Liver Int. 2010 Aug 29. [Epub ahead of print]
Myers RP, Crotty P, Pomier-Layrargues G, Ma M, Urbanski SJ, Elkashab M.
Liver Unit, Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada.
Abstract
Abstract Background and aims: Liver stiffness measurement (LSM) by transient elastography (TE) is widely used for the noninvasive assessment of fibrosis. Our objectives were to examine the prevalence, risk factors and causes of discordance between fibrosis estimated by TE and liver biopsy. Methods: Two hundred and fifty-one patients with hepatitis B, C and nonalcoholic fatty liver disease underwent LSM by TE and liver biopsy. Predictors of discordance (>/=2 fibrosis stages) between measures, which occurred in 14% of patients (n=35), were identified by comparing patient, TE and biopsy characteristics of discordant and nondiscordant cases. Results: According to predefined criteria, 40% of discordances were attributed to TE error and 23% to biopsy error; 37% were indeterminate. In multivariate analysis, mild fibrosis (F0-2 vs. F3-4), and higher body mass index (BMI), ALT and LSM variability [assessed by the ratio of the interquartile range to median LSM (IQR/M)] were independently associated with discordance. Discordance was three-fold more common in patients with obesity (28 vs. 9%), ALT>/=60 U/L (20 vs. 7%) and IQR/M >/=0.17 (22 vs. 7%; all P<0.005). Based on these variables, a discordance risk score assigning 1 point to each factor was developed. The prevalence of discordance in patients with 0, 1, 2 and 3 factors were 2, 7, 20, and 55% respectively (P<0.0005). Conclusions: Discordance between liver fibrosis estimated by TE and biopsy occurs in one in seven patients. In assessing the validity of TE results, clinicians must recognize risk factors for discordance and in at-risk patients, consider alternative measures including biomarkers and possibly biopsy.
PMID: 20807336 [PubMed - as supplied by publisher]
Source
September 21, 2010
Intensified peginterferon alfa-2a/ribavirin therapy for patients with HCV genotype 1, weight >/=85 kg and high viral load: randomized trial
Gastroenterology. 2010 Sep 2. [Epub ahead of print]
Reddy KR, Shiffman ML, Rodriguez-Torres M, Cheinquer H, Abdurakhmanov D, Bakulin I, Morozov V, Silva GF, Geyvandova N, Stanciu C, Rabbia M, McKenna M, Thommes JA, Harrison SA; PROGRESS Study Investigators.
Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA.
Abstract
BACKGROUND & AIMS: Patients infected with hepatitis C virus (HCV) genotype 1, body weights >/=85 kg and high baseline viral loads respond poorly to standard doses of peginterferon and ribavirin. We evaluated the effects of intensified therapy with peginterferon alfa-2a plus ribavirin.
METHODS: We performed a double-blind, randomized trial of outpatients from hepatology clinics who were infected with HCV genotype 1. Patients in the study had body weights >/=85 kg and HCV RNA titers >/=400,000 IU/mL. Patients were randomized to 180 mug/week peginterferon alfa-2a for 48 weeks in combination with 1200 mg/day ribavirin (standard of care) (group A, N=191) or 1400/1600 mg/day ribavirin (group B, N=189). Additional groups included those who received 360 mug/week peginterferon alfa-2a for 12 weeks and then 180 mug/week peginterferon alfa-2a for 36 weeks, combined with 1200 mg/day ribavirin (group C, N=382) or 1400/1600 mg/day ribavirin (group D, N=383). All patients were followed for 24 weeks after treatment.
RESULTS: Sustained virologic response rates (HCV RNA <15 IU/mL at the end of the follow-up period) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A+B vs. C+D: odds ratio [OR]=1.08, 95% confidence interval [CI]=0.83-1.39, P=0.584) or pooled ribavirin regimens (A+C vs. B+D: OR=1.00, 95% CI=0.79-1.28, P=0.974).
CONCLUSIONS: In patients infected with HCV genotype 1 who are difficult to treat (high viral load and body weight >/=85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen.
PMID: 20816836 [PubMed - as supplied by publisher]
Source
Reddy KR, Shiffman ML, Rodriguez-Torres M, Cheinquer H, Abdurakhmanov D, Bakulin I, Morozov V, Silva GF, Geyvandova N, Stanciu C, Rabbia M, McKenna M, Thommes JA, Harrison SA; PROGRESS Study Investigators.
Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA.
Abstract
BACKGROUND & AIMS: Patients infected with hepatitis C virus (HCV) genotype 1, body weights >/=85 kg and high baseline viral loads respond poorly to standard doses of peginterferon and ribavirin. We evaluated the effects of intensified therapy with peginterferon alfa-2a plus ribavirin.
METHODS: We performed a double-blind, randomized trial of outpatients from hepatology clinics who were infected with HCV genotype 1. Patients in the study had body weights >/=85 kg and HCV RNA titers >/=400,000 IU/mL. Patients were randomized to 180 mug/week peginterferon alfa-2a for 48 weeks in combination with 1200 mg/day ribavirin (standard of care) (group A, N=191) or 1400/1600 mg/day ribavirin (group B, N=189). Additional groups included those who received 360 mug/week peginterferon alfa-2a for 12 weeks and then 180 mug/week peginterferon alfa-2a for 36 weeks, combined with 1200 mg/day ribavirin (group C, N=382) or 1400/1600 mg/day ribavirin (group D, N=383). All patients were followed for 24 weeks after treatment.
RESULTS: Sustained virologic response rates (HCV RNA <15 IU/mL at the end of the follow-up period) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A+B vs. C+D: odds ratio [OR]=1.08, 95% confidence interval [CI]=0.83-1.39, P=0.584) or pooled ribavirin regimens (A+C vs. B+D: OR=1.00, 95% CI=0.79-1.28, P=0.974).
CONCLUSIONS: In patients infected with HCV genotype 1 who are difficult to treat (high viral load and body weight >/=85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen.
PMID: 20816836 [PubMed - as supplied by publisher]
Source
Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin
Hepatology. 2010 Aug;52(2):421-9.
Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H.
Department of Hepatology, Toranomon Hospital, Tokyo, Japan. akuta-gi@umin.ac.jp
Abstract
Genetic variation near the IL28B gene and substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG-IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the predictive factors of sustained virological response to a 12-week or 24-week regimen of triple therapy in 72 of 81 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 61% and 89%, respectively. Especially, the sustained virological response was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of sustained virological response. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished sustained virological response (84%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high sustained virological response (50%), and sustained virological response (12%) was the worst in patients who possessed both genotype non-TT and Gln70(His70). Conclusion: This study identified genetic variation near the IL28B gene and aa substitution of the core region as predictors of sustained virological response to a triple therapy of telaprevir/PEG-IFN/ribavirin in Japanese patients infected with HCV genotype 1b.
PMID: 20648473 [PubMed - indexed for MEDLINE]
Source
Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H.
Department of Hepatology, Toranomon Hospital, Tokyo, Japan. akuta-gi@umin.ac.jp
Abstract
Genetic variation near the IL28B gene and substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG-IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the predictive factors of sustained virological response to a 12-week or 24-week regimen of triple therapy in 72 of 81 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 61% and 89%, respectively. Especially, the sustained virological response was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of sustained virological response. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished sustained virological response (84%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high sustained virological response (50%), and sustained virological response (12%) was the worst in patients who possessed both genotype non-TT and Gln70(His70). Conclusion: This study identified genetic variation near the IL28B gene and aa substitution of the core region as predictors of sustained virological response to a triple therapy of telaprevir/PEG-IFN/ribavirin in Japanese patients infected with HCV genotype 1b.
PMID: 20648473 [PubMed - indexed for MEDLINE]
Source
Treatment of chronic hepatitis C in HIV-infected patients with compensated liver cirrhosis
J Viral Hepat. 2010 Aug 31. [Epub ahead of print]
Martín-Carbonero L, Tuma P, Vispo E, Medrano J, Labarga P, González-Lahoz J, Barreiro P, Soriano V.
Infectious Diseases Department, Hospital Carlos III, Madrid, Spain.
Abstract
Summary. The greatest benefit of hepatitis C virus (HCV) therapy is seen in cirrhotics attaining sustained virological response (SVR). However, concerns about toxicity and poorer responses often discourage treatment of cirrhotics. This may be particularly relevant in HIV-HCV-coinfected patients, in whom progression of liver fibrosis is faster and treatment responses lower. This is a retrospective analysis of HIV-HCV-coinfected patients who had received peginterferon-ribavirin therapy at our institution. Individuals naïve for interferon in whom liver fibrosis had been assessed using elastometry within the year before being treated were chosen. Response rates and toxicities were compared in cirrhotics (>14.5 KPa) and noncirrhotics. Patients with previous liver decompensation were excluded. Overall, 41 cirrhotics and 190 noncirrhotics entered the study. Groups were similar in age, gender, HCV genotypes and baseline serum HCV-RNA. SVR occurred at similar rates in cirrhotic and noncirrhotics, either considered by intention-to-treat (39%vs 45%; P = 0.4) or as treated (50%vs 52%, P = 0.8). In multivariate analysis (odds ratio, 95% CI, P), SVR was associated with HCV genotypes 2-3 (5, 2.9-11, <0.01) and lower serum HCV-RNA (2, 1.4-3.03 for every log decrease, <0.01) but not with cirrhosis (1.2, 0.4-3.6, 0.6). Treatment discontinuations because of adverse events tended to be more common in cirrhotics than in noncirrhotics (17%vs 12%; P = 0.2), but only severe thrombocytopenia was more frequent in cirrhotics than in non-cirrhotics (20%vs 3% at week 24; P < 0.01). Response to peginterferon-ribavirin therapy is similar in HIV-HCV coinfected patients with and without liver cirrhosis. Therefore, treatment must be encouraged in all compensated cirrhotic patients, although closer monitoring and management of side effects, mainly thrombocytopenia, may be warranted.
PMID: 20819149 [PubMed - as supplied by publisher
Source
Martín-Carbonero L, Tuma P, Vispo E, Medrano J, Labarga P, González-Lahoz J, Barreiro P, Soriano V.
Infectious Diseases Department, Hospital Carlos III, Madrid, Spain.
Abstract
Summary. The greatest benefit of hepatitis C virus (HCV) therapy is seen in cirrhotics attaining sustained virological response (SVR). However, concerns about toxicity and poorer responses often discourage treatment of cirrhotics. This may be particularly relevant in HIV-HCV-coinfected patients, in whom progression of liver fibrosis is faster and treatment responses lower. This is a retrospective analysis of HIV-HCV-coinfected patients who had received peginterferon-ribavirin therapy at our institution. Individuals naïve for interferon in whom liver fibrosis had been assessed using elastometry within the year before being treated were chosen. Response rates and toxicities were compared in cirrhotics (>14.5 KPa) and noncirrhotics. Patients with previous liver decompensation were excluded. Overall, 41 cirrhotics and 190 noncirrhotics entered the study. Groups were similar in age, gender, HCV genotypes and baseline serum HCV-RNA. SVR occurred at similar rates in cirrhotic and noncirrhotics, either considered by intention-to-treat (39%vs 45%; P = 0.4) or as treated (50%vs 52%, P = 0.8). In multivariate analysis (odds ratio, 95% CI, P), SVR was associated with HCV genotypes 2-3 (5, 2.9-11, <0.01) and lower serum HCV-RNA (2, 1.4-3.03 for every log decrease, <0.01) but not with cirrhosis (1.2, 0.4-3.6, 0.6). Treatment discontinuations because of adverse events tended to be more common in cirrhotics than in noncirrhotics (17%vs 12%; P = 0.2), but only severe thrombocytopenia was more frequent in cirrhotics than in non-cirrhotics (20%vs 3% at week 24; P < 0.01). Response to peginterferon-ribavirin therapy is similar in HIV-HCV coinfected patients with and without liver cirrhosis. Therefore, treatment must be encouraged in all compensated cirrhotic patients, although closer monitoring and management of side effects, mainly thrombocytopenia, may be warranted.
PMID: 20819149 [PubMed - as supplied by publisher
Source
The 61st Annual Meeting of the American Association for the Study of Liver Diseases
Boston, MA - Hynes Convention Center
October 30 - November 2, 2010
PR Newswire
ALEXANDRIA, Va., Sept 20
ALEXANDRIA, Va., Sept 20 /PRNewswire/ -- The Liver Meeting® is the premier meeting in the science and practice of hepatology, including the latest findings on new drugs, novel treatments, and the results from pilot and multicenter studies.
Approximately 10 percent of Americans have some form of liver disease, and the diseases strike disproportionately among certain populations but mostly regardless of lifestyle choices. There are now numerous treatments for both hepatitis B and C, and screening, treatment, and prevention of hepatitis remain important issues. Liver cancer is one of the few cancers growing in incidence, and the obesity epidemic has dire consequences for the nation's liver health and wellness.
The 2047 abstracts addressing these issues that will be presented are available to members of the press at our website (http://www.aasld.org/), including 258 abstracts that will be presented in oral sessions.
Boston, MA – October 30 - November 2, 2010
Poster Presentations: October 30 – November 2
Oral Presentations: October 31 – November 2
An AASLD President's press conference highlighting key abstracts and issues presented at the Liver Meeting® is scheduled for Saturday, October 30 at 4:00 pm.
This year's President's Choice Lecture will be given by the 14th Assistant Secretary for Health for the US Department of Health and Human Services, Dr. Howard Koh. The lecture will focus on the findings from the Institute of Medicine (IOM) study, "Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C." Dr. Koh has provided visionary and extraordinary leadership in assembling a US Department of Health and Human Services-wide team to begin to address the epidemic of viral hepatitis in the US. He will speak about his efforts and the steps the US administration is taking in response to the IOM report. AASLD has worked jointly with the Trust for America's Health (TFAH) to translate the IOM report into language that could be used to affect appropriations to support research and health care delivery for liver disease and also to be used in future legislation to make the screening, early detection, and treatment of viral hepatitis a reality. The AASLD/TFAH report will focus on the policy issues that need to be addressed to advance the implementation of the IOM's work.
Founded in 1950, AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD has grown into an international society responsible for all aspects of hepatology, and our annual meeting attracts 7,500 physicians, surgeons, researchers, and allied health professionals from around the world.
Please contact AASLD at 703-299-9766 for information about the above presentations, or to receive any additional information about The Liver Meeting® – or visit our website at http://www.aasld.org/.
This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.xpresspress.com/.
Contact:
Gregory Bologna, gbologna@aasld.org
Ann Haran, aharan@aasld.org
SOURCE American Association for the Study of Liver Diseases (AASLD)
Read more: http://www.digitaljournal.com/pr/117474#ixzz10CucnSV4
Source
October 30 - November 2, 2010
PR Newswire
ALEXANDRIA, Va., Sept 20
ALEXANDRIA, Va., Sept 20 /PRNewswire/ -- The Liver Meeting® is the premier meeting in the science and practice of hepatology, including the latest findings on new drugs, novel treatments, and the results from pilot and multicenter studies.
Approximately 10 percent of Americans have some form of liver disease, and the diseases strike disproportionately among certain populations but mostly regardless of lifestyle choices. There are now numerous treatments for both hepatitis B and C, and screening, treatment, and prevention of hepatitis remain important issues. Liver cancer is one of the few cancers growing in incidence, and the obesity epidemic has dire consequences for the nation's liver health and wellness.
The 2047 abstracts addressing these issues that will be presented are available to members of the press at our website (http://www.aasld.org/), including 258 abstracts that will be presented in oral sessions.
Boston, MA – October 30 - November 2, 2010
Poster Presentations: October 30 – November 2
Oral Presentations: October 31 – November 2
An AASLD President's press conference highlighting key abstracts and issues presented at the Liver Meeting® is scheduled for Saturday, October 30 at 4:00 pm.
This year's President's Choice Lecture will be given by the 14th Assistant Secretary for Health for the US Department of Health and Human Services, Dr. Howard Koh. The lecture will focus on the findings from the Institute of Medicine (IOM) study, "Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C." Dr. Koh has provided visionary and extraordinary leadership in assembling a US Department of Health and Human Services-wide team to begin to address the epidemic of viral hepatitis in the US. He will speak about his efforts and the steps the US administration is taking in response to the IOM report. AASLD has worked jointly with the Trust for America's Health (TFAH) to translate the IOM report into language that could be used to affect appropriations to support research and health care delivery for liver disease and also to be used in future legislation to make the screening, early detection, and treatment of viral hepatitis a reality. The AASLD/TFAH report will focus on the policy issues that need to be addressed to advance the implementation of the IOM's work.
Founded in 1950, AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD has grown into an international society responsible for all aspects of hepatology, and our annual meeting attracts 7,500 physicians, surgeons, researchers, and allied health professionals from around the world.
Please contact AASLD at 703-299-9766 for information about the above presentations, or to receive any additional information about The Liver Meeting® – or visit our website at http://www.aasld.org/.
This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.xpresspress.com/.
Contact:
Gregory Bologna, gbologna@aasld.org
Ann Haran, aharan@aasld.org
SOURCE American Association for the Study of Liver Diseases (AASLD)
Read more: http://www.digitaljournal.com/pr/117474#ixzz10CucnSV4
Source
Heterosexual Sex Not a Major Risk Factor for Hepatitis C Virus Transmission
SUMMARY: Sex between women and men does not appear to be a common route of hepatitis C virus (HCV) transmission, according to study results reported last week at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) in Boston. These findings confirm prior research showing a low rate of heterosexual HCV transmission, in contrast with the higher rate reported for HIV positive gay and bisexual men.
By Liz Highleyman
Over the past decade, researchers have reported several outbreaks of acute hepatitis C among men who have sex with men that appear to be due to sexual transmission. This conflicts with public health guidelines stating that sexual transmission of HCV is uncommon, but these were based on studies of monogamous heterosexual couples.
To shed further light on this issue, Monina Klevens from the U.S. Centers for Disease Control and Prevention (CDC) and colleagues collected data from surveillance of new HCV infections reported during 2005-2009 by health departments in Colorado, Connecticut, Minnesota, Oregon, and 34 counties in New York State.
Included cases met clinical criteria (acute illness with at least 1 sign or symptom of viral hepatitis and either jaundice or elevated alanine aminotransferase [ALT]) or laboratory criteria (confirmed positive HCV antibody test) for acute hepatitis C.
The health departments collected demographic and clinical data for each case, and asked patients or their healthcare providers for information about 21 potential HCV risk behaviors occurring 2 weeks to 6 months before the onset of symptoms.
Results
--76.5% with 2-5 partners;
--54.6% with 1 partner.
Investigator affiliations: CDC, Atlanta, GA; Colorado Dept. of Public Health and Environment, Denver, CO; Connecticut Dept. of Public Health, Hartford, CT; Minnesota Dept. of Health, St. Paul, MN; New York State Dept. of Health, Albany, NY; Oregon Public Health Div., Portland, OR.
9/21/10
Reference
M Klevens, D Daniels, K Iqbal, and others. Is Heterosexual Transmission an Important Risk Factor for Hepatitis C in the United States? 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. (Abstract V-1787).
Source
By Liz Highleyman
Over the past decade, researchers have reported several outbreaks of acute hepatitis C among men who have sex with men that appear to be due to sexual transmission. This conflicts with public health guidelines stating that sexual transmission of HCV is uncommon, but these were based on studies of monogamous heterosexual couples.
To shed further light on this issue, Monina Klevens from the U.S. Centers for Disease Control and Prevention (CDC) and colleagues collected data from surveillance of new HCV infections reported during 2005-2009 by health departments in Colorado, Connecticut, Minnesota, Oregon, and 34 counties in New York State.
Included cases met clinical criteria (acute illness with at least 1 sign or symptom of viral hepatitis and either jaundice or elevated alanine aminotransferase [ALT]) or laboratory criteria (confirmed positive HCV antibody test) for acute hepatitis C.
The health departments collected demographic and clinical data for each case, and asked patients or their healthcare providers for information about 21 potential HCV risk behaviors occurring 2 weeks to 6 months before the onset of symptoms.
Results
- A total of 575 cases of acute HCV infection were reported.
- 63 cases (11.0%) had no reported risk factors and were excluded from the present analysis.
- Of the remaining 512 cases, 247 patients (48.2%) reported using drugs.
- 202 people (39.5%) reported exposure through heterosexual sex.
- 20 people (3.9%) reported sex with a same-sex partner.
- Most of the infected individuals who reported heterosexual sex (126 of 202) or homosexual sex (14 of 20) also reported drug use.
- Drug use increased with the number of sexual partners:
--76.5% with 2-5 partners;
--54.6% with 1 partner.
- 42 out of 202 people (20.8%) reported sexual contact with a person confirmed or suspected to have HCV infection.
- Just 19 out of 202 heterosexuals (9.4%) reported no other risk behaviors other than sex with an opposite-sex partner.
- Individuals who had heterosexual sex as their only risk behavior were significantly older than those with more risk factors (43 vs 35 years, respectively), but otherwise similar including race/ethnicity.
Investigator affiliations: CDC, Atlanta, GA; Colorado Dept. of Public Health and Environment, Denver, CO; Connecticut Dept. of Public Health, Hartford, CT; Minnesota Dept. of Health, St. Paul, MN; New York State Dept. of Health, Albany, NY; Oregon Public Health Div., Portland, OR.
9/21/10
Reference
M Klevens, D Daniels, K Iqbal, and others. Is Heterosexual Transmission an Important Risk Factor for Hepatitis C in the United States? 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. (Abstract V-1787).
Source
NIH Statement on National Gay Men’s HIV/AIDS Awareness Day
From Anthony S. Fauci, M.D., NIAID Director, on September 27, 2010
The third annual National Gay Men’s HIV/AIDS Awareness Day on Sept. 27, 2010, marks an occasion to reflect on how profoundly HIV/AIDS has affected gay and bisexual men. It also is a fitting time to recognize how much this group has influenced the development and implementation of strategies to prevent and treat the virus and the disease.
The HIV/AIDS epidemic continues to exact a terrible toll on gay and bisexual men. In the United States it is estimated that since AIDS was first recognized in 1981, more than half a million gay and bisexual men have been diagnosed with the disease and more than 300,000 have died. Stigma and fear hamper efforts to make HIV/AIDS prevention and treatment accessible to all gay and bisexual men who would benefit from them, both in the United States and abroad. Yet many gay and bisexual men have been instrumental as AIDS activists in raising awareness about the public health impact of HIV/AIDS, shaping the HIV/AIDS research agenda and advocating that this research is well funded. In addition, gay and bisexual men catalyzed the movement to bring treatment and care to people with HIV/AIDS and to promote HIV prevention. Tens of thousands of gay and bisexual men have participated as volunteers in HIV/AIDS research, including several large studies in progress that are funded by NIAID.
To read the full statement, go to http://www.niaid.nih.gov/news/newsreleases/2010/Pages/GayMenAIDSAwareness.aspx.
You are subscribed to News Releases for National Institute of Allergy and Infectious Diseases. This information has recently been updated, and is now available.
Source: Received via email
The third annual National Gay Men’s HIV/AIDS Awareness Day on Sept. 27, 2010, marks an occasion to reflect on how profoundly HIV/AIDS has affected gay and bisexual men. It also is a fitting time to recognize how much this group has influenced the development and implementation of strategies to prevent and treat the virus and the disease.
The HIV/AIDS epidemic continues to exact a terrible toll on gay and bisexual men. In the United States it is estimated that since AIDS was first recognized in 1981, more than half a million gay and bisexual men have been diagnosed with the disease and more than 300,000 have died. Stigma and fear hamper efforts to make HIV/AIDS prevention and treatment accessible to all gay and bisexual men who would benefit from them, both in the United States and abroad. Yet many gay and bisexual men have been instrumental as AIDS activists in raising awareness about the public health impact of HIV/AIDS, shaping the HIV/AIDS research agenda and advocating that this research is well funded. In addition, gay and bisexual men catalyzed the movement to bring treatment and care to people with HIV/AIDS and to promote HIV prevention. Tens of thousands of gay and bisexual men have participated as volunteers in HIV/AIDS research, including several large studies in progress that are funded by NIAID.
To read the full statement, go to http://www.niaid.nih.gov/news/newsreleases/2010/Pages/GayMenAIDSAwareness.aspx.
You are subscribed to News Releases for National Institute of Allergy and Infectious Diseases. This information has recently been updated, and is now available.
Source: Received via email
Importance of Adherence to HCV Regimens
Melissa Palmer, MD
Clinical Professor of Medicine
Department of Hepatology
Director
NYU Hepatology Associates - Plainview
New York University
Plainview, New York
Maximizing sustained virologic response (SVR) rates (an undetectable HCV RNA level 24 weeks after discontinuation of therapy) is the primary goal of therapy for patients with hepatitis C virus (HCV). This endpoint depends on numerous factors (Table), and adherence to therapy is one of the few variables that can be influenced by the patient and/or the healthcare team by using a multidisciplinary approach. Despite the known importance of treatment adherence in achieving viral eradication, adherence continues to be suboptimal, a fact underscored in a recent study demonstrating that only approximately 60% of patients with HCV in the United States adhered to prescribed therapy.[1] The dawn of a new era of HCV treatment is upon us with the anticipated approval of 2 novel direct-acting antivirals (DAAs) in the latter half of 2011. The addition of a DAA to the current standard of care regimen (peginterferon and ribavirin) enhances SVR rates and diminishes length of treatment in many patients.[2-5] However, issues of adherence will likely become even more significant, as the incidence of adverse events may rise, dosing schedules will become more complex, dietary requirements may be needed, and pill burden will increase. Furthermore, the lack of adherence to DAAs may select for HCV drug resistance mutations, a potentially serious consequence not present with the current standard of care regimen.
Table. Factors Affecting SVR Rates
Ribavirin Adherence
Several studies have shown that suboptimal ribavirin dosing and/or adherence leads to lower response rates. Indeed, studies have demonstrated that exposure to weight-based ribavirin vs fixed-dose ribavirin is associated with improved early virologic response and SVR rates.[11,12] In addition, a retrospective analysis of 5 clinical trials concluded that patients with genotype 1 HCV exposed to > 13 mg/kg/day of ribavirin had a 2.15-times greater chance of achieving an undetectable HCV RNA by Week 4 (rapid virologic response [RVR]) vs patients exposed to < 13 mg/kg/day of ribavirin (Capsule Summary).[13] Furthermore, genotype 1 patients not achieving RVR were statistically significantly less likely to achieve SVR when cumulative ribavirin dose exposure (due to dose reduction, premature cessation, or skipped doses) was < 60%.[6] In a study by Bronowicki and colleagues,[14] Patients with genotype 1 HCV who discontinued ribavirin after achieving an undetectable HCV RNA by Week 24 were significantly less likely to achieve an SVR vs patients who continued their ribavirin therapy (52.8% vs 68.2%, respectively; P = .004). Finally, dose reduction of ribavirin during the initial 12-20 weeks of therapy has been associated with diminished SVR rates in genotype 1 patients.[7,15,16]
Whereas cumulative ribavirin dose exposure was found not to influence RVR and SVR in genotype 2 patients,[17] the importance of maintaining adequate doses of ribavirin throughout the entire course of treatment was emphasized by Andriulli and colleagues[18] who found that patients with genotype 2/3 HCV had a significantly diminished SVR (54% vs 82%) when ribavirin was discontinued by Week 6 of treatment, even if RVR was achieved (Capsule Summary).
The primary role of ribavirin in HCV treatment is to reduce the likelihood of relapse. Indeed, in an evaluation of 984 genotype 1 HCV–infected patients treated with peginterferon alfa-2b plus ribavirin, the degree of ribavirin exposure was found to be inversely correlated with relapse rates. Only 11% of patients receiving ≥ 12 mg/kg/day of ribavirin relapsed compared with 60% of those receiving < 6 mg/kg/day.[19] In addition, only 4% of patients with an early virologic response in this trial relapsed when exposed to ribavirin doses > 12 mg/kg/day, and ribavirin exposure beyond Week 12 continued to affect relapse rates, demonstrating that ribavirin is inversely dose dependent correlated with relapse in patients with genotype 1 HCV responding to peginterferon plus ribavirin. This study demonstrated the importance of adhering to a dose of ≥ 12 mg/kg/day of ribavirin during the entire treatment period, especially in patients achieving an early virologic response.
Despite these findings, ribavirin adherence continues to be a challenge that appears to be more difficult to overcome than interferon adherence.[20-22] The effect of simplifying ribavirin pill burden was assessed in 2 studies comparing adherence rates in HCV-infected patients treated with fewer, higher-dose ribavirin tablets—a 400-mg or 600-mg ribavirin tablet available in a unit dose blister pack—vs the traditional 200-mg bottled ribavirin tablets. Results from an observational study of 92 patients with HCV from a single center found that patients taking peginterferon with the more compact formulation of ribavirin allowing a reduced pill burden (same total dose) experienced fewer adverse events, improved quality of life, better adherence to prescribed HCV therapy, and a trend toward higher SVR rates vs patients taking peginterferon plus the standard dosing of ribavirin.[23] In the multicenter Accurate Dosing in Hepatitis C: Examining the RibaPak Experience (ADHERE) study, patients who received their ribavirin in the form of the higher-dose tablets provided in a unit dose blister pack were less likely to prematurely stop therapy and more likely to adhere to prescribed HCV treatment at Weeks 12 and 24 compared with patients taking traditional 200-mg ribavirin tablets.[24] Streamlining ribavirin dosing regimens by decreasing pill count may become an even more important factor contributing to enhanced adherence once DAAs become part of HCV therapy, further increasing the regimen pill burden.
Assessment of Adherence
Although there is no gold standard of adherence measurement, it is important for all clinicians to incorporate strategies into their practices to assess adherence to prescribed HCV medications and to differentiate nonadherent patients from those who are truly nonresponders. Adherence analysis by a combination of patient self-report and electronic monitoring of the 401 patients who participated in the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (VIRAHEP-C) trial revealed that patient self-report overestimates compliance, that adherence wanes over time, and that patients are more likely to miss doses of ribavirin than peginterferon.[20] When pharmacy refill data during the initial 12 weeks of treatment was retrospectively evaluated in 188 predominantly HCV-monoinfected US veterans, adherence to peginterferon was found to be better than adherence to ribavirin—a finding consistent with other adherence studies.[10] A prospective, real-life, observational study of genotype 2 and 3 patients revealed that by 3 months of treatment, 20% of HCV patients self-reported missing 1 peginterferon injection whereas approximately 28% of patients self-reported missing 1200-mg ribavirin within the previous 4-week treatment period and that missed dosages of both agents increased at 6 months of treatment.[21] Of importance, this study also demonstrated that adherence at 6 months was better in those receiving patient therapeutic education during the initial 12 weeks of therapy compared with those not receiving patient education.
Suboptimal Adherence Identification and Management
In addition to reinforcing the importance of treatment adherence to patients, identification of individuals at increased risk for adverse events and aggressive management of adverse events are also necessary components of good clinical care that will enhance patient outcomes.
More than 20% of patients must decrease dose, temporarily discontinue, or prematurely stop ribavirin and/or peginterferon because of adverse events.[16,25,26] However, certain subsets of individuals may have more difficulty tolerating treatment compared with others. Mitra and colleagues[1] found that patients with advanced disease are less likely to be adherent to HCV therapy than those with early disease, a finding likely related to an increased susceptibility to adverse events.[27] A recent study showed that 61% of HCV/HIV-coinfected women and 48% of coinfected men experienced adverse events requiring dose modification of standard of care therapy.[28] Whereas traditionally believed to be poor candidates for HCV treatment because of an increased likelihood of nonadherence and susceptibility to psychiatric adverse events associated with treatment, injection drug users, including active drug users, have been found to be adherent to treatment with comparable SVR rates so long as psychosocial support is supplied.[29-31]
Hepatitis C virus is more common among people with psychiatric conditions compared with the general population,[32] and psychiatric illness, in particular depression, has been found to be a risk factor for HCV medication nonadherence. Development of depression while receiving therapy, which has been noted to occur in between 20% to 35% of patients,[25,26] may lead to discontinuation or decrease in dosage of medication with a resultant negative impact on outcome.[33,34] Pretreatment with antidepressants, specifically paroxetine, has been shown to reduce the severity of depression while receiving treatment in individuals displaying depressive symptoms at baseline.[35] The initiation of citalopram after the onset of interferon-induced depression controlled symptoms and enabled patients to complete the full course of standard-of-care treatment.[36] Therefore, to improve adherence, practitioners must evaluate all HCV-infected patients at baseline and during therapy for psychiatric symptoms and initiate antidepressants or antipsychotics promptly, as needed.
Anemia is an adverse effect of both interferon and ribavirin, with a decrease of hemoglobin of > 3 g/dL occurring in more than one half of patients receiving standard-of-care treatment.[37] Anemia often results in dose reduction or discontinuation, particularly of ribavirin, which may negatively affect outcome, especially in patients with genotype 1 HCV.[25] Reduction of the incidence and severity of treatment-induced anemia with erythropoietin has been shown to encourage adherence and to enable patients to remain on higher doses of ribavirin.[37,38] In a prospective, randomized, controlled trial evaluating the effect of erythropoietin on SVR, it was demonstrated that erythropoietin improved quality of life and improved SVR rates in some—but not all—patients with HCV.[8] Rapid virologic response rates did not improve significantly in HCV/HIV-coinfected patients preemptively given erythropoietin.[39] However, in HCV-infected patients achieving a > 2 log decline in HCV RNA after 4 weeks of therapy, SVR rates were significantly improved when anemia was managed with erythropoietin vs ribavirin dose reductions (81.8% vs 45.0%, respectively).[40] Therefore, treatment with erythropoietin should be considered in specific patients as a tool for enhancing medication adherence and improving outcomes, with an eye toward avoiding overcorrection that may result in thrombotic events.[41]
Conclusion
Although great excitement exists surrounding the future of HCV treatment, it must be emphasized that the increased complexity of treatment regimens, coupled with an associated rise in incidence of adverse events and the risk for development of drug resistance, will require even greater attention to adherence issues. Since adherence to prescribed HCV medication has been shown to be enhanced by a combination of patient education, patient motivation, reduced pill burden, and careful and prompt adverse effect management, clinicians should consider a multidisciplinary team approach to assess and enforce adherence and to optimize HCV patient care.
Melissa Palmer, MD, has disclosed that she has received grants for research support from Bristol-Myers Squibb, Gilead Sciences, and Three Rivers Pharmaceuticals; has served as a consultant for Genentech, Gilead Sciences, Merck, and Three Rivers Pharmaceuticals; and has received fees for non-CME services from Genentech, Gilead Sciences, Merck, and Three Rivers Pharmaceuticals.
References
1. Mitra D, Davis KL, Beam C, Medjedovic J, Rustgi V. Treatment patterns and adherence among patients with chronic hepatitis C virus in a US managed care population. Value Health. 2010;13:479-486.
2. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292-1303.
3. Suzuki F, Akuta N, Suzuki Y, et al. Rapid loss of hepatitis C virus genotype 1b from serum in patients receiving a triple treatment with telaprevir (MP-424), pegylated interferon and ribavirin for 12 weeks. Hepatol Res. 2009;39:1056-1063.
4. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;[Epub ahead of print].
5. Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology. 2007;132:1270-1278.
6. Reddy KR, Shiffman ML, Morgan TR, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5:124-129.
7. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069.
8. Shiffman ML, Ghany MG, Morgan TR, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology. 2007;132:103-112.
9. Raptopoulou M, Tsantoulas D, Vafiadi I, et al. The effect of adherence to therapy on sustained response in daily or three times a week interferon alpha-2b plus ribavirin treatment of naive and nonresponder chronic hepatitis C patients. J Viral Hepat. 2005;12:91-95.
10. Lo Re V 3rd, Amorosa VK, Localio AR, et al. Adherence to hepatitis C virus therapy and early virologic outcomes. Clin Infect Dis. 2009;48:186-193.
11. Bain VG, Lee SS, Peltekian K, et al. Clinical trial: exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection treated with peginterferon alfa-2a plus ribavirin. Aliment Pharmacol Ther. 2008; 28:43-50.
12. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:971-981.
13. Rodriguez-Torres M, Sulkowski M, Chung RT, Hamzeh FM, Jensen DM. Association of pre-treatment and on-treatment factors with rapid virologic response in HCV genotype 1 infected patients treated with peginterferon alfa-2a/ribavirin. Program and abstracts of the 58th Annual Meeting of the American Association for the Study of Liver Diseases; November 2-6, 2007; Boston, Massachusetts. Abstract 1305.
14. Bronowicki JP, Ouzan D, Asselah T, et al. Effect of ribavirin in genotype 1 patients with HCV responding to pegylated interferon alfa a plus ribavirin. Gastroenterology. 2006;131:1040-1048.
15. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645-652.
16. Shiffman ML. Side effects of medical therapy for chronic hepatitis C. Ann Hepatol. 2004;3:5-10.
17. Inoue Y, Hiramatsu N, Oze T, et al. Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alpha-2b and ribavirin: reducing drug doses has no impact on rapid and sustained virological responses. J Viral Hepat. 2010;17:336-344.
18. Andriulli A, Cursaro C, Cozzolongo R, et al. Early discontinuation of ribavirin in HCV-2 and HCV-3 patients responding to peg-interferon alfa-2a and ribavirin. Program and abstracts of the 58th Annual Meeting of the American Association for the Study of Liver Diseases; November 2-6, 2007; Boston, Massachusetts. Abstract 234.
19. Hiramatsu N, Oze T, Yakushijin T, et al. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin. J Viral Hepat. 2009;16:586-594.
20. Smith SR, Wahed AS, Kelley SS, Conjeevaram HS, Robuck PR, Fried MW. Assessing the validity of self-reported medication adherence in hepatitis C treatment. Ann Pharmacother. 2007;41:1116-1123.
21. Cacoub P, Ouzan D, Melin P, et al. Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: a prospective, real-life, observational study. World J Gastroenterol. 2008;14:6195-6203.
22. Weiss JJ, Bhatti L, Dieterich DT, et al. Hepatitis C patients' self-reported adherence to treatment with pegylated interferon and ribavirin. Aliment Pharmacol Ther. 2008;28:289-293.
23. Palmer M. Improvement in treatment adherence in patients with chronic hepatitis C. Practical Gastroenterology. 2008;32:31-42.
24. Alam I, Stainbrook T, Cecil B, Kistler KD. Enhanced adherence to HCV therapy with higher dose ribavirin formulation: final analyses from the ADHERE registry. Aliment Pharmacol Ther. 2010;32:535-542.
25. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa 2b plus ribavirin compared with interferon alfa 2b plus ribavirin for the initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001;358:958-965.
26. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
27. Crippin JS, McCashland T, Terrault N, Sheiner P, Charlton MR. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl. 2002;8:350-355.
28. Bhattacharya D, Umbleja T, Carrat F, et al. Women experience higher rates of adverse events during hepatitis C virus therapy in HIV infection: a meta-analysis. J Acquir Immune Defic Syndr. 2010;[Epub ahead of print].
29. Robaeys G, Van Vlierberghe H, Matheï C, et al. Similar compliance and effect of treatment in chronic hepatitis C resulting from intravenous drug use in comparison with other infection causes. Eur J Gastroenterol Hepatol. 2006;18:159-166.
30. Bruggmann P, Falcato L, Dober S, et al. Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients. J Viral Hepat. 2008;15:747-752.
31. Melin P, Chousterman M, Fontanges T, et al. Effectiveness of chronic hepatitis C treatment in drug users in routine clinical practice: results of a prospective cohort study. Eur J Gastroenterol Hepatol. 2010;22:1050-1057.
32. Brunette MF, Drake RE, Marsh BJ, et al. Responding to blood-borne infections among persons with severe mental illness. Psychiatr Serv. 2003;54:860-865.
33. Raison CL, Broadwell SD, Borisov AS, et al. Depressive symptoms and viral clearance in patients receiving interferon-a and ribavirin for hepatitis C. Brain Behav Immun. 2005:19:23-27.
34. Sylvestre D. Treating hepatitis C in active substance users. Clin Infect Dis. 2005;40(suppl 5):S321-S324.
35. Raison CL, Woolwine BJ, Demetrashvili MF, et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharmacol Ther. 2007;25:1163-1174.
36. Kraus MR, Schäfer A, Schöttker K, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut. 2008;57:531-536.
37. Dieterich DT, Wasserman R, Bräu N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol. 2003;98:2491-2499.
38. Afdhal NH. Role of epoetin alfa in maintaining ribavirin dose. Gastroenterol Clin North Am. 2004;33(1 suppl):S25-S35.
39. Vispo E, Labarga P, Guardiola JM, et al. Preemptive erythropoietin plus high ribavirin doses to increase rapid virological responses in HIV patients treated for chronic hepatitis C. AIDS Res Hum Retroviruses. 2010;26:419-424.
40. Falasca K, Ucciferri C, Mancino P, Gorgoretti V, Pizzigallo E, Vecchiet J. Use of epoetin beta during combination therapy of infection with hepatitis c virus with ribavirin improves a sustained viral response. J Med Virol. 2010;82:49-56.
41. Fandrey J, Dicato M. Examining the involvement of erythropoiesis-stimulating agents in tumor proliferation (erythropoietin receptors, receptor binding, signal transduction), angiogenesis, and venous thromboembolic events. Oncologist. 2009;14(suppl 1):34-42.
Source
Clinical Professor of Medicine
Department of Hepatology
Director
NYU Hepatology Associates - Plainview
New York University
Plainview, New York
Maximizing sustained virologic response (SVR) rates (an undetectable HCV RNA level 24 weeks after discontinuation of therapy) is the primary goal of therapy for patients with hepatitis C virus (HCV). This endpoint depends on numerous factors (Table), and adherence to therapy is one of the few variables that can be influenced by the patient and/or the healthcare team by using a multidisciplinary approach. Despite the known importance of treatment adherence in achieving viral eradication, adherence continues to be suboptimal, a fact underscored in a recent study demonstrating that only approximately 60% of patients with HCV in the United States adhered to prescribed therapy.[1] The dawn of a new era of HCV treatment is upon us with the anticipated approval of 2 novel direct-acting antivirals (DAAs) in the latter half of 2011. The addition of a DAA to the current standard of care regimen (peginterferon and ribavirin) enhances SVR rates and diminishes length of treatment in many patients.[2-5] However, issues of adherence will likely become even more significant, as the incidence of adverse events may rise, dosing schedules will become more complex, dietary requirements may be needed, and pill burden will increase. Furthermore, the lack of adherence to DAAs may select for HCV drug resistance mutations, a potentially serious consequence not present with the current standard of care regimen.
Table. Factors Affecting SVR Rates
Adherence Affects Response Rates
Suboptimal drug exposure of ribavirin and/or interferon has been demonstrated to result in reduced SVR rates in numerous studies of both treatment-naive and treatment-experienced patients.[6-10] Genotype 1 patients who were unable to complete ≥ 80% of the prescribed doses of both peginterferon and ribavirin ≥ 80% of the time had a 34% SVR rate vs a 51% SVR rate in those who completed > 80% of both drugs > 80% of the time.[7] Consistent with these findings, a retrospective analysis of 188 HCV-infected Veteran Affairs patients found that adherence to ≥ 85% of prescribed peginterferon plus ribavirin positively correlated with degree of viral suppression and ability to achieve early virologic response (defined as a ≥ 2 log reduction from baseline or undetectable serum HCV RNA at Week 12 of therapy).[10]
Ribavirin Adherence
Several studies have shown that suboptimal ribavirin dosing and/or adherence leads to lower response rates. Indeed, studies have demonstrated that exposure to weight-based ribavirin vs fixed-dose ribavirin is associated with improved early virologic response and SVR rates.[11,12] In addition, a retrospective analysis of 5 clinical trials concluded that patients with genotype 1 HCV exposed to > 13 mg/kg/day of ribavirin had a 2.15-times greater chance of achieving an undetectable HCV RNA by Week 4 (rapid virologic response [RVR]) vs patients exposed to < 13 mg/kg/day of ribavirin (Capsule Summary).[13] Furthermore, genotype 1 patients not achieving RVR were statistically significantly less likely to achieve SVR when cumulative ribavirin dose exposure (due to dose reduction, premature cessation, or skipped doses) was < 60%.[6] In a study by Bronowicki and colleagues,[14] Patients with genotype 1 HCV who discontinued ribavirin after achieving an undetectable HCV RNA by Week 24 were significantly less likely to achieve an SVR vs patients who continued their ribavirin therapy (52.8% vs 68.2%, respectively; P = .004). Finally, dose reduction of ribavirin during the initial 12-20 weeks of therapy has been associated with diminished SVR rates in genotype 1 patients.[7,15,16]
Whereas cumulative ribavirin dose exposure was found not to influence RVR and SVR in genotype 2 patients,[17] the importance of maintaining adequate doses of ribavirin throughout the entire course of treatment was emphasized by Andriulli and colleagues[18] who found that patients with genotype 2/3 HCV had a significantly diminished SVR (54% vs 82%) when ribavirin was discontinued by Week 6 of treatment, even if RVR was achieved (Capsule Summary).
The primary role of ribavirin in HCV treatment is to reduce the likelihood of relapse. Indeed, in an evaluation of 984 genotype 1 HCV–infected patients treated with peginterferon alfa-2b plus ribavirin, the degree of ribavirin exposure was found to be inversely correlated with relapse rates. Only 11% of patients receiving ≥ 12 mg/kg/day of ribavirin relapsed compared with 60% of those receiving < 6 mg/kg/day.[19] In addition, only 4% of patients with an early virologic response in this trial relapsed when exposed to ribavirin doses > 12 mg/kg/day, and ribavirin exposure beyond Week 12 continued to affect relapse rates, demonstrating that ribavirin is inversely dose dependent correlated with relapse in patients with genotype 1 HCV responding to peginterferon plus ribavirin. This study demonstrated the importance of adhering to a dose of ≥ 12 mg/kg/day of ribavirin during the entire treatment period, especially in patients achieving an early virologic response.
Despite these findings, ribavirin adherence continues to be a challenge that appears to be more difficult to overcome than interferon adherence.[20-22] The effect of simplifying ribavirin pill burden was assessed in 2 studies comparing adherence rates in HCV-infected patients treated with fewer, higher-dose ribavirin tablets—a 400-mg or 600-mg ribavirin tablet available in a unit dose blister pack—vs the traditional 200-mg bottled ribavirin tablets. Results from an observational study of 92 patients with HCV from a single center found that patients taking peginterferon with the more compact formulation of ribavirin allowing a reduced pill burden (same total dose) experienced fewer adverse events, improved quality of life, better adherence to prescribed HCV therapy, and a trend toward higher SVR rates vs patients taking peginterferon plus the standard dosing of ribavirin.[23] In the multicenter Accurate Dosing in Hepatitis C: Examining the RibaPak Experience (ADHERE) study, patients who received their ribavirin in the form of the higher-dose tablets provided in a unit dose blister pack were less likely to prematurely stop therapy and more likely to adhere to prescribed HCV treatment at Weeks 12 and 24 compared with patients taking traditional 200-mg ribavirin tablets.[24] Streamlining ribavirin dosing regimens by decreasing pill count may become an even more important factor contributing to enhanced adherence once DAAs become part of HCV therapy, further increasing the regimen pill burden.
Assessment of Adherence
Although there is no gold standard of adherence measurement, it is important for all clinicians to incorporate strategies into their practices to assess adherence to prescribed HCV medications and to differentiate nonadherent patients from those who are truly nonresponders. Adherence analysis by a combination of patient self-report and electronic monitoring of the 401 patients who participated in the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (VIRAHEP-C) trial revealed that patient self-report overestimates compliance, that adherence wanes over time, and that patients are more likely to miss doses of ribavirin than peginterferon.[20] When pharmacy refill data during the initial 12 weeks of treatment was retrospectively evaluated in 188 predominantly HCV-monoinfected US veterans, adherence to peginterferon was found to be better than adherence to ribavirin—a finding consistent with other adherence studies.[10] A prospective, real-life, observational study of genotype 2 and 3 patients revealed that by 3 months of treatment, 20% of HCV patients self-reported missing 1 peginterferon injection whereas approximately 28% of patients self-reported missing 1200-mg ribavirin within the previous 4-week treatment period and that missed dosages of both agents increased at 6 months of treatment.[21] Of importance, this study also demonstrated that adherence at 6 months was better in those receiving patient therapeutic education during the initial 12 weeks of therapy compared with those not receiving patient education.
Suboptimal Adherence Identification and Management
In addition to reinforcing the importance of treatment adherence to patients, identification of individuals at increased risk for adverse events and aggressive management of adverse events are also necessary components of good clinical care that will enhance patient outcomes.
More than 20% of patients must decrease dose, temporarily discontinue, or prematurely stop ribavirin and/or peginterferon because of adverse events.[16,25,26] However, certain subsets of individuals may have more difficulty tolerating treatment compared with others. Mitra and colleagues[1] found that patients with advanced disease are less likely to be adherent to HCV therapy than those with early disease, a finding likely related to an increased susceptibility to adverse events.[27] A recent study showed that 61% of HCV/HIV-coinfected women and 48% of coinfected men experienced adverse events requiring dose modification of standard of care therapy.[28] Whereas traditionally believed to be poor candidates for HCV treatment because of an increased likelihood of nonadherence and susceptibility to psychiatric adverse events associated with treatment, injection drug users, including active drug users, have been found to be adherent to treatment with comparable SVR rates so long as psychosocial support is supplied.[29-31]
Hepatitis C virus is more common among people with psychiatric conditions compared with the general population,[32] and psychiatric illness, in particular depression, has been found to be a risk factor for HCV medication nonadherence. Development of depression while receiving therapy, which has been noted to occur in between 20% to 35% of patients,[25,26] may lead to discontinuation or decrease in dosage of medication with a resultant negative impact on outcome.[33,34] Pretreatment with antidepressants, specifically paroxetine, has been shown to reduce the severity of depression while receiving treatment in individuals displaying depressive symptoms at baseline.[35] The initiation of citalopram after the onset of interferon-induced depression controlled symptoms and enabled patients to complete the full course of standard-of-care treatment.[36] Therefore, to improve adherence, practitioners must evaluate all HCV-infected patients at baseline and during therapy for psychiatric symptoms and initiate antidepressants or antipsychotics promptly, as needed.
Anemia is an adverse effect of both interferon and ribavirin, with a decrease of hemoglobin of > 3 g/dL occurring in more than one half of patients receiving standard-of-care treatment.[37] Anemia often results in dose reduction or discontinuation, particularly of ribavirin, which may negatively affect outcome, especially in patients with genotype 1 HCV.[25] Reduction of the incidence and severity of treatment-induced anemia with erythropoietin has been shown to encourage adherence and to enable patients to remain on higher doses of ribavirin.[37,38] In a prospective, randomized, controlled trial evaluating the effect of erythropoietin on SVR, it was demonstrated that erythropoietin improved quality of life and improved SVR rates in some—but not all—patients with HCV.[8] Rapid virologic response rates did not improve significantly in HCV/HIV-coinfected patients preemptively given erythropoietin.[39] However, in HCV-infected patients achieving a > 2 log decline in HCV RNA after 4 weeks of therapy, SVR rates were significantly improved when anemia was managed with erythropoietin vs ribavirin dose reductions (81.8% vs 45.0%, respectively).[40] Therefore, treatment with erythropoietin should be considered in specific patients as a tool for enhancing medication adherence and improving outcomes, with an eye toward avoiding overcorrection that may result in thrombotic events.[41]
Conclusion
Although great excitement exists surrounding the future of HCV treatment, it must be emphasized that the increased complexity of treatment regimens, coupled with an associated rise in incidence of adverse events and the risk for development of drug resistance, will require even greater attention to adherence issues. Since adherence to prescribed HCV medication has been shown to be enhanced by a combination of patient education, patient motivation, reduced pill burden, and careful and prompt adverse effect management, clinicians should consider a multidisciplinary team approach to assess and enforce adherence and to optimize HCV patient care.
Melissa Palmer, MD, has disclosed that she has received grants for research support from Bristol-Myers Squibb, Gilead Sciences, and Three Rivers Pharmaceuticals; has served as a consultant for Genentech, Gilead Sciences, Merck, and Three Rivers Pharmaceuticals; and has received fees for non-CME services from Genentech, Gilead Sciences, Merck, and Three Rivers Pharmaceuticals.
References
1. Mitra D, Davis KL, Beam C, Medjedovic J, Rustgi V. Treatment patterns and adherence among patients with chronic hepatitis C virus in a US managed care population. Value Health. 2010;13:479-486.
2. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292-1303.
3. Suzuki F, Akuta N, Suzuki Y, et al. Rapid loss of hepatitis C virus genotype 1b from serum in patients receiving a triple treatment with telaprevir (MP-424), pegylated interferon and ribavirin for 12 weeks. Hepatol Res. 2009;39:1056-1063.
4. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;[Epub ahead of print].
5. Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology. 2007;132:1270-1278.
6. Reddy KR, Shiffman ML, Morgan TR, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5:124-129.
7. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069.
8. Shiffman ML, Ghany MG, Morgan TR, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology. 2007;132:103-112.
9. Raptopoulou M, Tsantoulas D, Vafiadi I, et al. The effect of adherence to therapy on sustained response in daily or three times a week interferon alpha-2b plus ribavirin treatment of naive and nonresponder chronic hepatitis C patients. J Viral Hepat. 2005;12:91-95.
10. Lo Re V 3rd, Amorosa VK, Localio AR, et al. Adherence to hepatitis C virus therapy and early virologic outcomes. Clin Infect Dis. 2009;48:186-193.
11. Bain VG, Lee SS, Peltekian K, et al. Clinical trial: exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection treated with peginterferon alfa-2a plus ribavirin. Aliment Pharmacol Ther. 2008; 28:43-50.
12. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:971-981.
13. Rodriguez-Torres M, Sulkowski M, Chung RT, Hamzeh FM, Jensen DM. Association of pre-treatment and on-treatment factors with rapid virologic response in HCV genotype 1 infected patients treated with peginterferon alfa-2a/ribavirin. Program and abstracts of the 58th Annual Meeting of the American Association for the Study of Liver Diseases; November 2-6, 2007; Boston, Massachusetts. Abstract 1305.
14. Bronowicki JP, Ouzan D, Asselah T, et al. Effect of ribavirin in genotype 1 patients with HCV responding to pegylated interferon alfa a plus ribavirin. Gastroenterology. 2006;131:1040-1048.
15. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645-652.
16. Shiffman ML. Side effects of medical therapy for chronic hepatitis C. Ann Hepatol. 2004;3:5-10.
17. Inoue Y, Hiramatsu N, Oze T, et al. Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alpha-2b and ribavirin: reducing drug doses has no impact on rapid and sustained virological responses. J Viral Hepat. 2010;17:336-344.
18. Andriulli A, Cursaro C, Cozzolongo R, et al. Early discontinuation of ribavirin in HCV-2 and HCV-3 patients responding to peg-interferon alfa-2a and ribavirin. Program and abstracts of the 58th Annual Meeting of the American Association for the Study of Liver Diseases; November 2-6, 2007; Boston, Massachusetts. Abstract 234.
19. Hiramatsu N, Oze T, Yakushijin T, et al. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin. J Viral Hepat. 2009;16:586-594.
20. Smith SR, Wahed AS, Kelley SS, Conjeevaram HS, Robuck PR, Fried MW. Assessing the validity of self-reported medication adherence in hepatitis C treatment. Ann Pharmacother. 2007;41:1116-1123.
21. Cacoub P, Ouzan D, Melin P, et al. Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: a prospective, real-life, observational study. World J Gastroenterol. 2008;14:6195-6203.
22. Weiss JJ, Bhatti L, Dieterich DT, et al. Hepatitis C patients' self-reported adherence to treatment with pegylated interferon and ribavirin. Aliment Pharmacol Ther. 2008;28:289-293.
23. Palmer M. Improvement in treatment adherence in patients with chronic hepatitis C. Practical Gastroenterology. 2008;32:31-42.
24. Alam I, Stainbrook T, Cecil B, Kistler KD. Enhanced adherence to HCV therapy with higher dose ribavirin formulation: final analyses from the ADHERE registry. Aliment Pharmacol Ther. 2010;32:535-542.
25. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa 2b plus ribavirin compared with interferon alfa 2b plus ribavirin for the initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001;358:958-965.
26. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
27. Crippin JS, McCashland T, Terrault N, Sheiner P, Charlton MR. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl. 2002;8:350-355.
28. Bhattacharya D, Umbleja T, Carrat F, et al. Women experience higher rates of adverse events during hepatitis C virus therapy in HIV infection: a meta-analysis. J Acquir Immune Defic Syndr. 2010;[Epub ahead of print].
29. Robaeys G, Van Vlierberghe H, Matheï C, et al. Similar compliance and effect of treatment in chronic hepatitis C resulting from intravenous drug use in comparison with other infection causes. Eur J Gastroenterol Hepatol. 2006;18:159-166.
30. Bruggmann P, Falcato L, Dober S, et al. Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients. J Viral Hepat. 2008;15:747-752.
31. Melin P, Chousterman M, Fontanges T, et al. Effectiveness of chronic hepatitis C treatment in drug users in routine clinical practice: results of a prospective cohort study. Eur J Gastroenterol Hepatol. 2010;22:1050-1057.
32. Brunette MF, Drake RE, Marsh BJ, et al. Responding to blood-borne infections among persons with severe mental illness. Psychiatr Serv. 2003;54:860-865.
33. Raison CL, Broadwell SD, Borisov AS, et al. Depressive symptoms and viral clearance in patients receiving interferon-a and ribavirin for hepatitis C. Brain Behav Immun. 2005:19:23-27.
34. Sylvestre D. Treating hepatitis C in active substance users. Clin Infect Dis. 2005;40(suppl 5):S321-S324.
35. Raison CL, Woolwine BJ, Demetrashvili MF, et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharmacol Ther. 2007;25:1163-1174.
36. Kraus MR, Schäfer A, Schöttker K, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut. 2008;57:531-536.
37. Dieterich DT, Wasserman R, Bräu N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol. 2003;98:2491-2499.
38. Afdhal NH. Role of epoetin alfa in maintaining ribavirin dose. Gastroenterol Clin North Am. 2004;33(1 suppl):S25-S35.
39. Vispo E, Labarga P, Guardiola JM, et al. Preemptive erythropoietin plus high ribavirin doses to increase rapid virological responses in HIV patients treated for chronic hepatitis C. AIDS Res Hum Retroviruses. 2010;26:419-424.
40. Falasca K, Ucciferri C, Mancino P, Gorgoretti V, Pizzigallo E, Vecchiet J. Use of epoetin beta during combination therapy of infection with hepatitis c virus with ribavirin improves a sustained viral response. J Med Virol. 2010;82:49-56.
41. Fandrey J, Dicato M. Examining the involvement of erythropoiesis-stimulating agents in tumor proliferation (erythropoietin receptors, receptor binding, signal transduction), angiogenesis, and venous thromboembolic events. Oncologist. 2009;14(suppl 1):34-42.
Source
September 20, 2010
Mild Alcohol Consumption is Not Associated With Increased Fibrosis in Patients With Chronic Hepatitis C
J Clin Gastroenterol. 2010 Sep 2. [Epub ahead of print]
Cheung O, Sterling RK, Salvatori J, Williams K, Hubbard S, Luketic VA, Stravitz TR, Sanyal AJ, Contos MJ, Mills S, Shiffman ML.
* Hepatology Section daggerDepartment of Pathology, Virginia Commonwealth University Medical Center, Richmond double daggerLiver Institute of Virginia, Bon Secours Health System, Newport News, VA.
Abstract
BACKGROUND: Excessive alcohol consumption is associated with an increased risk for fibrosis progression and cirrhosis in patients with chronic hepatitis C virus (HCV) infection. However, the impact of mild-moderate alcohol use on the severity of liver fibrosis is unclear.
GOALS: The objective of this retrospective study was to assess the impact of mild alcohol consumption on liver fibrosis in patients with chronic HCV.
STUDY: 857 patients with well-characterized chronic HCV were enrolled. All underwent liver biopsy to assess hepatic fibrosis. The duration of HCV infection was determined by detailed questionnaires and personal interviews. Alcohol use history was estimated by the Skinner Alcohol Examination Questionnaire. Mild alcohol use was defined as 1 to 3 alcoholic beverages/day (<30 grams/d). Participants were divided into 4 groups based on their average lifetime daily alcohol consumption (essentially none, <1, 1 to 3 or >3 drinks/d) and into quartiles based on their presumed duration of HCV infection (<23, 23 to 31, 31 to 38, or >38 y).
RESULTS: Mean alcohol consumption was 2.7 drinks/d; mean duration of HCV infection was 29 years. Daily alcohol consumption was not significantly higher among participants with advanced fibrosis (bridging fibrosis or cirrhosis) when compared with those with none or portal fibrosis (3.2 vs. 2.2 drinks/d, respectively, P=NS). The degree of fibrosis increased significantly with the duration of HCV infection (P<0.0001) and was independent of mild-moderate alcohol consumption.
CONCLUSIONS: Mild alcohol use does not seem to adversely affect the severity of fibrosis in patients with chronic HCV.
PMID: 20818236 [PubMed - as supplied by publisher]
Source
Cheung O, Sterling RK, Salvatori J, Williams K, Hubbard S, Luketic VA, Stravitz TR, Sanyal AJ, Contos MJ, Mills S, Shiffman ML.
* Hepatology Section daggerDepartment of Pathology, Virginia Commonwealth University Medical Center, Richmond double daggerLiver Institute of Virginia, Bon Secours Health System, Newport News, VA.
Abstract
BACKGROUND: Excessive alcohol consumption is associated with an increased risk for fibrosis progression and cirrhosis in patients with chronic hepatitis C virus (HCV) infection. However, the impact of mild-moderate alcohol use on the severity of liver fibrosis is unclear.
GOALS: The objective of this retrospective study was to assess the impact of mild alcohol consumption on liver fibrosis in patients with chronic HCV.
STUDY: 857 patients with well-characterized chronic HCV were enrolled. All underwent liver biopsy to assess hepatic fibrosis. The duration of HCV infection was determined by detailed questionnaires and personal interviews. Alcohol use history was estimated by the Skinner Alcohol Examination Questionnaire. Mild alcohol use was defined as 1 to 3 alcoholic beverages/day (<30 grams/d). Participants were divided into 4 groups based on their average lifetime daily alcohol consumption (essentially none, <1, 1 to 3 or >3 drinks/d) and into quartiles based on their presumed duration of HCV infection (<23, 23 to 31, 31 to 38, or >38 y).
RESULTS: Mean alcohol consumption was 2.7 drinks/d; mean duration of HCV infection was 29 years. Daily alcohol consumption was not significantly higher among participants with advanced fibrosis (bridging fibrosis or cirrhosis) when compared with those with none or portal fibrosis (3.2 vs. 2.2 drinks/d, respectively, P=NS). The degree of fibrosis increased significantly with the duration of HCV infection (P<0.0001) and was independent of mild-moderate alcohol consumption.
CONCLUSIONS: Mild alcohol use does not seem to adversely affect the severity of fibrosis in patients with chronic HCV.
PMID: 20818236 [PubMed - as supplied by publisher]
Source
Androgen Receptor May Explain Male Dominance in Liver Cancer
ScienceDaily (Sep. 14, 2010) — A University of Rochester study helps to explain why men get liver cancer more often than women and opens the door for a new treatment pathway, by showing a direct link between the androgen receptor, which is more active in men, and the hepatitis B virus as it relates to the deadly cancer.
The study is published May 19, 2010, in Science Translational Medicine.
Primary liver cancer is the fifth most common cancer in men. It often arises after infection from the hepatitis B virus (HBV), which is widespread across the globe and growing in the United States. Other studies of liver cancer have focused on risk factors such as age, family history, and use of alcohol and cigarettes, but those epidemiology studies have not explained the mechanisms driving hepatocellular carcinoma and why men are more susceptible.
Now, corresponding author Chawnshang Chang, Ph.D., the George Hoyt Whipple Distinguished Professor of Pathology at the University of Rochester Medical Center, and colleagues, showed that the androgen receptor (AR), a protein that mediates male sex hormones, promotes liver cancer when hepatitis B is present by altering DNA replication of the virus. Chang's laboratory created a mouse model for HBV-induced liver cancer and reported that knocking out AR suppressed the HBV-induced cancer.
According to an accompanying editorial in the journal, the identification of the AR pathway is a potential new treatment target that could translate to the clinic.
"Our study is the first in vivo evidence to demonstrate a direct connection between HBV-induced liver cancer and the AR," Chang said. "This is important because so far most work has focused on eliminating total serum androgen levels, a type of therapy that has shown little success."
"This important paper offers insight into something we have long observed but not entirely understood, namely that men with HBV are much more likely to develop cancer than women with the same infection," said Aram Hezel, M.D., a gastrointestinal oncologist at the James P. Wilmot Cancer Center at University of Rochester Medical Center. "This is great use of the tools of genetics and mouse modeling to explain a clinical finding and most importantly turn our attention to potentially more promising treatment approaches for patients with hepatocellular carcinoma."
"This study also raises the possibility of prevention among men with HBV infection through inhibition of the androgen receptor," Hezel added. "The potential impact on clinical care is great."
For decades Chang has focused on the particular role of the AR in human health. In 1988 he successfully cloned AR, which led to breakthroughs in several AR-related diseases such as prostate and bladder cancer, and Kennedy's neuron disease, a rare and progressive motor disorder similar to Lou Gehrig's disease, and that affects only men.
The AR is central to the action of testosterone and has a profound effect on many organs. In previous experiments, Chang has shown that mice without AR have dramatically lower rates of bladder cancer, a cancer that strikes men three times more often than women.
Male dominance in liver cancer suggested that the AR would be a key factor, as well. (About 74 percent of liver cancer cases occur in men.) Chang's objective was to locate a new pathway for treatment that would not require depletion of androgen levels in the entire body, which amounts to castration and causes severe side effects for patients.
His study took the first step toward demonstrating this could be done, at least for early stage liver cancer. Researchers showed that an experimental drug, ASC-J9, attacked and degraded the faulty AR, and suppressed liver tumors in mice.
Chang developed ASC-J9 earlier this decade and first reported on its clinical potential in March 2007 in the journal Nature Medicine. The drug is a synthetic compound loosely based on the compounds found in curcumin, the polyphenol that gives the spice tumeric its yellow color. It has been used for centuries as a folk medicine in Asia and India. In this case, however, scientists significantly altered the natural substance to be more powerful, and are carefully screening it for safety and effectiveness.
AndroScience Corp., a biotech company founded by Chang and others in 2000, is evaluating ASC-J9 in several clinical settings, although not yet in the treatment of liver cancer, Chang said. The URMC owns a stake in AndroScience, and has licensed several of Chang's research findings.
In the current study, researchers found that AR cooperates with the hepatitis B virus to trigger the expression of several oncogenes, resulting in normal liver cells transforming into cancer cells. Furthermore, they showed that liver tumors without the AR had fewer proliferating cancer cells, which helps to explain the gender disparity in the disease.
Some of the findings are in agreement with earlier studies by Chang's lab on the role of AR in prostate cancer. Just as in prostate cancer, the liver tumor microenvironment is rich in various cell types, each of which has a distinct role in promoting the cancer.
"It will be interesting to see if targeting AR at different stages or in different liver cancer cell types may also lead to differential effects during the progression of cancer," the paper concluded.
The hepatitis B and C viruses account for approximately 80 percent of primary liver cancer cases worldwide. Newborn vaccines and screenings for HBV and HCV, particularly in Asian and African countries, have reduced the incidence of liver cancer in later years. Still, an estimated 560,000 new cases are diagnosed annually. In high-risk areas such as China, Japan and sub-Saharan Africa the male-to-female ratio of liver cancer can be as high as 8 to 1. The current best treatment is surgery; median survival is generally six months.
The National Institutes of Health and the George Whipple Professorship Endowment funded the research. Co-authors from the Whipple Lab and the URMC James P. Wilmot Cancer Center are: Ming-Heng Wu, Wen-Lung Ma, Cheng-Lung Hsu, Yuh-Ling Chen, Charlotte Kathryn Ryan and Shuyuan Yeh. Additional co-authors include Jing-Hsiung James Ou, of the Department of Molecular Microbiology and Immunology at the University of Southern California, Los Angeles; Yao-Ching Hung and Wen-Lung Ma, of the Sex Hormone Research Center at China Medical University/Hospital in Taiwan. Ming-Heng Wu is also associated with Cheng Gung University in Taiwan; and Cheng-Lung Hsu, with Chang Gong University in Taiwan.
Source
The study is published May 19, 2010, in Science Translational Medicine.
Primary liver cancer is the fifth most common cancer in men. It often arises after infection from the hepatitis B virus (HBV), which is widespread across the globe and growing in the United States. Other studies of liver cancer have focused on risk factors such as age, family history, and use of alcohol and cigarettes, but those epidemiology studies have not explained the mechanisms driving hepatocellular carcinoma and why men are more susceptible.
Now, corresponding author Chawnshang Chang, Ph.D., the George Hoyt Whipple Distinguished Professor of Pathology at the University of Rochester Medical Center, and colleagues, showed that the androgen receptor (AR), a protein that mediates male sex hormones, promotes liver cancer when hepatitis B is present by altering DNA replication of the virus. Chang's laboratory created a mouse model for HBV-induced liver cancer and reported that knocking out AR suppressed the HBV-induced cancer.
According to an accompanying editorial in the journal, the identification of the AR pathway is a potential new treatment target that could translate to the clinic.
"Our study is the first in vivo evidence to demonstrate a direct connection between HBV-induced liver cancer and the AR," Chang said. "This is important because so far most work has focused on eliminating total serum androgen levels, a type of therapy that has shown little success."
"This important paper offers insight into something we have long observed but not entirely understood, namely that men with HBV are much more likely to develop cancer than women with the same infection," said Aram Hezel, M.D., a gastrointestinal oncologist at the James P. Wilmot Cancer Center at University of Rochester Medical Center. "This is great use of the tools of genetics and mouse modeling to explain a clinical finding and most importantly turn our attention to potentially more promising treatment approaches for patients with hepatocellular carcinoma."
"This study also raises the possibility of prevention among men with HBV infection through inhibition of the androgen receptor," Hezel added. "The potential impact on clinical care is great."
For decades Chang has focused on the particular role of the AR in human health. In 1988 he successfully cloned AR, which led to breakthroughs in several AR-related diseases such as prostate and bladder cancer, and Kennedy's neuron disease, a rare and progressive motor disorder similar to Lou Gehrig's disease, and that affects only men.
The AR is central to the action of testosterone and has a profound effect on many organs. In previous experiments, Chang has shown that mice without AR have dramatically lower rates of bladder cancer, a cancer that strikes men three times more often than women.
Male dominance in liver cancer suggested that the AR would be a key factor, as well. (About 74 percent of liver cancer cases occur in men.) Chang's objective was to locate a new pathway for treatment that would not require depletion of androgen levels in the entire body, which amounts to castration and causes severe side effects for patients.
His study took the first step toward demonstrating this could be done, at least for early stage liver cancer. Researchers showed that an experimental drug, ASC-J9, attacked and degraded the faulty AR, and suppressed liver tumors in mice.
Chang developed ASC-J9 earlier this decade and first reported on its clinical potential in March 2007 in the journal Nature Medicine. The drug is a synthetic compound loosely based on the compounds found in curcumin, the polyphenol that gives the spice tumeric its yellow color. It has been used for centuries as a folk medicine in Asia and India. In this case, however, scientists significantly altered the natural substance to be more powerful, and are carefully screening it for safety and effectiveness.
AndroScience Corp., a biotech company founded by Chang and others in 2000, is evaluating ASC-J9 in several clinical settings, although not yet in the treatment of liver cancer, Chang said. The URMC owns a stake in AndroScience, and has licensed several of Chang's research findings.
In the current study, researchers found that AR cooperates with the hepatitis B virus to trigger the expression of several oncogenes, resulting in normal liver cells transforming into cancer cells. Furthermore, they showed that liver tumors without the AR had fewer proliferating cancer cells, which helps to explain the gender disparity in the disease.
Some of the findings are in agreement with earlier studies by Chang's lab on the role of AR in prostate cancer. Just as in prostate cancer, the liver tumor microenvironment is rich in various cell types, each of which has a distinct role in promoting the cancer.
"It will be interesting to see if targeting AR at different stages or in different liver cancer cell types may also lead to differential effects during the progression of cancer," the paper concluded.
The hepatitis B and C viruses account for approximately 80 percent of primary liver cancer cases worldwide. Newborn vaccines and screenings for HBV and HCV, particularly in Asian and African countries, have reduced the incidence of liver cancer in later years. Still, an estimated 560,000 new cases are diagnosed annually. In high-risk areas such as China, Japan and sub-Saharan Africa the male-to-female ratio of liver cancer can be as high as 8 to 1. The current best treatment is surgery; median survival is generally six months.
The National Institutes of Health and the George Whipple Professorship Endowment funded the research. Co-authors from the Whipple Lab and the URMC James P. Wilmot Cancer Center are: Ming-Heng Wu, Wen-Lung Ma, Cheng-Lung Hsu, Yuh-Ling Chen, Charlotte Kathryn Ryan and Shuyuan Yeh. Additional co-authors include Jing-Hsiung James Ou, of the Department of Molecular Microbiology and Immunology at the University of Southern California, Los Angeles; Yao-Ching Hung and Wen-Lung Ma, of the Sex Hormone Research Center at China Medical University/Hospital in Taiwan. Ming-Heng Wu is also associated with Cheng Gung University in Taiwan; and Cheng-Lung Hsu, with Chang Gong University in Taiwan.
Source
Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in HCV cell culture models
Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)
Emmanuel Thomas 1, Jordan J. Feld 1,2, Qisheng Li 1, Zongyi Hu 1, Michael W. Fried 3, T. Jake Liang 1,*
DOI: 10.1002/hep.23985
Copyright © 2010 American Association for the Study of Liver Diseases
Author Information
1 Liver Diseases Branch, NIDDK/NIH, 10 Center Dr., Building 10, 9B17, Bethesda, MD, 20892, USA
2 Toronto Western Hospital Liver Centre, Department of Medicine, Division of Gastroenterology, 6B Fell Pavillion Room 160, 399 Bathurst St, Toronto, ON M5T 2S8, Canada
3 Division of Gastroenterology and Hepatology, University of North Carolina, CB 7584, Room 8015 Burnett Womack Building, Chapel Hill, NC, 27514, USA
Email: T. Jake Liang (JakeL@bdg10.niddk.nih.gov)
* Correspondence: T. Jake Liang, Liver Diseases Branch, NIDDK/NIH, 10 Center Dr., Building 10, 9B17, Bethesda, MD, 20892, USA
Publication History
Accepted manuscript online: 14 SEP 2010 08:04AM EST
Manuscript Accepted: 4 SEP 2010
Manuscript Revised: 2 SEP 2010
Manuscript Received: 25 MAR 2010
Funded by
The combination of peginterferon and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection [1]. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-α, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-KappaB pathways in the action of ribavirin. In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals. (HEPATOLOGY 2010.)
Source
Accepted Article (Accepted, unedited articles published online for future issues)
Emmanuel Thomas 1, Jordan J. Feld 1,2, Qisheng Li 1, Zongyi Hu 1, Michael W. Fried 3, T. Jake Liang 1,*
DOI: 10.1002/hep.23985
Copyright © 2010 American Association for the Study of Liver Diseases
Author Information
1 Liver Diseases Branch, NIDDK/NIH, 10 Center Dr., Building 10, 9B17, Bethesda, MD, 20892, USA
2 Toronto Western Hospital Liver Centre, Department of Medicine, Division of Gastroenterology, 6B Fell Pavillion Room 160, 399 Bathurst St, Toronto, ON M5T 2S8, Canada
3 Division of Gastroenterology and Hepatology, University of North Carolina, CB 7584, Room 8015 Burnett Womack Building, Chapel Hill, NC, 27514, USA
Email: T. Jake Liang (JakeL@bdg10.niddk.nih.gov)
* Correspondence: T. Jake Liang, Liver Diseases Branch, NIDDK/NIH, 10 Center Dr., Building 10, 9B17, Bethesda, MD, 20892, USA
Publication History
Accepted manuscript online: 14 SEP 2010 08:04AM EST
Manuscript Accepted: 4 SEP 2010
Manuscript Revised: 2 SEP 2010
Manuscript Received: 25 MAR 2010
Funded by
- The Intramural Research Program
- The National Institute of Diabetes and Digestive and Kidney Diseases
- NIH
- NIH K24 mentoring award. Grant Number: DK066144
The combination of peginterferon and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection [1]. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-α, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-KappaB pathways in the action of ribavirin. In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals. (HEPATOLOGY 2010.)
Source
FDA Hepatitis Update -- Availability of draft Guidance: Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment
Below is an email message that I received from the FDA:
You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.
The Food and Drug Administration (FDA) is announcing the availability of draft guidance for industry entitled “Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment.” At present, there are a large number of drugs for the treatment of chronic hepatitis C (CHC) in active development. The purpose of this guidance is to assist sponsors in all phases of development of direct-acting antiviral agents (DAAs), defined as agents that interfere with specific steps in the hepatitis C virus (HCV) replication cycle. The guidance outlines the types of nonclinical studies and clinical trials recommended throughout the drug development process, such as early phases of clinical development, phase 3 protocol designs, and endpoints for the treatment of CHC to support approval of treatments for CHC, including patients with compensated and decompensated cirrhosis and those co-infected with HIV. The guidance also addresses pre-approval access in the form of treatment investigational new drug applications (INDs) and intermediate-sized safety protocols (collectively known as expanded access).
Important issues addressed in this guidance include: drug development methods to reduce the emergence of drug resistance, types of trial designs to assess optimal dose and treatment duration, combination therapy with multiple investigational drugs, recommendations on development of drugs to meet unmet medical needs, and use of treatment INDs or other smaller safety protocols to provide early access of multiple DAAs for patients at risk of imminent progression of liver disease.
The draft guidance, when finalized, will represent the agency’s current thinking on developing DAAs for treatment of CHC virus infection. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
The draft guidance is available on the FDA web site at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf
Although comments are accepted for any guidance at any time, to ensure that the agency considers your comment on this draft guidance before it begins work on the final version of the guidance, please submit written or electronic comments on the draft guidance by November 15, 2010, and include the docket number, FDA-2010-D-0462, in any comment you submit.
You may submit written comments on the draft guidance to the
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061,
Rockville, MD 20852
You may also submit electronic comments at http://www.regulations.gov/search/Regs/home.html#submitComment?R=0900006480b4e9b3.
FOR FURTHER INFORMATION CONTACT:
Jeffrey Murray,
Center for Drug Evaluation and Research,
Food and Drug Administration,
10903 New Hampshire Ave.,
Bldg. 22, rm. 6360,
Silver Spring, MD 20993-0002,
301-796-1500.
The complete Federal Register Notice announcing availability of this draft guidance is available at http://edocket.access.gpo.gov/2010/pdf/2010-22806.pdf
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Source: Received via email
You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.
The Food and Drug Administration (FDA) is announcing the availability of draft guidance for industry entitled “Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment.” At present, there are a large number of drugs for the treatment of chronic hepatitis C (CHC) in active development. The purpose of this guidance is to assist sponsors in all phases of development of direct-acting antiviral agents (DAAs), defined as agents that interfere with specific steps in the hepatitis C virus (HCV) replication cycle. The guidance outlines the types of nonclinical studies and clinical trials recommended throughout the drug development process, such as early phases of clinical development, phase 3 protocol designs, and endpoints for the treatment of CHC to support approval of treatments for CHC, including patients with compensated and decompensated cirrhosis and those co-infected with HIV. The guidance also addresses pre-approval access in the form of treatment investigational new drug applications (INDs) and intermediate-sized safety protocols (collectively known as expanded access).
Important issues addressed in this guidance include: drug development methods to reduce the emergence of drug resistance, types of trial designs to assess optimal dose and treatment duration, combination therapy with multiple investigational drugs, recommendations on development of drugs to meet unmet medical needs, and use of treatment INDs or other smaller safety protocols to provide early access of multiple DAAs for patients at risk of imminent progression of liver disease.
The draft guidance, when finalized, will represent the agency’s current thinking on developing DAAs for treatment of CHC virus infection. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
The draft guidance is available on the FDA web site at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf
Although comments are accepted for any guidance at any time, to ensure that the agency considers your comment on this draft guidance before it begins work on the final version of the guidance, please submit written or electronic comments on the draft guidance by November 15, 2010, and include the docket number, FDA-2010-D-0462, in any comment you submit.
You may submit written comments on the draft guidance to the
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061,
Rockville, MD 20852
You may also submit electronic comments at http://www.regulations.gov/search/Regs/home.html#submitComment?R=0900006480b4e9b3.
FOR FURTHER INFORMATION CONTACT:
Jeffrey Murray,
Center for Drug Evaluation and Research,
Food and Drug Administration,
10903 New Hampshire Ave.,
Bldg. 22, rm. 6360,
Silver Spring, MD 20993-0002,
301-796-1500.
The complete Federal Register Notice announcing availability of this draft guidance is available at http://edocket.access.gpo.gov/2010/pdf/2010-22806.pdf
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Source: Received via email
TV Show Delivers Hope for Hepatitis C
September 8, 2010
A recent television news piece helped boost awareness of Hepatitis C - but it also may have created false hope by alluding to the speedy arrival of a Hep C cure.
by Nicole Cutler, L.Ac.
As the number of people receiving a Hepatitis C diagnosis grows, media attention focusing on this virus has intensified. Education about the prevalence and potential severity of Hepatitis C is badly needed to raise awareness of this highly communicable and often asymptomatic (until it's too late) disease. A television program broadcast in June of 2010 is to be commended for spearheading such an awareness campaign; but it also has some people expecting a cure for Hepatitis C to arrive unrealistically soon.
As described in a recent TV presentation, scientists around the world are fervently working to find effective, safe drugs for treating and preventing Hepatitis C. However, those who are not familiar with the process of drug development could easily misinterpret the progress described on television with the notion that a vaccine for Hepatitis C will hit the market any day now.
Believed to currently infect between four and five million Americans, those infected with Hepatitis C far outnumber those with HIV, the virus that causes AIDS. A leading cause of chronic liver disease that has no vaccine or reliable cure, Hepatitis C presents many challenges to the medical community. Among those challenges are:
· The current treatment in effect is only successful in about half of all cases.
· The virus demonstrates an ability to develop drug resistance.
· Chronic Hepatitis C can progress to severe or even fatal liver disease.
According to their website, KQED Public Television 9 is one of the nation's most-watched public television stations during primetime with more than 1.5 million households viewing per month. A KQED weekly program, This Week in Northern California with host Belva Davis follows a magazine format and is committed to news and public affairs. The June 25, 2010 episode of This Week in Northern California featured an informative piece entitled "Hepatitis C: The Silent Epidemic." Summing up this segment, KQED reports:
"A San Francisco Task Force on Hepatitis C is helping to find a cure for the disease, which is four times more prevalent in the Bay Area as AIDS. ...Dr. Jeffrey Glenn and his team of researchers at the Stanford University School Of Medicine are looking for compounds that will prevent the Hepatitis C virus from replicating. And at the Gladstone Institutes at UCSF, Dr. Melanie Ott and her staff are doing groundbreaking research on the relationship between the virus and fat droplets in the liver that could soon lead to a cure."
Watching the video segment delivers hope to those waiting for a reliable solution for Hepatitis C. The researcher interviewed appears excited to be a part of a Hepatitis C-soon-to-be-cure. While it is hard not to get caught up in the excitement, the research from Stanford and UCSF's Gladstone Institutes are still in the beginning stages of making progress against this virus.
A scientific discovery that further unravels the mystery behind Hepatitis C is definitely reason for celebration, but it is far from delivering a cure. After realizing the clinical impact of the discovery, scientists begin the process of identifying potential substances that could inhibit or fight the virus. Once a promising medication is apparent, the testing of that drug is a long process. Typically taking about 12 years to come to fruition, a new drug must persevere through pre-clinical testing, clinical trials and U.S. Food and Drug Association (FDA) approval before it finally reaches the marketplace. For more detailed information about this process, read "An Overview of the HCV Drug Development Process."
The research described in the KQED segment is encouraging. Scientists at the Gladstone Institute of Virology and Immunology found that an important viral protein, called the "core" protein, localizes to the mitochondria. Through examining liver fat droplets in the mitochondria, new mechanisms for treating Hepatitis C could follow. While drugs capitalizing on this information could be in the future, there are others that are closer to actualization. This television program focused solely on San Francisco Bay area developments. However, there are other medications, such as telaprevir, that have already endured years of development. Shown to drastically boost the Hepatitis C cure rate, telaprevir could be available to the public as early as 2011.
Good job to KQED for bringing the lack of Hepatitis C awareness and education to the forefront. The research focusing on fat droplets in the liver is invaluable to the eventual conquering of the Hepatitis C virus, but it has not yet produced a cure. As we see more education campaigns exposing the gravity of Hepatitis C infection, a greater level of comprehension will also be needed to understand the drug development process. In the meantime, rest assured that progress is being made - and even if it doesn't end the Hepatitis C epidemic this year - the scientific community is certainly headed in that direction.
References:
http://news.ucsf.edu/fyi/daily/2010/06/28/, UCSF Television Coverage, Retrieved August 26, 2010, The Regents of the University of California, 2010.
http://www.gladstone.ucsf.edu/wp/2010/02/hepcviralprotein/, Hepatitis C Viral Protein Associates with the Mitochondria, Retrieved August 25, 2010, J. David Gladstone Institutes, 2010.
http://www.hepatitis-central.com/mt/archives/general_hepatitis_c_newsupdates/, An Overview of the HCV Drug Development Process, Nicole Cutler, L.Ac., Retrieved August 28, 2010, Natural Wellness, 2010.
http://www.kqed.org/tv/programs/thisweek/watch/archive/226569/b, Hepatitis C: The Silent Epidemic, Retrieved August 26, 2010, KQED, 2010.
http://www.mdpi.com/1999-4915/2/5/1195/, Lipid Metabolism and HCV Infection, Paul Targett-Adams, et al, Retrieved August 25, 2010, Viruses, May 2010.
Sourcehttp://www.hepatitis-central.com/mt/archives/2010/09/tv_show_deliver.html?eml=hepcen115
A recent television news piece helped boost awareness of Hepatitis C - but it also may have created false hope by alluding to the speedy arrival of a Hep C cure.
by Nicole Cutler, L.Ac.
As the number of people receiving a Hepatitis C diagnosis grows, media attention focusing on this virus has intensified. Education about the prevalence and potential severity of Hepatitis C is badly needed to raise awareness of this highly communicable and often asymptomatic (until it's too late) disease. A television program broadcast in June of 2010 is to be commended for spearheading such an awareness campaign; but it also has some people expecting a cure for Hepatitis C to arrive unrealistically soon.
As described in a recent TV presentation, scientists around the world are fervently working to find effective, safe drugs for treating and preventing Hepatitis C. However, those who are not familiar with the process of drug development could easily misinterpret the progress described on television with the notion that a vaccine for Hepatitis C will hit the market any day now.
Believed to currently infect between four and five million Americans, those infected with Hepatitis C far outnumber those with HIV, the virus that causes AIDS. A leading cause of chronic liver disease that has no vaccine or reliable cure, Hepatitis C presents many challenges to the medical community. Among those challenges are:
· The current treatment in effect is only successful in about half of all cases.
· The virus demonstrates an ability to develop drug resistance.
· Chronic Hepatitis C can progress to severe or even fatal liver disease.
According to their website, KQED Public Television 9 is one of the nation's most-watched public television stations during primetime with more than 1.5 million households viewing per month. A KQED weekly program, This Week in Northern California with host Belva Davis follows a magazine format and is committed to news and public affairs. The June 25, 2010 episode of This Week in Northern California featured an informative piece entitled "Hepatitis C: The Silent Epidemic." Summing up this segment, KQED reports:
"A San Francisco Task Force on Hepatitis C is helping to find a cure for the disease, which is four times more prevalent in the Bay Area as AIDS. ...Dr. Jeffrey Glenn and his team of researchers at the Stanford University School Of Medicine are looking for compounds that will prevent the Hepatitis C virus from replicating. And at the Gladstone Institutes at UCSF, Dr. Melanie Ott and her staff are doing groundbreaking research on the relationship between the virus and fat droplets in the liver that could soon lead to a cure."
Watching the video segment delivers hope to those waiting for a reliable solution for Hepatitis C. The researcher interviewed appears excited to be a part of a Hepatitis C-soon-to-be-cure. While it is hard not to get caught up in the excitement, the research from Stanford and UCSF's Gladstone Institutes are still in the beginning stages of making progress against this virus.
A scientific discovery that further unravels the mystery behind Hepatitis C is definitely reason for celebration, but it is far from delivering a cure. After realizing the clinical impact of the discovery, scientists begin the process of identifying potential substances that could inhibit or fight the virus. Once a promising medication is apparent, the testing of that drug is a long process. Typically taking about 12 years to come to fruition, a new drug must persevere through pre-clinical testing, clinical trials and U.S. Food and Drug Association (FDA) approval before it finally reaches the marketplace. For more detailed information about this process, read "An Overview of the HCV Drug Development Process."
The research described in the KQED segment is encouraging. Scientists at the Gladstone Institute of Virology and Immunology found that an important viral protein, called the "core" protein, localizes to the mitochondria. Through examining liver fat droplets in the mitochondria, new mechanisms for treating Hepatitis C could follow. While drugs capitalizing on this information could be in the future, there are others that are closer to actualization. This television program focused solely on San Francisco Bay area developments. However, there are other medications, such as telaprevir, that have already endured years of development. Shown to drastically boost the Hepatitis C cure rate, telaprevir could be available to the public as early as 2011.
Good job to KQED for bringing the lack of Hepatitis C awareness and education to the forefront. The research focusing on fat droplets in the liver is invaluable to the eventual conquering of the Hepatitis C virus, but it has not yet produced a cure. As we see more education campaigns exposing the gravity of Hepatitis C infection, a greater level of comprehension will also be needed to understand the drug development process. In the meantime, rest assured that progress is being made - and even if it doesn't end the Hepatitis C epidemic this year - the scientific community is certainly headed in that direction.
References:
http://news.ucsf.edu/fyi/daily/2010/06/28/, UCSF Television Coverage, Retrieved August 26, 2010, The Regents of the University of California, 2010.
http://www.gladstone.ucsf.edu/wp/2010/02/hepcviralprotein/, Hepatitis C Viral Protein Associates with the Mitochondria, Retrieved August 25, 2010, J. David Gladstone Institutes, 2010.
http://www.hepatitis-central.com/mt/archives/general_hepatitis_c_newsupdates/, An Overview of the HCV Drug Development Process, Nicole Cutler, L.Ac., Retrieved August 28, 2010, Natural Wellness, 2010.
http://www.kqed.org/tv/programs/thisweek/watch/archive/226569/b, Hepatitis C: The Silent Epidemic, Retrieved August 26, 2010, KQED, 2010.
http://www.mdpi.com/1999-4915/2/5/1195/, Lipid Metabolism and HCV Infection, Paul Targett-Adams, et al, Retrieved August 25, 2010, Viruses, May 2010.
Sourcehttp://www.hepatitis-central.com/mt/archives/2010/09/tv_show_deliver.html?eml=hepcen115
Partial Hep C Treatment Response Offers Health Benefits
September 17, 2010
Even a partial response to hepatitis C virus (HCV) therapy confers significant health benefits to people coinfected with both HIV and HCV, though not as much as a full response. These data were presented September 14 at the 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Boston.
The goal of HCV therapy is total eradication of the virus. This outcome, called a sustained virological response (SVR), means that a person achieves and maintains undetectable HCV levels for at least six months after completing a course of pegylated interferon and ribavirin treatment, which is the standard of care for hepatitis C. People who achieve an SVR are generally considered to be “cured” of their HCV infection.
Unfortunately, standard treatment is not particularly effective for people infected with HCV genotype 1, the most common and difficult to treat strain in the United States. SVR rates in people coinfected with both HIV and HCV genotype 1 are generally no higher than 25 percent. There is, however, a segment of people who have undetectable HCV levels at the end of treatment, but who see their virus come back in subsequent months. These people are considered to have an end of treatment response (ETR). What remains unknown is whether and to what degree these individuals have benefited from taking HCV treatment.
To explore this question, Juan Berenguer, MD, from the Hospital Universitario Gregorio Maranon in Madrid, and his colleagues, analyzed data from the GESIDA 3603 cohort, which follows HIV and HCV coinfected people from 19 clinics across Spain. Out of the 1,428 people in the analysis, 697 did not respond to HCV treatment (non-responders), 211 had an ETR, and 520 had an SVR.
The analysis looked at the rate of developing a variety of liver problems over a four-year period after completing HCV treatment. The presentation did not report on the participants’ average age, CD4 counts, distribution of HCV genotypes or other demographic factors, but those factors were included in the analysis.
Berenguer’s team found that although people with an ETR had poorer outcomes than people who achieved an SVR, they still did far better than non-responders. People with an ETR were 60 percent less likely to have liver damage (decompensation) than non-responders. People with an SVR were 92 percent less likely. People with ETRs and SVRs were both about 95 percent less likely to die from liver disease than non-responders.
The best treatment outcomes were achieved with an SVR, the authors concluded. They added, however, that ETR was associated with less liver-related mortality and liver decompensation than a non-response to treatment.
Search: Hepatitis C, HCV, genotype 1, ICAAC, SVR, ETR, liver, liver decompensation, Juan Berenguer
Source
Even a partial response to hepatitis C virus (HCV) therapy confers significant health benefits to people coinfected with both HIV and HCV, though not as much as a full response. These data were presented September 14 at the 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Boston.
The goal of HCV therapy is total eradication of the virus. This outcome, called a sustained virological response (SVR), means that a person achieves and maintains undetectable HCV levels for at least six months after completing a course of pegylated interferon and ribavirin treatment, which is the standard of care for hepatitis C. People who achieve an SVR are generally considered to be “cured” of their HCV infection.
Unfortunately, standard treatment is not particularly effective for people infected with HCV genotype 1, the most common and difficult to treat strain in the United States. SVR rates in people coinfected with both HIV and HCV genotype 1 are generally no higher than 25 percent. There is, however, a segment of people who have undetectable HCV levels at the end of treatment, but who see their virus come back in subsequent months. These people are considered to have an end of treatment response (ETR). What remains unknown is whether and to what degree these individuals have benefited from taking HCV treatment.
To explore this question, Juan Berenguer, MD, from the Hospital Universitario Gregorio Maranon in Madrid, and his colleagues, analyzed data from the GESIDA 3603 cohort, which follows HIV and HCV coinfected people from 19 clinics across Spain. Out of the 1,428 people in the analysis, 697 did not respond to HCV treatment (non-responders), 211 had an ETR, and 520 had an SVR.
The analysis looked at the rate of developing a variety of liver problems over a four-year period after completing HCV treatment. The presentation did not report on the participants’ average age, CD4 counts, distribution of HCV genotypes or other demographic factors, but those factors were included in the analysis.
Berenguer’s team found that although people with an ETR had poorer outcomes than people who achieved an SVR, they still did far better than non-responders. People with an ETR were 60 percent less likely to have liver damage (decompensation) than non-responders. People with an SVR were 92 percent less likely. People with ETRs and SVRs were both about 95 percent less likely to die from liver disease than non-responders.
The best treatment outcomes were achieved with an SVR, the authors concluded. They added, however, that ETR was associated with less liver-related mortality and liver decompensation than a non-response to treatment.
Search: Hepatitis C, HCV, genotype 1, ICAAC, SVR, ETR, liver, liver decompensation, Juan Berenguer
Source
A Multidisciplinary Therapeutic Approach for Reducing the Risk of Psychiatric Side Effects in Patients With Chronic Hepatitis C Treated With Pegylated Interferon α and Ribavirin
J Clin Gastroenterol. 2010 Oct;44(9):e210-e217.
Neri S, Bertino G, Petralia A, Giancarlo C, Rizzotto A, Calvagno GS, Mauceri B, Abate G, Boemi P, Di Pino A, Ignaccolo L, Vadalà G, Misseri M, Maiorca D, Mastrosimone G, Judica A, Palermo F.
Departments of *Internal Medicine †Psychiatry ∥Internal and Specialty Medicine, Center of Statistics, University of Catania §Research Doctorate in Hepatology, University of Catania ‡School of Psychology, Kore University, Enna, Italy.
Abstract
GOALS: To evaluate the effectiveness of psychiatric counseling in reducing the rate of development of psychiatric side effects of antiviral therapy with interferon-α and ribavirin among study participants compared with standard clinical monitoring alone.
BACKGROUND: Interferon-α is used to treat chronic hepatitis C. Interferons may induce adverse events that usually, but not always, reverse within a few days after the end of therapy.
STUDY: Two hundred eleven patients with chronic hepatitis C, genotype 1b were treated with peginterferon and ribavirin for 48 weeks in a prospective trial. Two groups were randomly created. Group A was interviewed by a team of gastroenterologists, psychiatrists, and psychologists and treated with psychotherapy once a month. Group B was monitored once a month according to a conventional protocol that did not include psychotherapy. SVR (sustained viral response), severe psychiatric symptom onset, and mood progression were assessed (P calculated using Fisher exact test, Friedman test, Dunn posttest, and Mann-Whitney U-test).
RESULTS: At baseline, there was no difference in depressive symptoms or liver histologic score between the 2 groups. The onset rate of severe psychiatric manifestations was 4.7% (Group A) and 16.1% (Group B) between the 24th and 36th weeks (P<0.01). Fifteen participants in Group A and 39 in Group B required antidepressants and benzodiazepines (P<0.05).
CONCLUSIONS: Patients can develop depressive symptoms during interferon therapy. Multidisciplinary medical treatment with psychiatric counseling provided during the treatment of chronic hepatitis C may contribute to the decrease or prevent the higher rates of depression associated with interferon treatment.
PMID: 20838237 [PubMed - as supplied by publisher
Source
Neri S, Bertino G, Petralia A, Giancarlo C, Rizzotto A, Calvagno GS, Mauceri B, Abate G, Boemi P, Di Pino A, Ignaccolo L, Vadalà G, Misseri M, Maiorca D, Mastrosimone G, Judica A, Palermo F.
Departments of *Internal Medicine †Psychiatry ∥Internal and Specialty Medicine, Center of Statistics, University of Catania §Research Doctorate in Hepatology, University of Catania ‡School of Psychology, Kore University, Enna, Italy.
Abstract
GOALS: To evaluate the effectiveness of psychiatric counseling in reducing the rate of development of psychiatric side effects of antiviral therapy with interferon-α and ribavirin among study participants compared with standard clinical monitoring alone.
BACKGROUND: Interferon-α is used to treat chronic hepatitis C. Interferons may induce adverse events that usually, but not always, reverse within a few days after the end of therapy.
STUDY: Two hundred eleven patients with chronic hepatitis C, genotype 1b were treated with peginterferon and ribavirin for 48 weeks in a prospective trial. Two groups were randomly created. Group A was interviewed by a team of gastroenterologists, psychiatrists, and psychologists and treated with psychotherapy once a month. Group B was monitored once a month according to a conventional protocol that did not include psychotherapy. SVR (sustained viral response), severe psychiatric symptom onset, and mood progression were assessed (P calculated using Fisher exact test, Friedman test, Dunn posttest, and Mann-Whitney U-test).
RESULTS: At baseline, there was no difference in depressive symptoms or liver histologic score between the 2 groups. The onset rate of severe psychiatric manifestations was 4.7% (Group A) and 16.1% (Group B) between the 24th and 36th weeks (P<0.01). Fifteen participants in Group A and 39 in Group B required antidepressants and benzodiazepines (P<0.05).
CONCLUSIONS: Patients can develop depressive symptoms during interferon therapy. Multidisciplinary medical treatment with psychiatric counseling provided during the treatment of chronic hepatitis C may contribute to the decrease or prevent the higher rates of depression associated with interferon treatment.
PMID: 20838237 [PubMed - as supplied by publisher
Source
Kidney Grafts From HCV-Positive Donors: Advantages and Disadvantages
Transplant Proc. 2010 Sep;42(7):2436-46.
Maluf DG, Archer KJ, Mas VR.
Division of Transplantation Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.
Abstract
The Organ Procurement and Transplantation Network database (2001-2006) was reviewed for kidney transplant (KT) recipients, to evaluate the effects of use of grafts from donors positive for hepatitis C virus (HCV) on recipient outcome. Data for 76,787 de novo adult KT recipients were included in the analysis. Serologic tests revealed HCV positivity in 6.25% of cadaver kidneys and 2.97% of living-donor kidneys. Median follow-up in patients still alive was 36 months. At multivariable Cox regression analysis in recipients of cadaver kidney, HCV serostatus was significantly associated with overall and graft survival (both P < .001), with a hazard ratio for HCV-positive patients of 1.43 for overall survival and 1.48 for graft survival. Similar results were obtained for living-donor kidney recipients. Recipients of HCV-positive organs tended to be male and African American and to have a shorter waiting time. Infection was the most commonly reported cause of death in recipients of organs from HCV-positive donors. In patients willing to accept HCV-positive grafts (929 [25.6%]), waiting time was significantly shortened (P < .001). However, this benefit was offset by decreased patient survival (P < .001) and graft survival (P = .007).
PMID: 20832522 [PubMed - in process]
Source
Maluf DG, Archer KJ, Mas VR.
Division of Transplantation Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.
Abstract
The Organ Procurement and Transplantation Network database (2001-2006) was reviewed for kidney transplant (KT) recipients, to evaluate the effects of use of grafts from donors positive for hepatitis C virus (HCV) on recipient outcome. Data for 76,787 de novo adult KT recipients were included in the analysis. Serologic tests revealed HCV positivity in 6.25% of cadaver kidneys and 2.97% of living-donor kidneys. Median follow-up in patients still alive was 36 months. At multivariable Cox regression analysis in recipients of cadaver kidney, HCV serostatus was significantly associated with overall and graft survival (both P < .001), with a hazard ratio for HCV-positive patients of 1.43 for overall survival and 1.48 for graft survival. Similar results were obtained for living-donor kidney recipients. Recipients of HCV-positive organs tended to be male and African American and to have a shorter waiting time. Infection was the most commonly reported cause of death in recipients of organs from HCV-positive donors. In patients willing to accept HCV-positive grafts (929 [25.6%]), waiting time was significantly shortened (P < .001). However, this benefit was offset by decreased patient survival (P < .001) and graft survival (P = .007).
PMID: 20832522 [PubMed - in process]
Source
Individualized treatment with combination of Peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3
J Hepatol. 2010 Aug 4. [Epub ahead of print]
Mangia A, Bandiera F, Montalto G, Mottola L, Piazzolla V, Minerva N, Pellicelli A, Ricci GL, Cela M, Carretta V, Scotto G, Bacca D, Annicchiarico B, Romano M, Russello M, Barbarini G, Agostinacchio E, Andriulli A.
Liver Unit, IRCCS, "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
Abstract
BACKGROUND & AIMS: The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established.
METHODS: Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200mg of ribavirin daily according with body weight > or <75kg. Patients were randomized to standard 24weeks (Std24) or to a 12 or 36weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36weeks duration.
RESULTS: At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treatment (EOT) responses were 80.4% (CI 85.4-95.3) and 97.6% (CI 94.9-99.9) in the two arms, respectively (p=0.019). In patients without wk4-R, corresponding rates were 61.9% (50.6-73.2) and 75.3% (CI 65.9-84.6) (p=0.08). SVR was attained in 302 patients, 71.4% (CI 65.3-77.6) in the St24 group and 74.3% (CI 58.4-80.3) in the variable 12/36 arm. Among patients with wk4-R, SVR was 81.6% (CI 75.1-88.1) and 82.5% (75.9-89.1), respectively. In patients without wk4-R, SVR amounted to 52.1% (CI 40.4-63.7) and 61.7 (CI 51.1-72.3) in the two arms (p=0.25).
CONCLUSIONS: HCV genotype 3 patients with week4-R may be treated safely with 12weeks of therapy, provided that sufficiently high doses of ribavirin are administered. For patients still viremic at treatment week 4, SVR rates were numerically higher after 36weeks of treatment than after the currently recommended 24weeks.
PMID: 20843575 [PubMed - as supplied by publisher]
Source
Mangia A, Bandiera F, Montalto G, Mottola L, Piazzolla V, Minerva N, Pellicelli A, Ricci GL, Cela M, Carretta V, Scotto G, Bacca D, Annicchiarico B, Romano M, Russello M, Barbarini G, Agostinacchio E, Andriulli A.
Liver Unit, IRCCS, "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
Abstract
BACKGROUND & AIMS: The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established.
METHODS: Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200mg of ribavirin daily according with body weight > or <75kg. Patients were randomized to standard 24weeks (Std24) or to a 12 or 36weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36weeks duration.
RESULTS: At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treatment (EOT) responses were 80.4% (CI 85.4-95.3) and 97.6% (CI 94.9-99.9) in the two arms, respectively (p=0.019). In patients without wk4-R, corresponding rates were 61.9% (50.6-73.2) and 75.3% (CI 65.9-84.6) (p=0.08). SVR was attained in 302 patients, 71.4% (CI 65.3-77.6) in the St24 group and 74.3% (CI 58.4-80.3) in the variable 12/36 arm. Among patients with wk4-R, SVR was 81.6% (CI 75.1-88.1) and 82.5% (75.9-89.1), respectively. In patients without wk4-R, SVR amounted to 52.1% (CI 40.4-63.7) and 61.7 (CI 51.1-72.3) in the two arms (p=0.25).
CONCLUSIONS: HCV genotype 3 patients with week4-R may be treated safely with 12weeks of therapy, provided that sufficiently high doses of ribavirin are administered. For patients still viremic at treatment week 4, SVR rates were numerically higher after 36weeks of treatment than after the currently recommended 24weeks.
PMID: 20843575 [PubMed - as supplied by publisher]
Source
Pretreatment prediction of response to peginterferon plus ribavirin therapy in genotype 1 chronic hepatitis C using data mining analysis
J Gastroenterol. 2010 Sep 10. [Epub ahead of print]
Kurosaki M, Sakamoto N, Iwasaki M, Sakamoto M, Suzuki Y, Hiramatsu N, Sugauchi F, Yatsuhashi H, Izumi N.
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino, Tokyo, 180-8610, Japan, kurosaki@musashino.jrc.or.jp.
Abstract
BACKGROUND: This study aimed to develop a model for the pre-treatment prediction of sustained virological response (SVR) to peg-interferon plus ribavirin therapy in chronic hepatitis C.
METHODS: Data from 800 genotype 1b chronic hepatitis C patients with high viral load (>100,000 IU/ml) treated by peg-interferon plus ribavirin at 6 hospitals in Japan were randomly assigned to a model building (n = 506) or an internal validation (n = 294). Data from 524 patients treated at 29 hospitals in Japan were used for an external validation. Factors predictive of SVR were explored using data mining analysis.
RESULTS: Age (<50 years), alpha-fetoprotein (AFP) (<8 ng/mL), platelet count (≥120 × 10(9)/l), gamma-glutamyltransferase (GGT) (<40 IU/l), and male gender were used to build the decision tree model, which divided patients into 7 subgroups with variable rates of SVR ranging from 22 to 77%. The reproducibility of the model was confirmed by the internal and external validation (r (2) = 0.92 and 0.93, respectively). When reconstructed into 3 groups, the rate of SVR was 75% for the high probability group, 44% for the intermediate probability group and 23% for the low probability group. Poor adherence to drugs lowered the rate of SVR in the low probability group, but not in the high probability group.
CONCLUSIONS: A decision tree model that includes age, gender, AFP, platelet counts, and GGT is useful for predicting the probability of response to therapy with peg-interferon plus ribavirin and has the potential to support clinical decisions regarding the selection of patients for therapy.
PMID: 20830599 [PubMed - as supplied by publisher]
Source
Kurosaki M, Sakamoto N, Iwasaki M, Sakamoto M, Suzuki Y, Hiramatsu N, Sugauchi F, Yatsuhashi H, Izumi N.
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino, Tokyo, 180-8610, Japan, kurosaki@musashino.jrc.or.jp.
Abstract
BACKGROUND: This study aimed to develop a model for the pre-treatment prediction of sustained virological response (SVR) to peg-interferon plus ribavirin therapy in chronic hepatitis C.
METHODS: Data from 800 genotype 1b chronic hepatitis C patients with high viral load (>100,000 IU/ml) treated by peg-interferon plus ribavirin at 6 hospitals in Japan were randomly assigned to a model building (n = 506) or an internal validation (n = 294). Data from 524 patients treated at 29 hospitals in Japan were used for an external validation. Factors predictive of SVR were explored using data mining analysis.
RESULTS: Age (<50 years), alpha-fetoprotein (AFP) (<8 ng/mL), platelet count (≥120 × 10(9)/l), gamma-glutamyltransferase (GGT) (<40 IU/l), and male gender were used to build the decision tree model, which divided patients into 7 subgroups with variable rates of SVR ranging from 22 to 77%. The reproducibility of the model was confirmed by the internal and external validation (r (2) = 0.92 and 0.93, respectively). When reconstructed into 3 groups, the rate of SVR was 75% for the high probability group, 44% for the intermediate probability group and 23% for the low probability group. Poor adherence to drugs lowered the rate of SVR in the low probability group, but not in the high probability group.
CONCLUSIONS: A decision tree model that includes age, gender, AFP, platelet counts, and GGT is useful for predicting the probability of response to therapy with peg-interferon plus ribavirin and has the potential to support clinical decisions regarding the selection of patients for therapy.
PMID: 20830599 [PubMed - as supplied by publisher]
Source
Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C
Hepatology. 2010 Jul 29. [Epub ahead of print]
Roomer R, Hansen BE, Janssen HL, de Knegt RJ.
Departments of Gastroenterology and Hepatology, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Abstract
Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment. In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment. The baseline mean absolute neutrophil count (ANC) was 3,420 cells/μL, and 16 patients had a baseline ANC of <1,500 cells/μL. During treatment, neutropenia, which was defined as ANC <750 cells/μL, was observed in 95 patients (29.7%) and ANC <375/μL was observed in 16 patients (5%). Ninety-six infections were observed in 70 patients (21.8%). Thirteen infections (13.5%) were defined as severe. Infections were not correlated with neutropenia during treatment. Dose reductions did not lead to a decrease in infection rate. Multivariate logistic regression analysis revealed that age >55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment. Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection. Conclusion: Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment. (HEPATOLOGY 2010).
PMID: 20830784 [PubMed - as supplied by publisher]
Source
Roomer R, Hansen BE, Janssen HL, de Knegt RJ.
Departments of Gastroenterology and Hepatology, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Abstract
Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment. In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment. The baseline mean absolute neutrophil count (ANC) was 3,420 cells/μL, and 16 patients had a baseline ANC of <1,500 cells/μL. During treatment, neutropenia, which was defined as ANC <750 cells/μL, was observed in 95 patients (29.7%) and ANC <375/μL was observed in 16 patients (5%). Ninety-six infections were observed in 70 patients (21.8%). Thirteen infections (13.5%) were defined as severe. Infections were not correlated with neutropenia during treatment. Dose reductions did not lead to a decrease in infection rate. Multivariate logistic regression analysis revealed that age >55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment. Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection. Conclusion: Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment. (HEPATOLOGY 2010).
PMID: 20830784 [PubMed - as supplied by publisher]
Source
Statin therapy improves sustained virologic response among diabetic patients with chronic hepatitis C
Gastroenterology. 2010 Sep 9. [Epub ahead of print]
Rao GA, Pandya PK.
Kansas City Veterans Affairs Medical Center, 4801 E. Linwood Blvd, Kansas City, MO 64128; Arnold School of Public Health, University of South Carolina, 800 Sumter St, Columbia, SC 29208.
Abstract
BACKGROUND & AIMS: Patients with chronic hepatitis C infection are 2-3-fold more likely to develop type-2 diabetes, which reduces their chances of achieving a sustained virologic response (SVR). To identify differences in predictors of SVR in patients with and without diabetes who received combination antiviral therapy, we conducted a retrospective analysis of national Veterans Affairs (VA) administrative database.
METHODS: We analyzed data from VA Medical SAS Datasets and Decision Support System for entire cohort and separately for diabetics (n=1704) and non-diabetics (n=6589). Significant predictors of SVR were identified by logistic regression analysis.
RESULTS: Diabetics had a lower SVR compared to non-diabetics (21% vs. 27%, p < 0.001). Diabetics had higher clustering of previously established negative predictors of SVR. On multivariate analysis of diabetics for SVR, the positive predictors were higher low density lipoprotein (OR=1.45, p=0.0129), use of statin (OR = 1.52, p = 0.0124) and lower baseline viral load (OR = 2.31, p < 0.001), while insulin therapy (0.7, p = 0.0278) was a negative predictor. Diabetics on statins had a higher pre-treatment viral loads (log 6.2vs.6.4, p= 0.006) but better early virologic response. There was a graded inverse relationship between HbA1c and SVR rate (p=0.0482). This relationship was highest among insulin users (p=0.0154) and lost among metformin users (p=0.5853).
CONCLUSIONS: Statin use was associated with an improved SVR among both diabetics and non-diabetics receiving combination antiviral therapy. Diabetics who received insulin achieved lower SVR compared to those not receiving insulin. Poor diabetes control was associated with lower SVR rates.
PMID: 20833169 [PubMed - as supplied by publisher]
Source
Rao GA, Pandya PK.
Kansas City Veterans Affairs Medical Center, 4801 E. Linwood Blvd, Kansas City, MO 64128; Arnold School of Public Health, University of South Carolina, 800 Sumter St, Columbia, SC 29208.
Abstract
BACKGROUND & AIMS: Patients with chronic hepatitis C infection are 2-3-fold more likely to develop type-2 diabetes, which reduces their chances of achieving a sustained virologic response (SVR). To identify differences in predictors of SVR in patients with and without diabetes who received combination antiviral therapy, we conducted a retrospective analysis of national Veterans Affairs (VA) administrative database.
METHODS: We analyzed data from VA Medical SAS Datasets and Decision Support System for entire cohort and separately for diabetics (n=1704) and non-diabetics (n=6589). Significant predictors of SVR were identified by logistic regression analysis.
RESULTS: Diabetics had a lower SVR compared to non-diabetics (21% vs. 27%, p < 0.001). Diabetics had higher clustering of previously established negative predictors of SVR. On multivariate analysis of diabetics for SVR, the positive predictors were higher low density lipoprotein (OR=1.45, p=0.0129), use of statin (OR = 1.52, p = 0.0124) and lower baseline viral load (OR = 2.31, p < 0.001), while insulin therapy (0.7, p = 0.0278) was a negative predictor. Diabetics on statins had a higher pre-treatment viral loads (log 6.2vs.6.4, p= 0.006) but better early virologic response. There was a graded inverse relationship between HbA1c and SVR rate (p=0.0482). This relationship was highest among insulin users (p=0.0154) and lost among metformin users (p=0.5853).
CONCLUSIONS: Statin use was associated with an improved SVR among both diabetics and non-diabetics receiving combination antiviral therapy. Diabetics who received insulin achieved lower SVR compared to those not receiving insulin. Poor diabetes control was associated with lower SVR rates.
PMID: 20833169 [PubMed - as supplied by publisher]
Source
Alcoholic liver disease-related mortality in the United States: 1980-2003
Am J Gastroenterol. 2010 Aug;105(8):1782-7. Epub 2010 Feb 23.
Paula H, Asrani SK, Boetticher NC, Pedersen R, Shah VH, Kim WR.
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Abstract
OBJECTIVES: Data on temporal changes in alcoholic liver disease (ALD)-related mortality in the United States are lacking. This longitudinal assessment is important, given the divergent data on trends in worldwide ALD-related mortality, concerns for underestimation of mortality attributed to ALD in previous investigations, and shifting attention to hepatitis C virus (HCV)-related mortality.
METHODS: We analyzed mortality data compiled in the multiple cause-of-death public-use data file from the National Vital Statistics System from 1980 to 2003 using categorization by both International Classification of Diseases (ICD)-9 and ICD-10 systems. The main outcome measure was age- and sex-adjusted death rates attributable to ALD, HCV, or both (ALD/HCV) listed as immediate or underlying cause of death.
RESULTS: A total of 287,365 deaths were observed over the 24-year period. Age- and sex- adjusted incidence rates of ALD-related deaths decreased from 6.9/100,000 persons in 1980 to 4.4/100,000 persons by 2003. After introduction of HCV diagnostic testing, HCV-related liver mortality increased to 2.9/100,000 persons by 2003. Death rates for subjects with concomitant ALD/HCV rose to 0.2/100,000 persons by 1999 and then remained unchanged through 2003. Age-specific mortality related to ALD was highest in the ages of 45-64 years. Between 1980 and 2003, the age- and sex-adjusted ALD-related mortality (per 100,000 persons) decreased from 6.3 to 4.5 among Caucasians, 11.6 to 4.1 among African Americans, and 8.0 to 3.7 among the "other" race group.
CONCLUSIONS: Despite a decline in ALD-related mortality, the proportion of alcohol-related liver deaths is still considerably large and comparable in scope to that of HCV.
PMID: 20179691 [PubMed - indexed for MEDLINE] PMCID: PMC2916935
Free Author Manuscript
Source
Paula H, Asrani SK, Boetticher NC, Pedersen R, Shah VH, Kim WR.
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Abstract
OBJECTIVES: Data on temporal changes in alcoholic liver disease (ALD)-related mortality in the United States are lacking. This longitudinal assessment is important, given the divergent data on trends in worldwide ALD-related mortality, concerns for underestimation of mortality attributed to ALD in previous investigations, and shifting attention to hepatitis C virus (HCV)-related mortality.
METHODS: We analyzed mortality data compiled in the multiple cause-of-death public-use data file from the National Vital Statistics System from 1980 to 2003 using categorization by both International Classification of Diseases (ICD)-9 and ICD-10 systems. The main outcome measure was age- and sex-adjusted death rates attributable to ALD, HCV, or both (ALD/HCV) listed as immediate or underlying cause of death.
RESULTS: A total of 287,365 deaths were observed over the 24-year period. Age- and sex- adjusted incidence rates of ALD-related deaths decreased from 6.9/100,000 persons in 1980 to 4.4/100,000 persons by 2003. After introduction of HCV diagnostic testing, HCV-related liver mortality increased to 2.9/100,000 persons by 2003. Death rates for subjects with concomitant ALD/HCV rose to 0.2/100,000 persons by 1999 and then remained unchanged through 2003. Age-specific mortality related to ALD was highest in the ages of 45-64 years. Between 1980 and 2003, the age- and sex-adjusted ALD-related mortality (per 100,000 persons) decreased from 6.3 to 4.5 among Caucasians, 11.6 to 4.1 among African Americans, and 8.0 to 3.7 among the "other" race group.
CONCLUSIONS: Despite a decline in ALD-related mortality, the proportion of alcohol-related liver deaths is still considerably large and comparable in scope to that of HCV.
PMID: 20179691 [PubMed - indexed for MEDLINE] PMCID: PMC2916935
Free Author Manuscript
Source
Study Spells End of the Road for One Anti-HIV Gel
By Michael Smith, North American Correspondent, MedPage Today
Published: September 19, 2010
Reviewed by Barry S. Zingman, MD; Professor of Clinical Medicine, Albert Einstein College of Medicine, Bronx, NY
and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
A microbicide gel -- PRO2000 -- aimed at preventing HIV infection in women was ineffective, despite promising early clinical trials, researchers reported.
In a large randomized phase III trial, the PRO2000 microbicide was safe, but did nothing to prevent women from acquiring HIV, according to Sheena McCormack, MD, of the MRC Clinical Trials Unit in London, and colleagues.
The report, online in The Lancet, comes only a few weeks after researchers studying another microbicide gel combined with an antiretroviral drug reported partial success -- a significant 39% reduction in the risk of HIV infection. Further studies of microbicides that include antiretroviral drugs are underway.
The PRO2000 compound is a synthetic naphthalene sulphonate polymer that -- in animals and the lab -- had shown anti-HIV activity, McCormack and colleagues noted. A phase II/IIb trial, reported in 2009, also found a nonsignificant but promising trend toward protection in humans.
But only a few days after that report, the data monitoring committee of this study called a halt to one of the arms -- testing a 2% solution of PRO2000 -- on the grounds that there was little likelihood of benefit. The other arm, testing a 0.5% solution, was allowed to continue to completion, McCormack and colleagues reported.
The study, conducted in 13 clinics in South Africa, Tanzania, Uganda, and Zambia, randomly assigned sexually active, HIV-negative women to get one of three gels -- a hydroxyethylcellulose placebo, 0.5% PRO2000, or 2% PRO2000.
The researchers reported two efficacy analyses -- all three arms compared at the time of the 2% PRO2000 discontinuation and the placebo and 0.5% PRO2000 arms compared at the planned end of the study.
Overall, McCormack and colleagues found, adherence was high, with an average reported gel use at the last sex act of 89%.
Despite that, the incidence of HIV was much the same in both analyses:
• At the discontinuation of the 2% PRO2000 arm, the incidence per 100 woman-years was 4.7 for 2% PRO2000, 3.9 for 0.5% PRO2000, and 3.9 for placebo. Neither treatment was significantly better than placebo.
• At study's end, the incidence per 100 woman-years was 4.5 for 0.5% PRO2000 and 4.3 for placebo. The 1.05 hazard ratio had a 95% confidence interval from 0.82 to 1.34 and was nonsignificant at P=0.71.
The primary safety endpoint was an adverse event of grade 3 or worse, and again there was little difference -- 4.6 per 100 woman-years in the 0.5% PRO2000 group and 3.9 in the placebo group at study's end. It was 4.5 in the 2% PRO2000 group at discontinuation, the researchers reported.
The findings are "disappointing," especially in view of the earlier trial that showed a nearly significant result, according to Sandra McCoy, PhD, of the University of California Berkeley, and colleagues.
Writing in an accompanying commentary, McCoy and colleagues said the report "will certainly indicate the end of the road for PRO2000 as a potential HIV-prevention tool for women."
But, they noted, the positive results of the latest microbicide study, combined with other interventions that are showing promise in reducing HIV incidence among women, "have the potential to greatly expand prevention options for women in sub-Saharan Africa."
The study was supported by the Microbicides Development Programme, the U.K. Department for International Development, the European and Developing Countries Clinical Trials Partnership, and the U.K. Medical Research Council. Study gels were provided by Endo Pharmaceutical Solutions. McCormack reported no conflicts.
Commentary author Charlotte Watts, of the London School of Hygiene and Tropical Medicine, is supported by the Sigrid Rausing Trust and the Microbicides Development Programme.
All authors said they had no conflicts.
Primary source: The Lancet
Source reference:
McCormack S, et al "PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial" Lancet 2010; DOI: 10.1016/S0140-6736(10)61086-0.
Additional source: The Lancet
Source reference:
McCoy SI, et al "Preventing HIV infection: Turning the tide for young women" Lancet 2010; DOI: 10.1016/S0140-6736(10)61309-8.
Source
Published: September 19, 2010
Reviewed by Barry S. Zingman, MD; Professor of Clinical Medicine, Albert Einstein College of Medicine, Bronx, NY
and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
A microbicide gel -- PRO2000 -- aimed at preventing HIV infection in women was ineffective, despite promising early clinical trials, researchers reported.
In a large randomized phase III trial, the PRO2000 microbicide was safe, but did nothing to prevent women from acquiring HIV, according to Sheena McCormack, MD, of the MRC Clinical Trials Unit in London, and colleagues.
The report, online in The Lancet, comes only a few weeks after researchers studying another microbicide gel combined with an antiretroviral drug reported partial success -- a significant 39% reduction in the risk of HIV infection. Further studies of microbicides that include antiretroviral drugs are underway.
The PRO2000 compound is a synthetic naphthalene sulphonate polymer that -- in animals and the lab -- had shown anti-HIV activity, McCormack and colleagues noted. A phase II/IIb trial, reported in 2009, also found a nonsignificant but promising trend toward protection in humans.
But only a few days after that report, the data monitoring committee of this study called a halt to one of the arms -- testing a 2% solution of PRO2000 -- on the grounds that there was little likelihood of benefit. The other arm, testing a 0.5% solution, was allowed to continue to completion, McCormack and colleagues reported.
The study, conducted in 13 clinics in South Africa, Tanzania, Uganda, and Zambia, randomly assigned sexually active, HIV-negative women to get one of three gels -- a hydroxyethylcellulose placebo, 0.5% PRO2000, or 2% PRO2000.
The researchers reported two efficacy analyses -- all three arms compared at the time of the 2% PRO2000 discontinuation and the placebo and 0.5% PRO2000 arms compared at the planned end of the study.
Overall, McCormack and colleagues found, adherence was high, with an average reported gel use at the last sex act of 89%.
Despite that, the incidence of HIV was much the same in both analyses:
• At the discontinuation of the 2% PRO2000 arm, the incidence per 100 woman-years was 4.7 for 2% PRO2000, 3.9 for 0.5% PRO2000, and 3.9 for placebo. Neither treatment was significantly better than placebo.
• At study's end, the incidence per 100 woman-years was 4.5 for 0.5% PRO2000 and 4.3 for placebo. The 1.05 hazard ratio had a 95% confidence interval from 0.82 to 1.34 and was nonsignificant at P=0.71.
The primary safety endpoint was an adverse event of grade 3 or worse, and again there was little difference -- 4.6 per 100 woman-years in the 0.5% PRO2000 group and 3.9 in the placebo group at study's end. It was 4.5 in the 2% PRO2000 group at discontinuation, the researchers reported.
The findings are "disappointing," especially in view of the earlier trial that showed a nearly significant result, according to Sandra McCoy, PhD, of the University of California Berkeley, and colleagues.
Writing in an accompanying commentary, McCoy and colleagues said the report "will certainly indicate the end of the road for PRO2000 as a potential HIV-prevention tool for women."
But, they noted, the positive results of the latest microbicide study, combined with other interventions that are showing promise in reducing HIV incidence among women, "have the potential to greatly expand prevention options for women in sub-Saharan Africa."
The study was supported by the Microbicides Development Programme, the U.K. Department for International Development, the European and Developing Countries Clinical Trials Partnership, and the U.K. Medical Research Council. Study gels were provided by Endo Pharmaceutical Solutions. McCormack reported no conflicts.
Commentary author Charlotte Watts, of the London School of Hygiene and Tropical Medicine, is supported by the Sigrid Rausing Trust and the Microbicides Development Programme.
All authors said they had no conflicts.
Primary source: The Lancet
Source reference:
McCormack S, et al "PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial" Lancet 2010; DOI: 10.1016/S0140-6736(10)61086-0.
Additional source: The Lancet
Source reference:
McCoy SI, et al "Preventing HIV infection: Turning the tide for young women" Lancet 2010; DOI: 10.1016/S0140-6736(10)61309-8.
Source
Atorvastatin and Antioxidants for the Treatment of Nonalcoholic Fatty Liver Disease: The St Francis Heart Study Randomized Clinical Trial.
Am J Gastroenterol. 2010 Sep 14. [Epub ahead of print]
Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD.
Department of Medicine, University of California, Los Angeles, California, USA.
Abstract
OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is defined as the spectrum of benign fatty liver to necroinflammation and fibrosis. Its prevalence has been found to be as high as 39%. It is estimated that up to 15% of those affected will go on to have progressive liver disease. Currently, there is no proven therapy for NAFLD. In this study, we aim to determine whether statin therapy may be an effective treatment for NAFLD and identify independent predictors of NAFLD.
METHODS: In all, 1,005 men and women, aged 50-70 years were randomized to receive either a daily combination of atorvastatin 20 mg, vitamin C 1 g, and vitamin E 1,000 IU vs. matching placebo, as part of the St Francis Heart Study randomized clinical trial. Liver to spleen (LS) ratios were calculated on 455 subjects with available computed tomography scans performed at baseline and follow-up to determine NAFLD prevalence. Baseline and final LS ratios were compared within treatment groups, and results were compared between the treatment and placebo groups using univariate and multivariate analyses. Mean duration of follow-up was 3.6 years.
RESULTS: There were 80 patients with NAFLD at baseline. We identified baseline triglyceride levels (odds ratio (OR)=1.003, P<0.001) and body mass index (OR=0.10, P<0.001) as independent correlates of NAFLD. Treatment with atorvastatin combined with vitamins E and C significantly reduced the odds of NAFLD at the end of follow-up, 70 vs. 34% (OR=0.29, P<0.001).
CONCLUSIONS: In conclusion, atorvastatin 20 mg combined with vitamins C and E is effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD at baseline after 4 years of active therapy.Am J Gastroenterol advance online publication, 14 September 2010; doi:10.1038/ajg.2010.299.
PMID: 20842109 [PubMed - as supplied by publisher]
Source
Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD.
Department of Medicine, University of California, Los Angeles, California, USA.
Abstract
OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is defined as the spectrum of benign fatty liver to necroinflammation and fibrosis. Its prevalence has been found to be as high as 39%. It is estimated that up to 15% of those affected will go on to have progressive liver disease. Currently, there is no proven therapy for NAFLD. In this study, we aim to determine whether statin therapy may be an effective treatment for NAFLD and identify independent predictors of NAFLD.
METHODS: In all, 1,005 men and women, aged 50-70 years were randomized to receive either a daily combination of atorvastatin 20 mg, vitamin C 1 g, and vitamin E 1,000 IU vs. matching placebo, as part of the St Francis Heart Study randomized clinical trial. Liver to spleen (LS) ratios were calculated on 455 subjects with available computed tomography scans performed at baseline and follow-up to determine NAFLD prevalence. Baseline and final LS ratios were compared within treatment groups, and results were compared between the treatment and placebo groups using univariate and multivariate analyses. Mean duration of follow-up was 3.6 years.
RESULTS: There were 80 patients with NAFLD at baseline. We identified baseline triglyceride levels (odds ratio (OR)=1.003, P<0.001) and body mass index (OR=0.10, P<0.001) as independent correlates of NAFLD. Treatment with atorvastatin combined with vitamins E and C significantly reduced the odds of NAFLD at the end of follow-up, 70 vs. 34% (OR=0.29, P<0.001).
CONCLUSIONS: In conclusion, atorvastatin 20 mg combined with vitamins C and E is effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD at baseline after 4 years of active therapy.Am J Gastroenterol advance online publication, 14 September 2010; doi:10.1038/ajg.2010.299.
PMID: 20842109 [PubMed - as supplied by publisher]
Source
September 9, 2010
Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis
FibroTest (FT) is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoproteinA1, haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of three fibrosis markers (hyaluronic acid, amino-terminalpropeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1).
While a systematic review has shown comparable results for both individual markers, there has been no direct comparison of both markers.
Methods: In the present study, the ELF-test was analyzed retrospectively in patients with chronic liver disease, who received a liver biopsy, transient elastography (TE) and the FibroTest using histology as the reference method. Histology was classified according to METAVIR and the Ludwig's classification (F0-F4) for patients with chronic hepatitis C and B virus (HCV, HBV) infection and primary biliary cirrhosis (PBC), respectively.
Results: Seventy-four patients were analysed: 36 with HCV, 10 with HBV, and 28 with PBC.
The accuracy (AUROC) for the diagnosis of significant fibrosis (F[greater than or equal to]2) for ELF and FibroTest was 0.78 (95%CI:0.67-0.89) and 0.69 (95%-CI:0.57-0.82), respectively (difference not statistically significant, n.s.). The AUROC for the diagnosis of liver cirrhosis was 0.92 (95%CI:0.83-1,00), and 0.91 (95%CI:0.83-0.99), respectively (n.s.).
For 66 patients with reliable TE measurements the AUROC for the diagnosis of significant fibrosis (cirrhosis) for TE, ELF and FT were 0.80 (0.94), 0.76 (0.92), and 0.67 (0.91), respectively (n.s.).
Conclusion: FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography.
Author: Mireen Friedrich-RustWilliam RosenbergJulie ParkesEva HerrmannStefan ZeuzemChristoph Sarrazin
Credits/Source: BMC Gastroenterology 2010, 10:103
Published on: 2010-09-09
Source
While a systematic review has shown comparable results for both individual markers, there has been no direct comparison of both markers.
Methods: In the present study, the ELF-test was analyzed retrospectively in patients with chronic liver disease, who received a liver biopsy, transient elastography (TE) and the FibroTest using histology as the reference method. Histology was classified according to METAVIR and the Ludwig's classification (F0-F4) for patients with chronic hepatitis C and B virus (HCV, HBV) infection and primary biliary cirrhosis (PBC), respectively.
Results: Seventy-four patients were analysed: 36 with HCV, 10 with HBV, and 28 with PBC.
The accuracy (AUROC) for the diagnosis of significant fibrosis (F[greater than or equal to]2) for ELF and FibroTest was 0.78 (95%CI:0.67-0.89) and 0.69 (95%-CI:0.57-0.82), respectively (difference not statistically significant, n.s.). The AUROC for the diagnosis of liver cirrhosis was 0.92 (95%CI:0.83-1,00), and 0.91 (95%CI:0.83-0.99), respectively (n.s.).
For 66 patients with reliable TE measurements the AUROC for the diagnosis of significant fibrosis (cirrhosis) for TE, ELF and FT were 0.80 (0.94), 0.76 (0.92), and 0.67 (0.91), respectively (n.s.).
Conclusion: FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography.
Author: Mireen Friedrich-RustWilliam RosenbergJulie ParkesEva HerrmannStefan ZeuzemChristoph Sarrazin
Credits/Source: BMC Gastroenterology 2010, 10:103
Published on: 2010-09-09
Source
Bone Loss in HIV-Positive Men Tied to AIDS Diagnosis, Opiate Use and Hep C
September 9, 2010
Heroin and methadone users who’ve ever been diagnosed with AIDS are at dramatically higher risk of bone loss as they get older, according to a study published in the September 24 issue of AIDS.
Potent combination antiretroviral (ARV) therapy has significantly cut the death rate and led to longer life spans in people with HIV. This means that people are now living into older age, when additional health problems typically strike. In fact, experts project that by 2015 more than half of all people with HIV in the United States will be older than 50.
A growing concern is bone mineral loss—called osteopenia when it is mild and osteoporosis when it is more severe. Numerous studies have found higher rates of bone mineral loss among people with HIV than their HIV-negative counterparts. This is particularly true of HIV-positive men.
A further risk factor for decreased bone mineral density (BMD) is use of opiates, including heroin and methadone. Both drugs have been associated with osteopenia and osteoporosis. Since a significant number of people with HIV are current or former drug users, Anjali Sharma, MD, MS, and her colleagues from the State University of New York Downstate Medical Center in Brooklyn set out to measure bone health within this population.
Sharma’s team enrolled 389 men in the Bronx, New York, ages 49 and older who were HIV positive or at risk for infection. In total, 230 were HIV positive, and 159 were HIV negative. The men’s average age was 56, and most were of average height and weight. More than half of the HIV-positive men had been positive for at least 10 years, and 77 percent of them reported using protease inhibitors. More than half were African American, roughly one quarter were Latino, and the remainder were white or another race. The median CD4 count among the HIV-positive men was 398, and 42 percent had a history of an AIDS diagnosis.
All of the men underwent extensive interviews to determine their behavioral and medical histories. Each of them also underwent dual energy X-ray absorptiometry (DEXA) scans to measure their bone health in the thigh, hip and lower back, both at the time they entered the study and roughly three years later.
Risk factors associated with diminished BMD were common: 88 percent had a history of cocaine use, almost all had a history of smoking (64 percent were current smokers), 47 percent had evidence of alcoholism, and 47 percent had low serum testosterone.
At time of first DEXA, 46 percent of the men overall had normal BMD, while 42 percent had osteopenia, and 12 percent had osteoporosis. Of the men who initially had a normal BMD, 14 percent progressed to osteopenia, and 86 percent continued to have healthy bones. The risk for developing osteopenia among this group was nearly three times higher in the HIV-positive men. Of those who were initially diagnosed with osteopenia, roughly 12 percent progressed to osteoporosis. The rate of progression here was the same for HIV-positive men as for HIV-negative men.
Most of the typical factors for reduced BMD were associated with bone loss in this study, including, age, race, use of corticosteroids or testosterone, and hepatitis C virus (HCV) infection.
Sharma’s team, however, found a powerful interaction between use of heroin and a history of an AIDS diagnosis, such that the people with the greatest bone loss were heroin users who’d ever received an AIDS diagnosis. This held up after adjusting for all other risk factors. HCV status and current methadone use were also highly predictive. CD4 count and types of ARVs did not affect BMD.
Oddly, cigarette smoking was not significantly associated with bone loss. However, the authors comment that “the lack of an independent association of BMD loss with cigarette smoking might be due in part to the fact that nearly 90 percent of participants in the cohort were current or former smokers.”
“Taken together, these data suggest that HIV-infected opioid-using men may be at particular risk of bone loss as they age, as a result of comorbid disease such as hepatitis C infection, opioid substitution treatment with methadone, ongoing heroin use, progression to AIDS, or a combination of these factors,” the authors concluded.
“An improved understanding of factors associated with ongoing bone loss and fracture risk is needed,” they continued, “to help guide thresholds for assessment of BMD and for osteopenia treatment in HIV-infected persons and opioid users.”
Source
Heroin and methadone users who’ve ever been diagnosed with AIDS are at dramatically higher risk of bone loss as they get older, according to a study published in the September 24 issue of AIDS.
Potent combination antiretroviral (ARV) therapy has significantly cut the death rate and led to longer life spans in people with HIV. This means that people are now living into older age, when additional health problems typically strike. In fact, experts project that by 2015 more than half of all people with HIV in the United States will be older than 50.
A growing concern is bone mineral loss—called osteopenia when it is mild and osteoporosis when it is more severe. Numerous studies have found higher rates of bone mineral loss among people with HIV than their HIV-negative counterparts. This is particularly true of HIV-positive men.
A further risk factor for decreased bone mineral density (BMD) is use of opiates, including heroin and methadone. Both drugs have been associated with osteopenia and osteoporosis. Since a significant number of people with HIV are current or former drug users, Anjali Sharma, MD, MS, and her colleagues from the State University of New York Downstate Medical Center in Brooklyn set out to measure bone health within this population.
Sharma’s team enrolled 389 men in the Bronx, New York, ages 49 and older who were HIV positive or at risk for infection. In total, 230 were HIV positive, and 159 were HIV negative. The men’s average age was 56, and most were of average height and weight. More than half of the HIV-positive men had been positive for at least 10 years, and 77 percent of them reported using protease inhibitors. More than half were African American, roughly one quarter were Latino, and the remainder were white or another race. The median CD4 count among the HIV-positive men was 398, and 42 percent had a history of an AIDS diagnosis.
All of the men underwent extensive interviews to determine their behavioral and medical histories. Each of them also underwent dual energy X-ray absorptiometry (DEXA) scans to measure their bone health in the thigh, hip and lower back, both at the time they entered the study and roughly three years later.
Risk factors associated with diminished BMD were common: 88 percent had a history of cocaine use, almost all had a history of smoking (64 percent were current smokers), 47 percent had evidence of alcoholism, and 47 percent had low serum testosterone.
At time of first DEXA, 46 percent of the men overall had normal BMD, while 42 percent had osteopenia, and 12 percent had osteoporosis. Of the men who initially had a normal BMD, 14 percent progressed to osteopenia, and 86 percent continued to have healthy bones. The risk for developing osteopenia among this group was nearly three times higher in the HIV-positive men. Of those who were initially diagnosed with osteopenia, roughly 12 percent progressed to osteoporosis. The rate of progression here was the same for HIV-positive men as for HIV-negative men.
Most of the typical factors for reduced BMD were associated with bone loss in this study, including, age, race, use of corticosteroids or testosterone, and hepatitis C virus (HCV) infection.
Sharma’s team, however, found a powerful interaction between use of heroin and a history of an AIDS diagnosis, such that the people with the greatest bone loss were heroin users who’d ever received an AIDS diagnosis. This held up after adjusting for all other risk factors. HCV status and current methadone use were also highly predictive. CD4 count and types of ARVs did not affect BMD.
Oddly, cigarette smoking was not significantly associated with bone loss. However, the authors comment that “the lack of an independent association of BMD loss with cigarette smoking might be due in part to the fact that nearly 90 percent of participants in the cohort were current or former smokers.”
“Taken together, these data suggest that HIV-infected opioid-using men may be at particular risk of bone loss as they age, as a result of comorbid disease such as hepatitis C infection, opioid substitution treatment with methadone, ongoing heroin use, progression to AIDS, or a combination of these factors,” the authors concluded.
“An improved understanding of factors associated with ongoing bone loss and fracture risk is needed,” they continued, “to help guide thresholds for assessment of BMD and for osteopenia treatment in HIV-infected persons and opioid users.”
Source
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