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M1781 Rapid Virologic Response Predicts Sustained Virologic Response in Hepatitis C Patients Treated with Pegylated Interferon and Ribavirin Therapy
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AASLD Abstracts
Characteristics and Impact of Methamphetamine Use in Patients with Chronic Hepatitis C Brian Curley, Dana E. Riley, Shannon K. Robinson, Jeffrey K. Lee, Erik J. Groessl, Samuel B. Ho Methamphetamine (Me) use has increased in the US in the last 20 years and is a risk factor for hepatitis C (HCV). The US is second to Asia/Pacific Islands in the population percentage of amphetamine users, with an estimated 3.7 million current users in North America (UN World Drug Report 2008). No data exists regarding the potential impact of Me addiction or dependence on HCV patients in terms of compliance with HCV evaluation and treatment. The purpose of this study was to determine the characteristics and HCV-related outcomes of patients with Me dependence. Methods: Subjects consisted of newly entered patients in the VA HCV registry, a record of all HCV cases in the local VA system identified daily by new HCV antibody positivity or ICD9 diagnosis, from 1/1/04 to 6/30/04. Medical records were reviewed, and outcomes recorded included demographics, severity of substance use, psychiatric conditions, SUD treatment, HCV clinic attendance, and antiviral treatment outcomes through 2008. Results: 201 cases were entered into the local VA HCV registry. Of these, 28 were excluded based on severe illness or severe ESLD, leaving 173 new patients for analysis. Of the 173 patients, 34% had a history of Me use. One third of Me patients had documented active Me use at initial contact. Me patients were younger (mean 46.4 yrs) with fewer minority (34%) compared with non-Me patients (mean 53.4 yrs and 40% minority). Me users were 4 times more likely to be current or past marijuana users compared with non-Me patient (p<0.0001). 90% of the 173 patients had a history of alcohol (ETOH) use with 52% reporting active abuse. Multivariate analyses indicated that Me use did not adversely affect referral, evaluation, or treatment rates compared with patients without Me use and patients with prior ETOH abuse. Active ETOH users had lower treatment initiation and success rates compared with Me groups. Patients actively using illicit drugs were 66% less likely to attend a liver biopsy (p=0.015). Conclusions: Me use is common in recent US veterans diagnosed with hepatitis C and occurs in younger patients with frequent concomitant marijuana use. Prior history or recent/active Me use alone does not appear to adversely affect overall HCV clinic referral, testing, evaluation, or treatment compared with new HCV patients without Me use and patients with prior ETOH abuse. Although, overall rates of treatment initiation are low in all groups at 17-20% and tended to be lowest in patients with active ETOH abuse (12%). These data indicate that facilitated access to SUD treatment in HCV clinics may be of benefit for multiple SUD issues to increase HCV treatment rates.(VA HSR&D grant IIR 07-101-3)
M1780 Association of Autophagy with HCV Replication in Chronic Hepatitis C Patients Shunhei Yamashina, Tomokazu Mizui, Motoki Takashima, Hisafumi Yamagata, Tomonori Aoyama, Reiko Yaginuma, Kazuyoshi Kon, Kenichi Ikejima, Sumio Watanabe Background: Previous investigation revealed that autophagy, which involved the bulk degradation of cellular contents during nutrition starvation, is required for viral RNA replication. Recently, it was reported that HCV replicon induced autophagosome formation and autophagic proteolysis plays a pivotal role in replication of HCV replicon. Here we examined if the induction of autophagy correlates with viral replication, liver fibrosis, inflammation and sensitivity to interferon therapy in patients with chronic hepatitis C. Patients and Methods: The subjects of this study were 68 patients infected with hepatitis C virus who underwent liver biopsy, and 58 of 68 patients received interferon therapy. Liver Histology was classified into five stages and four grades according to the METAVIR classification. Cytoplasmic double membrane vesicle of hepatocytes into liver section was identified as autophagosome or autolysosome and counted by using transmission electron microscope. Serum HCV-RNA was quantified by competitive RT-PCR methods. Data were statistically analyzed by Pearson correlation test or ANOVA. Results: The distribution of HCV genotype was: 1b: 55 patients, 2a and 2b: 13 patients. The number of autophagosome of hepatocyte in genotype 1b (4.17 ± 0.22 /100μm2) is not significant difference from 2a and 2b (5.05 ± 0.49 /100μm2). The number of autophagosome in 1b was correlated with serum HCVRNA values (r=0.66, p<0.01). On the other hand, liver histological grade was not significantly associated with the number of autophagosome of hepatocyte(r=-0.12, p=0.48). Liver histological stage was significantly associated with the number of autophagosome of hepatocyte(r=0.34, p<0.05). In early virological response (EVR) of HCV genotype 1b-infected patients, measured as HCV-RNA negatively 1 month into treatment, the number of autophagosome was significantly less than in non EVR of 1b-infected patients (p<0.01). Conclusion: It is likely that the number of autophagosome of hepatocyte in patients with chronic hepatitis C is associated with not only the replication of HCV but also viral clearance during IFN therapy. These findings suggest that the number of autophagosome is useful as a new therapeutic marker to predict the efficacy of IFN therapy in patients with chronic hepatitis C.
M1779 Risk Factors for Hepatitis C Acquisition Are More Likely to Be Unidentifiable in Asian-Americans Compared to Caucasians or Hispanics (Prospective Study) Edith Y. Ho, Nghiem B. Ha, Mindie H. Nguyen Background/Aim: Hepatitis C virus (HCV) infections are generally associated with a history of blood transfusions, injecting drug use, body tattoos, intranasal cocaine use, and multiple sexual partners. We hypothesized that risk factors for HCV acquisition are more likely to be unidentifiable in Asian-Americans(AA) compared to Caucasians(CAU) or Hispanics(HIS). Methods: We performed a prospective study with a detailed risk assessment questionnaire of 494 HCV patients at a liver center in California, USA in 2001-2008. Results: 55% identified themselves as CAU, 20% as HIS, and 25% as AA. Among these groups, 19% of CAU, 30% of HIS, and 59% of AA were foreign born (p<0.0001). Genotype 1 was most common in all groups (74-75%). 4% of CAU, 7% of HIS, and 15% of AA reported no known risk factors such as blood transfusions, injection drug use, acupuncture, body tattoos, or snorting cocaine; 18% CAU, 22% of HIS, and 45% of AA reported one risk factor; 78% of CAU, 71% of HIS, and 41% AA reported more than one risk factor (p<0.0001) -Figure. Injection drug use, cocaine snorting, and tattoos were significantly higher in CAU and HIS compared to AA, who were more likely to have exposure to acupuncture (p<0.0001). Of the AAs who reported one risk factor, 42% was due to acupuncture. Conclusions: AA are more likely to present with unidentifiable risk exposures for HCV while CAU and HIS are more likely to present with multiple risk exposures. Therefore, commonly known risk factors for HCV may be more appropriate for risk assessment of CAU and HIS, but not AA. These findings pose major implications for developing strategies for HCV screening in our increasingly culturally diverse population.
AASLD Abstracts
M1781 Rapid Virologic Response Predicts Sustained Virologic Response in Hepatitis C Patients Treated with Pegylated Interferon and Ribavirin Therapy Shahzad Sarwar, Masood Iqbal, P Aiden McCormick, Cliona O'Farrelly, John E. Hegarty Introduction: Pegylated interferon and ribavirin is the standard treatment for chronic hepatitis C. Due to differences in viral characteristics genotype 1 is treated for 12 months and genotype 3 for 6 months. Recent data suggest that efficacy of treatment depends upon rapidity of virological clearance. We hypothesised that rapid virological response (RVR) predicts sustained virological response (SVR). Aims: To evaluate the predictive value of RVR on SVR in chronic Hepatitis C patients treated with pegylated interferon and ribavirin therapy Methods: We performed a retrospective review of 191 patients undergoing treatment for hepatitis C between May 2001 and March 2007. Patients who had HCV RNA tested at baseline, 4 weeks, and 24 weeks after the end of treatment were included in the study (n=123). All patients received peg-INF- α2a 180 ug / week or peg-INF- α2b 1.5 ug/kg/ week subcutaneously with ribavirin. Patients with genotype 1 were treated for 12 months and genotypes 2 and 3 for 6 months. RVR was defined as undetectable HCV RNA 4 weeks after starting treatment. SVR was defined as undetectable HCV RNA 24 weeks after completion of treatment. Results: Of the 123 patients in this study, 81 were male and 42 female with the mean age of 42 years. 62 patients were genotype 1, 55 genotype 3 and 6 genotype 2. Due to
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similar response rates genotype 2 and 3 were analysed together. Overall, 86 patients (69.9%) achieved RVR and of these, 77 (89.5%) had SVR. RVR rates for genotype 1 patients (53.2%) were significantly lower (86.8%) than genotype 2 and 3 (chi(2)=16.563, p=0.000). SVR rates for genotype 1 patients who had achieved RVR (90.4%) were significantly higher than those (9.6%) who had not achieved RVR (chi(2)= 3.232, p=0.000). Of 33 patients with genotype 1 who had achieved RVR, 27 (81.8%) had SVR and of 29 patients who did not achieve RVR, only 4 (13.7%) had SVR. Similarly, of 53 patients with genotypes 2 and 3 who had RVR, 50 (94.3%) had SVR and of 8 patients who did not have RVR, 4 (50%) had SVR. Significant factors associated with SVR were RVR (chi(2)=56.011, p=0.000), genotype (chi(2)=19.319, p=0.000), baseline AST level (p=0.031) and baseline viral load (p=0.049). The positive and negative predictive values of RVR in genotype 1 patients were 82% and 86% respectively and in genotype 2 and 3, 94% and 50% respectively. Conclusion: RVR in patients with chronic hepatitis C, genotype 1 was significantly lower than genotypes 2 and 3. SVR rates were significantly higher in patients who had achieved RVR. RVR predicts SVR in genotypes 1, 2 and 3. RVR, Genotype, baseline viral load and baseline AST level were significant factors for predicting SVR.
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Background: Veteran patients with hepatitis C (HCV) often suffer from depression, which can worsen during antiviral treatment and contribute to treatment non-compliance. Aim: To compare the effects of using a standardized questionnaire to recognize and treat depression with those of patient self-reporting of depression symptoms on the outcome of treatment for chronic HCV with pegylated interferonα-2b and ribavirin. Methods: 129 naive patients who were about to start treatment for chronic HCV were randomized to receive periodic assessment of depression symptoms during antiviral therapy using either the Centers for Epidemiology Studies for Depression Scale (CES-D) questionnaire (group A, n=57) or by asking the patients to self-report depression symptoms (group B, n=72). For patients in group A, antidepressants (ADs) were begun when CES-D scores were between 11 and 13, whereas ADs were started for patients in group B based solely on the physician's evaluation of the need for AD therapy. Baseline patient characteristics recorded included age, gender, ethnicity, HCV genotype, liver disease stage, laboratory values, prior treatment with ADs, and history of depression and other psychiatric disorders. Results: There were no significant differences in baseline characteristics between the two groups; a prior history of depression was common in both groups (49% group A, 51% group B) as was a history of other psychiatric disorders (26% group A, 27% group B). At the conclusion of antiviral therapy, there were no significant differences between the groups in rates of SVR (30% group A, 35% group B) or in rates of overall compliance with therapy (% patients receiving >80% of prescribed therapy: 82% group A, 80% group B). Overall, Chi Square analysis revealed that those who started an antidepressant at 0-12 weeks of treatment were significantly more likely to be in >90% compliance category than patients who did not receive early AD therapy (X2 = 4.5, p = .025 and ribavirin compliance X2 = 18.4, p=.005). Conclusion:The use of the CES-D questionnaire to recognize and treat depression had no significant advantage over patient self-reporting of depression symptoms on the outcome of antiviral therapy for HCV with respect to rates of SVR and compliance with treatment. Irrespective of how depression is recognized, however, the early use of AD treatment (within the first 12 weeks of antiviral therapy) is associated with significantly better rates of compliance.
M1782 Characteristics of HBeAg-Positive Patients with HBsAg Loss/Seroconversion Following Treatment with Tenofovir Disoproxil Fumarate (TDF) Jenny Heathcote, George Germanidis, Geoffrey M. Dusheiko, Ira M. Jacobson, Robert A. De Man, Paul Nikolaidis, Patrick Marcellin, Jeff Sorbel, Jane Anderson, Elsa Mondou, Joe Quinn, Franck Rousseau Background: In the phase 3 study in HBeAg-positive patients (study 103), HBsAg loss was observed in significantly more TDF-treated patients versus adefovir dipivoxil (ADV) at Week (W) 48: 3.2% TDF versus 0% ADV (p=0.02). Methods: Patients with HBeAg-positive chronic hepatitis B (CHB) were randomized to double-blind, once daily TDF 300 mg (N=176) or adefovir dipivoxil 10 mg (ADV) (N=90). After W48, eligible patients (with a week 48 biopsy) initiated open-label TDF for an additional 7 years. Results: Six percent of patients (10 TDFTDF and 5 ADV-TDF) experienced HBsAg loss by W96 (11/15 anti-HBs). Of these 15, 100% were Caucasian, 80% men and 80% from Europe with a median (min, max) age of 35 years (20, 64). All patients were naïve to interferon. Median baseline HBsAg levels were 5.11 log10IU/mL (4.62, 5.38), HBV DNA levels were 9.48 log10 copies/mL (8.47, 9.64), median ALT 150 U/L (75, 425) and the median pretreatment Knodell necroinflammatory score was 9.4 (5.0, 12.0). Sixty-seven percent had bridging fibrosis or cirrhosis prior to treatment. Sixty percent (n=9) harbored genotype A and 40% (N=6) harbored genotype D virus. Although most patients lost HBeAg prior to HBsAg loss, this pattern was not uniform. Although no patient in the ADV arm achieved HBsAg loss within the first 48 weeks, by week 96 (after 48 weeks of open label TDF) the same percentage of patients achieved HBsAg loss. However, no ADV-TDF patient achieved HBsAg loss until week 80 or later. Patients with HBsAg loss had high HBV DNA and HBsAg levels at baseline however there was no clear correlation between baseline ALT levels and HBsAg loss. Conclusion: Tenofovir DF induces loss of HBsAg in Caucasian patients infected with genotype A or D virus and with high HBV DNA and high HBsAg levels prior to treatment.
M1785 Predictors of Sustained Virologic Response to Pegylated Interferon and Ribavirin in a National Cohort of Male HIV/HCV-Coinfected Veterans in Routine Medical Care Lisa I. Backus, Derek B. Boothroyd, Larry A. Mole BACKGROUND: Most information on HCV sustained virologic response (SVR) in HIV/HCV patients comes from clinical trials (e.g. APRICOT and ACTG A5071) and may not reflect the experience in routine care. We evaluated the predictors of SVR for Veterans Affairs (VA) HIV/HCV patients receiving pegylated interferon (PEG) and ribavirin (RBV) in routine care. METHODS: We identified patients in the VA HIV Clinical Case Registry with a first PEG prescription before 1 January 2005, a RBV prescription within 7 days of first PEG, a baseline detectable HCV RNA, a baseline CD4 count and HIV RNA prior to PEG/RBV, and HCV genotype (GT) 1, 2 or 3. We defined SVR as undetectable HCV RNA on all tests after PEG/ RBV with at least one test more than 12 weeks after stopping therapy. We excluded patients with undetectable HCV RNA but no test 12 weeks or more after treatment. Patients without a HCV RNA test after stopping PEG/RBV or with a detectable HCV RNA at any time after treatment were considered “no SVR.” We conducted single predictor analyses to compare patient demographics, baseline lab results and baseline clinical characteristics between patients who did and did not have a SVR. We then performed backward stepwise deletion multiple logistic regression analysis starting with variables differing at P<0.1 in single predictor analyses, fitting by penalized maximum likelihood and calculating p-values by profile likelihood. RESULTS: Among 346 HIV/HCV patients who began PEG/RBV, SVR rates were 9% for GT 1 (26/278), 49% for GT 2 (18/37), and 39% for GT 3 (12/31)(P<0.001). Of the baseline factors examined, race, ALT≥3xULN, HCV GT, HCV RNA<500,000 IU/mL, PEG form (2A or 2B), starting on a recommended PEG dose and starting on a recommended RBV dose differed in single predictor analyses at P<0.05 while nadir CD4 count and current diabetes differed at P<0.1. In multivariate analysis, lower HCV RNA, HCV GT (2 or 3 vs. 1), elevated ALT and PEG form 2A were significant positive predictors of SVR while diabetes was a significant negative predictor of SVR. Most treated VA patients would have been excluded from clinical trials. Of this cohort, 57% (196) would have been excluded from APRICOT for example based on prior interferon or lab criteria and a total of 74% (256) may have been excluded by including a current diagnosis of diabetes or depression. CONCLUSION: Our results confirm that HIV/HCV patients with lower baseline HCV RNA and HCV GT 2 or 3 are more likely to respond to PEG/RBV. Baseline ALT, PEG form and diabetes also substantially impact the likelihood of SVR. Response rates in routine practice are substantially lower than in clinical trials.
M1783 Effect of Pegylated-IFN-Alpha-2a Monotherapy in Patients with Chronic Hepatitis C Infected with Low Pretreatment Viremia and Relationship to Amino Acid Substitutions in NS5A Region Kazuhiko Hayashi, Yoshiaki Katano, Isao Nakano, Masatoshi Ishigami, Kentaro Yoshioka, Hidenori Toyoda, Takashi Kumada, Hidemi Goto (Background) Previous studies suggest that patients with chronic hepatitis C infected with a low pretreatment hepatitis C virus (HCV) level have a high sustained virologic response (SVR) rate, and there would be a subpopulation of patients in which HCV can be eradicated with pegylated-IFN-alpha alone without a decrease in SVR. However, the efficacy and safety of pegylated-IFN-alpha 2a monotherapy in patients with low pretreatment HCV-RNA level were unclear. There was a motif of the PKR binding domain in NS5A region of HCV which were called IFN sensitivity-determining region (ISDR) and thought to be inhibited the PKR which associated with IFN pathway. As a result, several studies reported relationship between ISDR and IFN responsiveness. However, this relation is controversial. The aim of the present study was to determine whether genomic heterogeneity of the ISDR among patients with low pretreatment HCV-RNA level affects the response to pegylated-IFN-alpha 2a monotherapy. (Methods) We studied 83 patients (49 men, 34 women; mean age, 54.4±13.2 years) infected with low HCV level. The low HCV level was defined as less than 200KIU/ml. HCV genotypes 1b (n = 26), 2a (n = 49), 2b (n = 6) and unknown (n =2) were detected. The ISDR were examined by direct sequencing and classification was counting the number of amino acid substitutions compared by consensus strains of each genotype. All patients received subcutaneous injections of pegylated-IFN-alpha 2a once a week for 24 or 48 weeks. (Results) Sixty eight of 83 (81.9%) patients showed rapid virologic response (RVR) as HCV negative at 4 weeks. Negativity of HCV at the end of treatment was 100%. Seventy-four of 83 (89.2%) patients showed a sustained virologic response (SVR). SVR rates according HCV genotype 1b, 2a and 2b were 76.9%, 93.9% and 100%, respectively. HCV genotype 1b was detected more frequently in patients with non-SVR (66.7%) than in patients with SVR (27.0%) (p= 0.024). Achievement to SVR occurred more frequently in patients without reduction of IFN (94.1%) than in those with reduction of IFN (66.7%) (P = 0.0082). Patients with SVR had a significantly higher number of mutations in the ISDR than did patients with non-SVR (p= 0.001). Factor related to SVR by multivariate analysis was ISDR (OR, 0.01; 95%CI, 0.010.625; p =0.0286). There were no significant differences in the factors, including sex, age, aspartate aminotransferase, alanine aminotransferase, platelet count, HCV genotypes, HCV viral load, total dose of IFN, and RVR. (Conclusions) Patients with low HCV levels and more than 2 mutations in the ISDR are significantly associated with good response to pegylated-IFN-alpha 2a monotherapy.
M1786 Response to Peginterferon (PEG IFN) and Ribavirin (RBV) in Asian Americans and Non-Asian Americans with Chronic Hepatitis C (CHC) in a Real-Life Community Setting: A Multi-Center Study Philip Vutien, Nghia H. Nguyen, Huy N. Trinh, Jiayi Li, Ruel T. Garcia, Carrie R. Wong, Emmet B. Keeffe, Gabriel Garcia, Khanh K. Nguyen, Huy A. Nguyen, Brian S. Levitt, Mindie H. Nguyen BACKGROUND: Per WHO, 95M out of 169M patients with CHC patients are Asian. However, only a few small studies to date have suggested that Asian patients with CHC may have higher SVR rates than non-Asian patients. Our goal is to compare treatment response to PEG-IFN + RBV in a large cohort of Asian Americans (AA) and Non-Asians (NA) with HCV
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AASLD Abstracts
AASLD Abstracts
Effects of Recognizing Depression with a Standardized Questionnaire (CES-D) vs. Patient Self-Reporting of Depression On the Outcome of Treatment for Hepatitis C with Pegylated Interferon α-2B and Ribavirin. Frances H. Phillips, Melanie Prebis, Teresa Hale, Catherine Grumbeck, Raul Cubillas, Geri Brown
AASLD Abstracts
Characteristics and Impact of Methamphetamine Use in Patients with Chronic Hepatitis C Brian Curley, Dana E. Riley, Shannon K. Robinson, Jeffrey K. Lee, Erik J. Groessl, Samuel B. Ho Methamphetamine (Me) use has increased in the US in the last 20 years and is a risk factor for hepatitis C (HCV). The US is second to Asia/Pacific Islands in the population percentage of amphetamine users, with an estimated 3.7 million current users in North America (UN World Drug Report 2008). No data exists regarding the potential impact of Me addiction or dependence on HCV patients in terms of compliance with HCV evaluation and treatment. The purpose of this study was to determine the characteristics and HCV-related outcomes of patients with Me dependence. Methods: Subjects consisted of newly entered patients in the VA HCV registry, a record of all HCV cases in the local VA system identified daily by new HCV antibody positivity or ICD9 diagnosis, from 1/1/04 to 6/30/04. Medical records were reviewed, and outcomes recorded included demographics, severity of substance use, psychiatric conditions, SUD treatment, HCV clinic attendance, and antiviral treatment outcomes through 2008. Results: 201 cases were entered into the local VA HCV registry. Of these, 28 were excluded based on severe illness or severe ESLD, leaving 173 new patients for analysis. Of the 173 patients, 34% had a history of Me use. One third of Me patients had documented active Me use at initial contact. Me patients were younger (mean 46.4 yrs) with fewer minority (34%) compared with non-Me patients (mean 53.4 yrs and 40% minority). Me users were 4 times more likely to be current or past marijuana users compared with non-Me patient (p<0.0001). 90% of the 173 patients had a history of alcohol (ETOH) use with 52% reporting active abuse. Multivariate analyses indicated that Me use did not adversely affect referral, evaluation, or treatment rates compared with patients without Me use and patients with prior ETOH abuse. Active ETOH users had lower treatment initiation and success rates compared with Me groups. Patients actively using illicit drugs were 66% less likely to attend a liver biopsy (p=0.015). Conclusions: Me use is common in recent US veterans diagnosed with hepatitis C and occurs in younger patients with frequent concomitant marijuana use. Prior history or recent/active Me use alone does not appear to adversely affect overall HCV clinic referral, testing, evaluation, or treatment compared with new HCV patients without Me use and patients with prior ETOH abuse. Although, overall rates of treatment initiation are low in all groups at 17-20% and tended to be lowest in patients with active ETOH abuse (12%). These data indicate that facilitated access to SUD treatment in HCV clinics may be of benefit for multiple SUD issues to increase HCV treatment rates.(VA HSR&D grant IIR 07-101-3)
M1780 Association of Autophagy with HCV Replication in Chronic Hepatitis C Patients Shunhei Yamashina, Tomokazu Mizui, Motoki Takashima, Hisafumi Yamagata, Tomonori Aoyama, Reiko Yaginuma, Kazuyoshi Kon, Kenichi Ikejima, Sumio Watanabe Background: Previous investigation revealed that autophagy, which involved the bulk degradation of cellular contents during nutrition starvation, is required for viral RNA replication. Recently, it was reported that HCV replicon induced autophagosome formation and autophagic proteolysis plays a pivotal role in replication of HCV replicon. Here we examined if the induction of autophagy correlates with viral replication, liver fibrosis, inflammation and sensitivity to interferon therapy in patients with chronic hepatitis C. Patients and Methods: The subjects of this study were 68 patients infected with hepatitis C virus who underwent liver biopsy, and 58 of 68 patients received interferon therapy. Liver Histology was classified into five stages and four grades according to the METAVIR classification. Cytoplasmic double membrane vesicle of hepatocytes into liver section was identified as autophagosome or autolysosome and counted by using transmission electron microscope. Serum HCV-RNA was quantified by competitive RT-PCR methods. Data were statistically analyzed by Pearson correlation test or ANOVA. Results: The distribution of HCV genotype was: 1b: 55 patients, 2a and 2b: 13 patients. The number of autophagosome of hepatocyte in genotype 1b (4.17 ± 0.22 /100μm2) is not significant difference from 2a and 2b (5.05 ± 0.49 /100μm2). The number of autophagosome in 1b was correlated with serum HCVRNA values (r=0.66, p<0.01). On the other hand, liver histological grade was not significantly associated with the number of autophagosome of hepatocyte(r=-0.12, p=0.48). Liver histological stage was significantly associated with the number of autophagosome of hepatocyte(r=0.34, p<0.05). In early virological response (EVR) of HCV genotype 1b-infected patients, measured as HCV-RNA negatively 1 month into treatment, the number of autophagosome was significantly less than in non EVR of 1b-infected patients (p<0.01). Conclusion: It is likely that the number of autophagosome of hepatocyte in patients with chronic hepatitis C is associated with not only the replication of HCV but also viral clearance during IFN therapy. These findings suggest that the number of autophagosome is useful as a new therapeutic marker to predict the efficacy of IFN therapy in patients with chronic hepatitis C.
M1779 Risk Factors for Hepatitis C Acquisition Are More Likely to Be Unidentifiable in Asian-Americans Compared to Caucasians or Hispanics (Prospective Study) Edith Y. Ho, Nghiem B. Ha, Mindie H. Nguyen Background/Aim: Hepatitis C virus (HCV) infections are generally associated with a history of blood transfusions, injecting drug use, body tattoos, intranasal cocaine use, and multiple sexual partners. We hypothesized that risk factors for HCV acquisition are more likely to be unidentifiable in Asian-Americans(AA) compared to Caucasians(CAU) or Hispanics(HIS). Methods: We performed a prospective study with a detailed risk assessment questionnaire of 494 HCV patients at a liver center in California, USA in 2001-2008. Results: 55% identified themselves as CAU, 20% as HIS, and 25% as AA. Among these groups, 19% of CAU, 30% of HIS, and 59% of AA were foreign born (p<0.0001). Genotype 1 was most common in all groups (74-75%). 4% of CAU, 7% of HIS, and 15% of AA reported no known risk factors such as blood transfusions, injection drug use, acupuncture, body tattoos, or snorting cocaine; 18% CAU, 22% of HIS, and 45% of AA reported one risk factor; 78% of CAU, 71% of HIS, and 41% AA reported more than one risk factor (p<0.0001) -Figure. Injection drug use, cocaine snorting, and tattoos were significantly higher in CAU and HIS compared to AA, who were more likely to have exposure to acupuncture (p<0.0001). Of the AAs who reported one risk factor, 42% was due to acupuncture. Conclusions: AA are more likely to present with unidentifiable risk exposures for HCV while CAU and HIS are more likely to present with multiple risk exposures. Therefore, commonly known risk factors for HCV may be more appropriate for risk assessment of CAU and HIS, but not AA. These findings pose major implications for developing strategies for HCV screening in our increasingly culturally diverse population.
AASLD Abstracts
M1781 Rapid Virologic Response Predicts Sustained Virologic Response in Hepatitis C Patients Treated with Pegylated Interferon and Ribavirin Therapy Shahzad Sarwar, Masood Iqbal, P Aiden McCormick, Cliona O'Farrelly, John E. Hegarty Introduction: Pegylated interferon and ribavirin is the standard treatment for chronic hepatitis C. Due to differences in viral characteristics genotype 1 is treated for 12 months and genotype 3 for 6 months. Recent data suggest that efficacy of treatment depends upon rapidity of virological clearance. We hypothesised that rapid virological response (RVR) predicts sustained virological response (SVR). Aims: To evaluate the predictive value of RVR on SVR in chronic Hepatitis C patients treated with pegylated interferon and ribavirin therapy Methods: We performed a retrospective review of 191 patients undergoing treatment for hepatitis C between May 2001 and March 2007. Patients who had HCV RNA tested at baseline, 4 weeks, and 24 weeks after the end of treatment were included in the study (n=123). All patients received peg-INF- α2a 180 ug / week or peg-INF- α2b 1.5 ug/kg/ week subcutaneously with ribavirin. Patients with genotype 1 were treated for 12 months and genotypes 2 and 3 for 6 months. RVR was defined as undetectable HCV RNA 4 weeks after starting treatment. SVR was defined as undetectable HCV RNA 24 weeks after completion of treatment. Results: Of the 123 patients in this study, 81 were male and 42 female with the mean age of 42 years. 62 patients were genotype 1, 55 genotype 3 and 6 genotype 2. Due to
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similar response rates genotype 2 and 3 were analysed together. Overall, 86 patients (69.9%) achieved RVR and of these, 77 (89.5%) had SVR. RVR rates for genotype 1 patients (53.2%) were significantly lower (86.8%) than genotype 2 and 3 (chi(2)=16.563, p=0.000). SVR rates for genotype 1 patients who had achieved RVR (90.4%) were significantly higher than those (9.6%) who had not achieved RVR (chi(2)= 3.232, p=0.000). Of 33 patients with genotype 1 who had achieved RVR, 27 (81.8%) had SVR and of 29 patients who did not achieve RVR, only 4 (13.7%) had SVR. Similarly, of 53 patients with genotypes 2 and 3 who had RVR, 50 (94.3%) had SVR and of 8 patients who did not have RVR, 4 (50%) had SVR. Significant factors associated with SVR were RVR (chi(2)=56.011, p=0.000), genotype (chi(2)=19.319, p=0.000), baseline AST level (p=0.031) and baseline viral load (p=0.049). The positive and negative predictive values of RVR in genotype 1 patients were 82% and 86% respectively and in genotype 2 and 3, 94% and 50% respectively. Conclusion: RVR in patients with chronic hepatitis C, genotype 1 was significantly lower than genotypes 2 and 3. SVR rates were significantly higher in patients who had achieved RVR. RVR predicts SVR in genotypes 1, 2 and 3. RVR, Genotype, baseline viral load and baseline AST level were significant factors for predicting SVR.
M1784
Background: Veteran patients with hepatitis C (HCV) often suffer from depression, which can worsen during antiviral treatment and contribute to treatment non-compliance. Aim: To compare the effects of using a standardized questionnaire to recognize and treat depression with those of patient self-reporting of depression symptoms on the outcome of treatment for chronic HCV with pegylated interferonα-2b and ribavirin. Methods: 129 naive patients who were about to start treatment for chronic HCV were randomized to receive periodic assessment of depression symptoms during antiviral therapy using either the Centers for Epidemiology Studies for Depression Scale (CES-D) questionnaire (group A, n=57) or by asking the patients to self-report depression symptoms (group B, n=72). For patients in group A, antidepressants (ADs) were begun when CES-D scores were between 11 and 13, whereas ADs were started for patients in group B based solely on the physician's evaluation of the need for AD therapy. Baseline patient characteristics recorded included age, gender, ethnicity, HCV genotype, liver disease stage, laboratory values, prior treatment with ADs, and history of depression and other psychiatric disorders. Results: There were no significant differences in baseline characteristics between the two groups; a prior history of depression was common in both groups (49% group A, 51% group B) as was a history of other psychiatric disorders (26% group A, 27% group B). At the conclusion of antiviral therapy, there were no significant differences between the groups in rates of SVR (30% group A, 35% group B) or in rates of overall compliance with therapy (% patients receiving >80% of prescribed therapy: 82% group A, 80% group B). Overall, Chi Square analysis revealed that those who started an antidepressant at 0-12 weeks of treatment were significantly more likely to be in >90% compliance category than patients who did not receive early AD therapy (X2 = 4.5, p = .025 and ribavirin compliance X2 = 18.4, p=.005). Conclusion:The use of the CES-D questionnaire to recognize and treat depression had no significant advantage over patient self-reporting of depression symptoms on the outcome of antiviral therapy for HCV with respect to rates of SVR and compliance with treatment. Irrespective of how depression is recognized, however, the early use of AD treatment (within the first 12 weeks of antiviral therapy) is associated with significantly better rates of compliance.
M1782 Characteristics of HBeAg-Positive Patients with HBsAg Loss/Seroconversion Following Treatment with Tenofovir Disoproxil Fumarate (TDF) Jenny Heathcote, George Germanidis, Geoffrey M. Dusheiko, Ira M. Jacobson, Robert A. De Man, Paul Nikolaidis, Patrick Marcellin, Jeff Sorbel, Jane Anderson, Elsa Mondou, Joe Quinn, Franck Rousseau Background: In the phase 3 study in HBeAg-positive patients (study 103), HBsAg loss was observed in significantly more TDF-treated patients versus adefovir dipivoxil (ADV) at Week (W) 48: 3.2% TDF versus 0% ADV (p=0.02). Methods: Patients with HBeAg-positive chronic hepatitis B (CHB) were randomized to double-blind, once daily TDF 300 mg (N=176) or adefovir dipivoxil 10 mg (ADV) (N=90). After W48, eligible patients (with a week 48 biopsy) initiated open-label TDF for an additional 7 years. Results: Six percent of patients (10 TDFTDF and 5 ADV-TDF) experienced HBsAg loss by W96 (11/15 anti-HBs). Of these 15, 100% were Caucasian, 80% men and 80% from Europe with a median (min, max) age of 35 years (20, 64). All patients were naïve to interferon. Median baseline HBsAg levels were 5.11 log10IU/mL (4.62, 5.38), HBV DNA levels were 9.48 log10 copies/mL (8.47, 9.64), median ALT 150 U/L (75, 425) and the median pretreatment Knodell necroinflammatory score was 9.4 (5.0, 12.0). Sixty-seven percent had bridging fibrosis or cirrhosis prior to treatment. Sixty percent (n=9) harbored genotype A and 40% (N=6) harbored genotype D virus. Although most patients lost HBeAg prior to HBsAg loss, this pattern was not uniform. Although no patient in the ADV arm achieved HBsAg loss within the first 48 weeks, by week 96 (after 48 weeks of open label TDF) the same percentage of patients achieved HBsAg loss. However, no ADV-TDF patient achieved HBsAg loss until week 80 or later. Patients with HBsAg loss had high HBV DNA and HBsAg levels at baseline however there was no clear correlation between baseline ALT levels and HBsAg loss. Conclusion: Tenofovir DF induces loss of HBsAg in Caucasian patients infected with genotype A or D virus and with high HBV DNA and high HBsAg levels prior to treatment.
M1785 Predictors of Sustained Virologic Response to Pegylated Interferon and Ribavirin in a National Cohort of Male HIV/HCV-Coinfected Veterans in Routine Medical Care Lisa I. Backus, Derek B. Boothroyd, Larry A. Mole BACKGROUND: Most information on HCV sustained virologic response (SVR) in HIV/HCV patients comes from clinical trials (e.g. APRICOT and ACTG A5071) and may not reflect the experience in routine care. We evaluated the predictors of SVR for Veterans Affairs (VA) HIV/HCV patients receiving pegylated interferon (PEG) and ribavirin (RBV) in routine care. METHODS: We identified patients in the VA HIV Clinical Case Registry with a first PEG prescription before 1 January 2005, a RBV prescription within 7 days of first PEG, a baseline detectable HCV RNA, a baseline CD4 count and HIV RNA prior to PEG/RBV, and HCV genotype (GT) 1, 2 or 3. We defined SVR as undetectable HCV RNA on all tests after PEG/ RBV with at least one test more than 12 weeks after stopping therapy. We excluded patients with undetectable HCV RNA but no test 12 weeks or more after treatment. Patients without a HCV RNA test after stopping PEG/RBV or with a detectable HCV RNA at any time after treatment were considered “no SVR.” We conducted single predictor analyses to compare patient demographics, baseline lab results and baseline clinical characteristics between patients who did and did not have a SVR. We then performed backward stepwise deletion multiple logistic regression analysis starting with variables differing at P<0.1 in single predictor analyses, fitting by penalized maximum likelihood and calculating p-values by profile likelihood. RESULTS: Among 346 HIV/HCV patients who began PEG/RBV, SVR rates were 9% for GT 1 (26/278), 49% for GT 2 (18/37), and 39% for GT 3 (12/31)(P<0.001). Of the baseline factors examined, race, ALT≥3xULN, HCV GT, HCV RNA<500,000 IU/mL, PEG form (2A or 2B), starting on a recommended PEG dose and starting on a recommended RBV dose differed in single predictor analyses at P<0.05 while nadir CD4 count and current diabetes differed at P<0.1. In multivariate analysis, lower HCV RNA, HCV GT (2 or 3 vs. 1), elevated ALT and PEG form 2A were significant positive predictors of SVR while diabetes was a significant negative predictor of SVR. Most treated VA patients would have been excluded from clinical trials. Of this cohort, 57% (196) would have been excluded from APRICOT for example based on prior interferon or lab criteria and a total of 74% (256) may have been excluded by including a current diagnosis of diabetes or depression. CONCLUSION: Our results confirm that HIV/HCV patients with lower baseline HCV RNA and HCV GT 2 or 3 are more likely to respond to PEG/RBV. Baseline ALT, PEG form and diabetes also substantially impact the likelihood of SVR. Response rates in routine practice are substantially lower than in clinical trials.
M1783 Effect of Pegylated-IFN-Alpha-2a Monotherapy in Patients with Chronic Hepatitis C Infected with Low Pretreatment Viremia and Relationship to Amino Acid Substitutions in NS5A Region Kazuhiko Hayashi, Yoshiaki Katano, Isao Nakano, Masatoshi Ishigami, Kentaro Yoshioka, Hidenori Toyoda, Takashi Kumada, Hidemi Goto (Background) Previous studies suggest that patients with chronic hepatitis C infected with a low pretreatment hepatitis C virus (HCV) level have a high sustained virologic response (SVR) rate, and there would be a subpopulation of patients in which HCV can be eradicated with pegylated-IFN-alpha alone without a decrease in SVR. However, the efficacy and safety of pegylated-IFN-alpha 2a monotherapy in patients with low pretreatment HCV-RNA level were unclear. There was a motif of the PKR binding domain in NS5A region of HCV which were called IFN sensitivity-determining region (ISDR) and thought to be inhibited the PKR which associated with IFN pathway. As a result, several studies reported relationship between ISDR and IFN responsiveness. However, this relation is controversial. The aim of the present study was to determine whether genomic heterogeneity of the ISDR among patients with low pretreatment HCV-RNA level affects the response to pegylated-IFN-alpha 2a monotherapy. (Methods) We studied 83 patients (49 men, 34 women; mean age, 54.4±13.2 years) infected with low HCV level. The low HCV level was defined as less than 200KIU/ml. HCV genotypes 1b (n = 26), 2a (n = 49), 2b (n = 6) and unknown (n =2) were detected. The ISDR were examined by direct sequencing and classification was counting the number of amino acid substitutions compared by consensus strains of each genotype. All patients received subcutaneous injections of pegylated-IFN-alpha 2a once a week for 24 or 48 weeks. (Results) Sixty eight of 83 (81.9%) patients showed rapid virologic response (RVR) as HCV negative at 4 weeks. Negativity of HCV at the end of treatment was 100%. Seventy-four of 83 (89.2%) patients showed a sustained virologic response (SVR). SVR rates according HCV genotype 1b, 2a and 2b were 76.9%, 93.9% and 100%, respectively. HCV genotype 1b was detected more frequently in patients with non-SVR (66.7%) than in patients with SVR (27.0%) (p= 0.024). Achievement to SVR occurred more frequently in patients without reduction of IFN (94.1%) than in those with reduction of IFN (66.7%) (P = 0.0082). Patients with SVR had a significantly higher number of mutations in the ISDR than did patients with non-SVR (p= 0.001). Factor related to SVR by multivariate analysis was ISDR (OR, 0.01; 95%CI, 0.010.625; p =0.0286). There were no significant differences in the factors, including sex, age, aspartate aminotransferase, alanine aminotransferase, platelet count, HCV genotypes, HCV viral load, total dose of IFN, and RVR. (Conclusions) Patients with low HCV levels and more than 2 mutations in the ISDR are significantly associated with good response to pegylated-IFN-alpha 2a monotherapy.
M1786 Response to Peginterferon (PEG IFN) and Ribavirin (RBV) in Asian Americans and Non-Asian Americans with Chronic Hepatitis C (CHC) in a Real-Life Community Setting: A Multi-Center Study Philip Vutien, Nghia H. Nguyen, Huy N. Trinh, Jiayi Li, Ruel T. Garcia, Carrie R. Wong, Emmet B. Keeffe, Gabriel Garcia, Khanh K. Nguyen, Huy A. Nguyen, Brian S. Levitt, Mindie H. Nguyen BACKGROUND: Per WHO, 95M out of 169M patients with CHC patients are Asian. However, only a few small studies to date have suggested that Asian patients with CHC may have higher SVR rates than non-Asian patients. Our goal is to compare treatment response to PEG-IFN + RBV in a large cohort of Asian Americans (AA) and Non-Asians (NA) with HCV
A-837
AASLD Abstracts
AASLD Abstracts
Effects of Recognizing Depression with a Standardized Questionnaire (CES-D) vs. Patient Self-Reporting of Depression On the Outcome of Treatment for Hepatitis C with Pegylated Interferon α-2B and Ribavirin. Frances H. Phillips, Melanie Prebis, Teresa Hale, Catherine Grumbeck, Raul Cubillas, Geri Brown