these variations are associated with drug resistance, leading to treatment failure. Current methods for detecting variations have
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Lack of Influence of Baseline Genotype On Antiviral Response in Subjects with Chronic Hepatitis B Infection Receiving Tenofovir Df 300 Mg Qd for 1 Year Zobair M. Younossi, Yves Benhamou, Ed J. Gane, Stefan Zeuzem, Jenny Heathcote, Patrick Marcellin, Jeff Sorbel, Katyna Borroto-Esoda, Franck Rousseau, Andrea SnowLampart
One hundred and twelve subjects originally randomized to ADV initiated TDF at WK48; 35 subjects had HBV DNA > 400 c/mL just prior to switching to TDF. At WK72 after 24 weeks of TDF, 108/112 subjects had HBV DNA < 400 c/mL; 33 of the 35 viremic subjects and 75 of 77 subjects with HBV DNA <400 c/mL at week 48. Two subjects had HBV DNA >400 c/mL and 2 subjects were missing data at WK72. For subjects treated with TDF during the first 48 weeks, 235 subjects continued TDF and 15 did not (10/15 subjects had HBV DNA <400 c/mL at their last visit): 6 discontinued (DC) prior to WK48 and 9 did not enter the study extension (5 refused WK48 biopsy, 2 withdrew consent, 2 subjects were at sites that did not participate in the study extension). At WK72, 222 subjects had HBV DNA <400 c/mL, 4 subjects had HBV DNA >400 c/mL and HBV DNA data were missing for 9 subjects (8 of whom had HBV DNA <400 c/mL at their last visit). TDF was well tolerated through WK72. Conclusion: Continuous therapy with TDF past 48 weeks produced additional viral suppression. A switch to TDF after 48 weeks of ADV treatment produced significant additional viral suppression. Tolerability of TDF for 72 weeks was good.
AASLD Abstracts
Analysis of Factors Affecting HBeAg Early Seroconversion to anti-HBe in Acute Exacerbation of HBeAg Positive Chronic Hepatitis B with Genotype C; a Prospective Study Hyoung Su Kim, Ji Won Park, Ji Sun Jang, Woon Geon Shin, Kyung Ho Kim, Jin Heon Lee, Hak Yang Kim, Myoung Kuk Jang Background/aims: Acute exacerbation (AE), abruptly elevated alanine aminotransferase (ALT) levels, were associated with a high chance of HBeAg seroconversion in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (HBeAg+ CHB), but seroconversion rates were lower in genotype C. To date, there were no studies about the predictors for HBeAg early seroconversion among only patients under AE with genotype C HBV infection. This study was performed to identify the predictive factors for HBeAg early seroconversion during AE of HBeAg+ CHB with genotype C. Methods: A total of 124 patients who experienced AE during follow-up of HBeAg+ CHB were prospectively enrolled. AE and severe AE (SAE) were defined as elevations of ALT to more than 5 times the upper limit of normal (ULN) and 10 times ULN with more than twice the patients' baseline values, respectively. HBeAg early seroconversion was defined as “HBeAg loss and anti-HBe appearance within 6 months after AE”. Clinical and laboratory data such as age, gender, transmission modes, the existence of cirrhosis, serum HBV DNA levels, and other biochemistry were analyzed. HBV was genotyped by RFLP. Various parameters were compared between early seroconversion group and nonseroconversion group using univariate and multivariate analyses. Results: After excluding 33 patients who were not followed up for at least 6 months or took anti-viral therapy before AE, remained 91 patients were analyzed. All HBVs were genotype C. Early seroconversion occurred in 35% (32/91). On univariate analysis, transmission mode (P=0.03), the existence of cirrhosis (P=0.04) and serum HBV DNA levels (P=0.001) and anti-viral therapy after AE (P=0.03) were significantly associated with early seroconversion. Age (P=0.1), gender (P= 0.8) and serum ALT levels (AE vs. SAE, P=0.08) during AE were not associated with early seroconversion. On multivariate analysis, transmission mode (non-vertical vs. vertical; RR= 3.696, 95% CI; 1.019-13.398, P=0.047) and serum HBV DNA levels (<5x7Log vs. ≥5x7Log copies/ml; RR=4.294, 95% CI; 1.500-12.294, P=0.007) were significant independent factors for predicting early seroconversion. Conclusions: Non-vertical transmission and low serum HBV DNA levels (less than 5x7Log copies/ml) were independent factors favoring for HBeAg early seroconversion. Therefore, we should take into account the transmission modes and HBV DNA levels to select the managing strategies such antiviral therapies in AE of HBeAg + CHB with genotype C.
M1909 Will Interferon and Anti-Viral Therapy Reduce Risk of HBV-Related Liver Cancer? Joseph J. Sung, Kelvin K. Tsoi, Kevin C. Li, Vincent W. Wong, Henry Lik-Yuen Chan Background: Chronic hepatitis B infection (CHB) increases the risk of hepatocellular carcinoma by nearly 100 fold. Objective: We studied effects of interferon (IFN) or nucleoside/ tide analog (NA) on the risk of developing HCC in CHB patients Method: Full publications and abstracts from MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects, and the International Pharmaceutical Abstracts were retrieved. Abstracts published in international conferences over the past 10 years were also manually searched. Both randomized controlled trials and case-control studies were included. Subgroup analysis were conducted to investigate the effects of cirrhosis, HBeAg status and drug resistance on HCC risk reduction. Result: 12 studies enrolling patients treated by IFN (n=1,292) versus control (n=1,450) showed that the overall risk of HCC after treatment was reduced by 34% (RR 0.66, 95%CI 0.48-0.89). Benefit is more significant among patients with early cirrhosis (RR 0.53, 95%CI 0.36-0.78) than those without (RR 0.72, 95%CI 0.16-3.15, p=0.66). Four studies compared the risk of HCC development after using NA (n=1,125) versus control (n=898). The overall risk of HCC after treatment was reduced by 78% (RR 0.22, 95%CI 0.09-0.53). HBeAg positive patients showed more significant reduced HCC risk with treatment (RR 0.20, 95%CI 0.09-0.45). Patients with no cirrhosis benefited more from the treatment (RR 0.21, 95%CI 0.10-0.47) than those with early cirrhosis. Resistance to NA has obviated the benefit of the treatment. Conclusion: Long term follow up shows IFN and NA treatment significantly reduce the risk of HCC.
M1907 Efficacy of Entecavir in Nucleoside-NaïVe Patients with Mildly Elevated ALT Stuart C. Gordon, Steven-Huy B. Han, Ting-Tsung Chang, Ching Lung Lai, Kwang-Hyub Han, You Chen Chao, Chee-Kiat Tan, William Sievert, Tawesak Tanwandee, B. L. Neo Background: International guidelines for the management of chronic hepatitis B (CHB) use HBV DNA and ALT to identify candidates for treatment: ALT > 2 x upper limit of normal (ULN) is a key requirement. Previous analysis of nucleoside-naïve patients enrolled in entecavir phase III studies showed that up to 75% of patients with elevated HBV DNA had clinically significant necroinflammation (Knodell necroinflammatory score ≥ 7) even when ALT is < 2 x ULN. This analysis examines responses at 48 weeks in nucleoside-naïve patients with mildly elevated ALT who were treated with entecavir or lamivudine. Methods: Phase III studies ETV-022 (HBeAg-positive) and ETV-027 (HBeAg-negative) enrolled patients with CHB who had ALT > 1.3 - 10 x ULN. Efficacy outcomes in patients with ALT < 2 x ULN were evaluated. Results: More than 35% of entecavir and lamivudine patients enrolled had ALT < 2 x ULN. Efficacy among these patients is reported below. Conclusions: Entecavir treatment of nucleoside-naïve patients with mildly elevated ALT (< 2 x ULN) results in large observed proportions of patients achieving histologic improvement, undetectable HBV DNA and ALT normalization.
M1910 Tenofovir Disoproxil Fumarate (TDF) Is Highly Active for Treatment of Chronic Hepatitis B in Subjects with Cirrhosis Chia Wang, Maria Buti, Stephanos J. Hadziyannis, Philipe Mathurin, Morris Sherman, Simone I. Strasser, Joerg Petersen, Myron J. Tong, Jeff Sorbel, Elsa Mondou, Jane Anderson, Franck Rousseau Background: TDF is a nucleotide analogue and obligate HBV DNA chain terminator with potent activity against HBV. A subset analysis of efficacy and safety was performed of cirrhotics with chronic hepatitis B (CHB) enrolled in two Phase 3 registration trials, GS174-0102 and GS-174-0103. Methods: In study 0102 (HBeAg- CHB) and 0103 (HBeAg+ CHB) subjects with compensated cirrhosis (Knodell fibrosis score=4) and non-cirrhotic liver disease were randomized 2:1 to double-blind TDF 300 mg or adefovir dipivoxil (ADV) 10 mg once daily for 48 weeks. Eligibility criteria required abnormal ALT and viremia HBV DNA >100,000 copies/mL with Roche COBAS TaqMan assay (LLOQ=169 copies/mL). Virologic (HBV DNA <400 copies/mL) and histologic response (≥2-point decrease in the Knodell necroinflammation without worsening fibrosis) were prospectively evaluated. Results: Onehundred-twenty-three subjects with cirrhosis (81 TDF; 42 ADV), 72 HBeAg- and 51 HBeAg+ enrolled (19% of all participants across studies). Mean age among cirrhotics was 47 (TDF) and 44 years (ADV), most were Caucasian (59%) and male (80%), with mean baseline HBV DNA of 7.49 (TDF) and 7.64 log copies/mL (ADV). Baseline characteristics were similar to noncirrhotics (n=511), although cirrhotic subjects were older with a higher mean Knodell necroinflammatory score (9.2 TDF; 8.7 ADV). TDF produced efficacy responses in a high proportion in the cirrhotic subset: histologic response in 79%, suppression of HBV DNA <400 copies/mL in 85%, and normal ALT in 69%, consistent with the results for the overall studies. TDF also provided significantly greater HBV DNA suppression (proportion <400 copies/mL) than ADV (48%), p<0.001, and comparable histologic and ALT response. TDF
* Patients with evaluable histology: > 5 portal areas available (to assess inflammation) and ≥ 2 cm (to assess fibrosis) M1908 Tenofovir Disoproxil Fumarate (TDF) for the Treatment of HBeAg-Negative Chronic Hepatitis B: Week 72 TDF Data and Week 24 Adefovir Dipivoxil Switch Data (Study 102) Patrick Marcellin, Ira M. Jacobson, Naoky Tsai, Natalie Bzowej, François Habersetzer, Hakan Senturk, Christopher D. Moyes, Gerlinde Teuber, Jeff Sorbel, Jane Anderson, Elsa Mondou, Joe Quinn, Franck Rousseau Background: TDF, a nucleotide analogue and obligate chain terminator has potent activity against hepatitis B virus (HBV). Methods: Subjects with HBeAg- CHB mono-infection were randomized 2:1 to double-blind TDF (N=250) or ADV (N=125) for the first 48 weeks. After 48 weeks eligible subjects with week (WK) 48 biopsy were switched to TDF for up to an additional 4 years. HBV DNA was measured using the Roche COBAS TaqMan assay. Results:
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had a safety profile in cirrhotics that was comparable to non-cirrhotic subjects, good renal tolerability, and numerically fewer serious adverse events than ADV among cirrhotic subjects. Conclusions: TDF demonstrated high efficacy, good tolerability, and superior HBV DNA suppression compared with ADV in subjects with compensated cirrhosis due to CHB.
within the TDF treatment group were observed for LAM-experienced subjects versus LAMnaïve subjects, respectively: 88% versus 86% with HBV DNA <400 c/mL (69 IU/mL); 80% versus 72% with histologic improvement; 78% versus 74% with normal ALT. Consistent with the overall findings of the pivotal studies, a greater antiviral response and a similar histologic response was observed for TDF versus ADV in both the LAM-experienced and LAM-naïve groups. The safety and tolerability were comparable between LAM-experienced and LAM-naïve TDF-treated subjects and between TDF and ADV treatment groups. Renal safety was excellent; no TDF treated subject had a confirmed 0.5 mg/dL creatinine increase or creatinine clearance value < 50 mL/min. Conclusion: The potent antiviral effect of TDF was the same at 48 weeks in the LAM naïve and experienced subgroup.
M1911 Cost-Effectiveness of Screening for Hepatitis B Infection Among AsianAmericans Undergoing Chemotherapy Walter G. Park, Maureen E. Morgan, Ahmad Kamal BACKGROUND: Although the cost-effectiveness of prophylactic lamivudine for patients with known hepatitis B virus (HBV) infection undergoing lymphoma treatment is well established, the cost effectiveness of screening persons with unknown HBV status prior to starting chemotherapy is unknown. Recent studies have shown that most cancer centers do not routinely perform such screening. We hypothesized that screening all high-risk patients for HBV prior to starting chemotherapy would be cost-effective. METHODS: For our base case, we considered a hypothetical cohort of 60 year old Asian-American males with Stage IIIV non-Hodgkin's lymphoma in whom chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) was planned. We used a decision analysis model to compare three competing strategies prior to initiation of chemotherapy: (1) no HBV prophylaxis, (2) prophylaxis with lamivudine only among patients with previously known HBV infection, and (3) screening all patients for HBV infection and giving prophylaxis to those found to be infected. We examined the cost effectiveness of each strategy over a time horizon of 1 year with no discounting. Sensitivity analysis was carried out on all variables, most notably prevalence of HBV infection and risk of reactivation. RESULTS: The universal screening strategy was associated with both a lower cost and higher effectiveness than the other two strategies. It remained the dominant strategy even if the prevalence of HBV infection fell to 1% (base case = 9%) or the risk of reactivation fell to 22% (base case = 43%). It also remained the preferred strategy over a wide range of costs for anti-viral medication, suggesting that newer agents such as entecavir and adefovir would be also be appropriate in this setting. CONCLUSION: Screening all Asian American patients for HBV infection prior to initiation of cytotoxic chemotherapy for lymphoma is highly cost-effective. The fact that it remains a preferred strategy even with a 1% prevalence of HBV infection suggests that screening might be advisable in lower-risk populations as well. Probabilities and Costs Used in Model
M1913
Background and Aims: To evaluate the influence of baseline (BL) viral genotype (A-H) on antiviral response among HBeAg + and HBeAg- subjects with chronic hepatitis B (CHB) virus receiving tenofovir DF (TDF) 300 mg QD. Methods: Subjects were enrolled in one of two double-blind, randomized studies [GS-US-174-0102 (HBeAg-) or GS-US-174-0103 (HBeAg+)]. At week 48, subjects were evaluated for biochemical, virological, serological and histological response. Viremia was assessed using the Roche Cobas TaqMan assay, with a lower limit of quantification (LOQ) of 169 copies/mL [cp/mL]. Viral genotypes were determined by phylogenetic mapping of the HBsAg nucleotide sequence. Fisher's exact test was used in a pairwise fashion to compare response between genotypes using a significance level of 0.05. Results: 426 subjects were randomized to receive TDF 300 mg QD for 48 weeks [GS-0102 n=250; GS-0103 n=176]. At baseline 69 (16%), 47 (11%), 72 (17%) and 211 (50%) subjects harbored genotype A, B, C and D HBV, respectively. Genotypes E, F, and H were rare (< 8 subjects each) and data were missing/un-evaluable for 10 subjects. Genotypes A and D were predominant among European subjects, 68% and 82%, respectively. Genotypes B and C were predominant among Australian/New Zealand and North American subjects, 30% and 56%, respectively. Asian subjects almost exclusively harbored HBV genotype B and C (94% and 89%, respectively) whereas Caucasian subjects harbored predominantly A and D (75% and 88%, respectively). At week 48, there were no significant differences in the proportion of subjects achieving normal ALT levels (74% A, 83% B, 73% C and 82% D) or those achieving HBV DNA < 400 cp/mL (95% A, 91% B, 91% C and 90% D). HBe and HBs antigen loss were observed in several different genotypes and were not limited to genotype A. Conclusions: Treatment with tenofovir DF 300 mg QD produced a potent virologic, serological and biochemical response associated with histological improvement across genotypes A-D. M1914 HBV Prevention Strategies Using anti-HBc Positive Liver Donors Robert P. Perrillo Background: The best prophylactic regimen for anti-HBc positive liver donation is unclear. It is not known how long nucleoside analog therapy needs to be given and what benefit, if any, HBIg has in this situation. Methods: To understand what is currently being done, a questionnaire was sent to 81 hepatologists, representing 76 transplant centers in the US Asia, and Europe. The following questions were asked about institutional policy: (1.) Is LAM used to prevent reactived infection (always, sometimes, never)? (2.) If not, what is (ADV, EC, Ldt, other)? (3) How long is nucleoside analog given (6 or 12 months, indefinitely, other)? (4) Is HBIg used (always, sometimes, never)? (5) If so, how is it given (anhepatic only; anhepatic + one week; monthly x 6 months; monthly x 12 months or other). The route of HBIg administration was also asked . Results: Responses were obtained from 76 sites: 50 US, 19 European, 5 Canadian, and 2 Asian/Australian centers. All use nucleoside analog therapy. Sixty (79%) always use LAM, an additional 11 (14%) use it sometimes and 5 (7%) never use it. Twenty eight (37%) always use HBIg, an additional 16 (21%) use it sometimes, and 32 (42%) never use HBIg. The majority of programs reported long term use of nucleoside analog therapy but wide disparity was observed in regard to HBIg usage patterns. More US centers reported use of HBIg than did non US centers (64 % vs 46 %, respectively, P =0.15). Use policy for nucleosides (n = 76 sites) were as follows: Given indefinitely, 78%; given x 6 mos, 8%; given x 12 mos, 9%; unclear, 5%. Use policy for HBIg (n = 44 sites): anhepatic only, 18%; anhepatic and wk 1, 7%; IV or IM x 6 mo, 20%; IV or IM x 12 mo, 23%; indefinitely, 7%; other, 25%. Conclusions: (1.) While use of nucleoside analog therapy is universal, not all centers use LAM and approximately 20% do not use it long term. (2.) A large number of centers routinely use HBIg but there is substantial variation in the duration of treatment, and it is more commonly used in the US (3.) These data support the need for a multinational study of nucleoside analog therapy, with and without HBIg. Such a study would be particularly relevant in countries with high prevalence for anti-HBc.
M1912 The Antiviral Response to Tenofovir Disoproxil Fumarate (TDF) Is Comparable in Lamivudine (LAM)-NaïVe and LAM-Experienced Subjects Treated for Chronic Hepatitis B (CHB) Nezam Afdhal, Michael P. Manns, Lennox J. Jeffers, Tuan Nguyen, Thomas Berg, Georgios N. Dalekos, Christian Trepo, Stuart K. Roberts, Martin Prieto, Jeff Sorbel, Jane Anderson, Elsa Mondou, Franck Rousseau Background: TDF, an obligate chain terminator and a nucleotide analogue, approved for the treatment of HIV-1 also has activity against hepatitis B virus (HBV). Treatment response for a subset of subjects from Studies 102 and 103 previously treated with LAM) was compared to subjects naïve to LAM in these two pivotal studies. Methods: These double-blind studies randomized mono-infected subjects with HBeAg positive (+) or HBeAg negative (-) chronic hepatitis B (CHB) in a 2:1 ratio to TDF or ADV. Entry criteria included 18-69 years of age, compensated liver disease, a Knodell necroinflammatory score≥3, ALT >2xULN (HBeAg+) or >ULN (HBeAg-), HBV DNA>106c/mL (HBeAg+) or > 105 c/mL (HBeAg-). Biopsies were performed pre-treatment and between Weeks 44 and 48. HBV DNA was measured using the Roche COBAS TaqMan assay (LLOQ=169c/mL or 29 IU/mL). Results: Seventy LAMexperienced (>12 weeks) subjects (49 TDF: 21ADV) and 571 LAM-naïve subjects (377 TDF: 194 ADV) were randomized and treated for 48 weeks. The majority of LAM-experienced subjects were HBeAg- (N=61). Baseline demographics, mean baseline HBV DNA, prior LAM exposure and ALT were comparable between both treatment groups. Similar responses
M1915 Hepatitis B Virus Variation Discovery in Patients Under Long-Term Lamivudine Treatment Using Base-Specific RNA Cleavage and Maldi-Tof Mass Spectrometry Ju Luan, Henry LY Chan, Joseph JY Sung, Chunming Ding Aim: Nucleoside analogs, such as Lamivudine, are widely used for treating hepatitis B virus (HBV) infection. A number of variations in the polymerase sequence of the HBV genome have been observed during antiviral treatment. Some of these variations are associated with drug resistance, leading to treatment failure. Current methods for detecting variations have
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AASLD Abstracts
AASLD Abstracts
Lack of Influence of Baseline Genotype On Antiviral Response in Subjects with Chronic Hepatitis B Infection Receiving Tenofovir Df 300 Mg Qd for 1 Year Zobair M. Younossi, Yves Benhamou, Ed J. Gane, Stefan Zeuzem, Jenny Heathcote, Patrick Marcellin, Jeff Sorbel, Katyna Borroto-Esoda, Franck Rousseau, Andrea SnowLampart