January 1, 2011

A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin

Gastroenterology. 2010 Nov;139(5):1593-601. Epub 2010 Jul 14.

Swain MG, Lai MY, Shiffman ML, Cooksley WG, Zeuzem S, Dieterich DT, Abergel A, Pessôa MG, Lin A, Tietz A, Connell EV, Diago M.

Health Research Innovation Center, University of Calgary, Calgary, Alberta, Canada. swain@ucalgary.ca


BACKGROUND & AIMS: A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown.

METHODS: The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years).

RESULTS: Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse.

CONCLUSIONS: In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.

Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 20637202 [PubMed - indexed for MEDLINE]


The impact of donor race on recurrent hepatitis C after liver transplantation

Transplant Proc. 2010 Dec;42(10):4175-7.

Moeller M, Zalawadia A, Alrayes A, Divine G, Brown K, Moonka D.


BACKGROUND: Several studies have demonstrated mixed results regarding the influence of donor race on patient and graft survival in patients infected with hepatitis C virus (HCV) after liver transplant. However, few studies have looked at the impact of donor race on recurrent HCV. This study is a retrospective analysis of the influence of patient and donor race on the severity of recurrent HCV at a single center.

METHODS: Of patients transplanted at our center between 2000 and 2006, 222 were infected with HCV. Of these, 165 were eligible to be evaluated for recurrent HCV after transplant. We excluded those with patient and graft loss within 1 year that was not related to recurrent HCV, patients with advanced fibrosis from other causes, those who did not undergo posttransplant liver biopsy, and those lost to follow-up. Patients were given a recurrent HCV score of 1, 2, or 3. A score of 1 was assigned if the patient had no more than mild portal fibrosis at 1 year and no bridging fibrosis at any point. A score of 2 was defined as moderate portal fibrosis or focal bridging fibrosis at 1 year or bridging fibrosis or cirrhosis after 3 years. A score of 3 was defined as bridging fibrosis, cirrhosis, or graft loss from HCV within 3 years. Baseline characteristics including donor and recipient age, race, sex, body mass index, ischemia time, hypertension, and diabetes were recorded. Analysis was performed with ordinal multivariate logistic regression modeling.

RESULTS: Of the 165 patients with a recurrent HCV score, 105 (64%) had a score of 1, 29 patients (17%) had a score of 2, and 31 patients (19%) had a score of 3. In all, 132 recipients (80%) had white donors, and 26 (16%) had African American donors, 115 patients (70%) were white and 40 (24%) were African American. The mean recurrent HCV scores for the patient donor and recipient race combinations are as follows: white donor and white recipient, 1.54; white donor and African American recipient, 1.89; African American donor and white recipient, 1.18; and African American donor and African American recipient, 1.23. Having a white donor also significantly associated with a higher recurrent HCV score regardless of recipient race (odds ratio 2.93, P = .044) in African American patients, having a white donor had an odds ratio of 4.62 (P = .046). After adjusting for donor age and sex and patient age and sex, having a white donor was still found to be associated with a higher recurrent HCV score (4.48, P = .0275) on multivariate analysis. For all 222 patients, donor race was not associated with overall patient and graft survival.

CONCLUSION: Patients receiving white donor grafts had significantly worse recurrent HCV than those receiving grafts from African American donors regardless of recipient race. This difference was especially marked in African American recipients and persisted on multivariate analysis. These data suggest a graft from a white donor is potentially one more important variable in identifying patients at risk for more aggressive recurrent HCV after orthotopic liver transplant.

Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 21168656 [PubMed - in process]


Liver transplantation as a model to better understand the cell entry of hepatitis C virus

J Hepatol. 2010 Dec 8. [Epub ahead of print]

Féray C.

INSERM U948, Hôtel-Dieu, 9 quai Moncousu, Nantes, France.


COMMENTARY ON: Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation. Samira Fafi-Kremer, Isabel Fofana, Eric Soulier, Patric Carolla, Philip Meuleman, Geert Leroux-Roels, Arvind H. Patel, François-Loïc Cosset, Patrick Pessaux, Michel Doffoël, Philippe Wolf, Françoise Stoll-Keller and Thomas F. Baumert.©The Rockefeller University Press. The Journal of Experimental Medicine, 2010; 207: 2019-2031. Abstract reprinted with permission from the Rockefeller University Press. End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive anti-viral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to re-infect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants re-infecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pre-transplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21167852 [PubMed - as supplied by publisher]


Early proteomic analysis may allow noninvasive identification of hepatitis C response to treatment with pegylated interferon α-2b and ribavirin

Eur J Gastroenterol Hepatol. 2010 Dec 15. [Epub ahead of print]

Devitt EJ, Power KA, Lawless MW, Browne JA, Gaora PO, Gallagher WM, Crowe J.

aCentre for Liver Disease bSchool of Medicine and Medical Science, Mater Misericordiae University Hospital cUCD School of Biomolecular and Biomedical Science cUCD School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.


BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection represents a significant disease burden worldwide. Approximately 170 million people are chronically infected. HCV can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Current standard treatment with pegylated interferon and ribavirin is suboptimal and up to 60% of patients fail to respond. Week 4 and 12 HCV RNA is used as a marker of response with nonresponders at 12 weeks discontinuing treatment. Earlier identification of nonresponders using novel biomarkers would be beneficial in preventing unnecessary toxicities and cost. This study profiled the proteomic response to treatment in HCV patients within the first 24 h using surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS).

METHODS: Serum from 25 HCV infected individuals during the initial 24 h of treatment was profiled using SELDI-TOF MS. Arrays were analyzed on the ProteinChip Reader and time-of-flight spectra were generated. Peak detection was performed by Biomarker Wizard software and analyzed using BioConductor packages.

RESULTS: Significant differences were seen between the proteomic profiles of responders and nonresponders to treatment. Overall 70 peaks differentiated responders from nonresponders. A random forest classifier identified a panel of 20 peaks, which differentiated responders from nonresponders with 87.4% accuracy. The CM10 chip revealed 16 peaks identifying genotype 1 responders from nonresponders.

CONCLUSION: This study identifies early proteomic spectra as potential predictors of HCV treatment response using SELDI-TOF MS. This illustrates the importance of early biomarkers in the prediction of response within the first 24 h, which may aid in tailoring HCV treatment regimens.

PMID: 21164346 [PubMed - as supplied by publisher]


Early viral and peripheral blood mononuclear cell responses to pegylated interferon and ribavirin treatment: the first 24 h

Eur J Gastroenterol Hepatol. 2010 Oct;22(10):1211-20.

Devitt E, Lawless MW, Sadlier D, Browne JA, Walsh C, Crowe J.

Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin, Ireland. emma.devitt@ucd.ie


OBJECTIVES: This study explored gene expression differences in predicting response to pegylated interferon (IFN-PEG) and ribavirin (RBV) in hepatitis C infection. Current treatment for hepatitis C virus (HCV) with IFN-PEG alpha-2a/b and RBV is an expensive regimen with frequent significant side-effects where less than 60% of patients ultimately achieve a sustained virological response. Responders and nonresponders may not be identified for up to 6 months post-treatment. This dichotomy may be because of differences in the molecular genetic response.

METHODS: Peripheral blood mononuclear cell samples were obtained from a cohort of 31 infected individuals within the first 24 h of treatment and the extracted RNA was hybridized to genome expression microarrays. Hepatitis C viral kinetics was also examined in these patients. The ability of differentially regulated genes to predict response to therapy was assessed with treatment outcome.

RESULTS: Distinct patterns of gene expression distinguished responders from nonresponders to HCV treatment. The ultimate response to treatment with IFN-PEG and RBV was observed within the first 24 h of treatment by a greater drop in viral load (mean HCV RNA decline of 1.92+/-1.26 log10 IU/ml) in responders compared with nonresponders (P<0.007). Induced genes achieved maximal response within 12 h of therapy which coincided with a rapid decline in HCV RNA between 12 and 24 h. This study revealed that peripheral blood mononuclear cell metallothionein 2A, CCRL2, tumour necrosis factor-alpha-induced protein 6 (TNFAIP6) and IFN-induced protein with tetratricopeptide repeats 2 expression predicted viral treatment response to therapy verified by quantitative real time polymerase chain reaction.

CONCLUSION: This study has identified a noninvasive gene microarray pattern and a set of verified genes to be predictive of hepatitis C patient response to IFN-PEG and RBV treatment within the first 24 h. The potential of this noninvasive diagnostic approach and identified genes as biomarkers of response to treatment warrants further investigation.

PMID: 20631625 [PubMed - indexed for MEDLINE]

Lymphocytosis as a predictor of poor response to treatment of hepatitis C

Gastroenterol Clin Biol. 2010 Dec 22. [Epub ahead of print]

Martinez-Camacho A, Khaoustov VI, Adam E, Lewis DE, Tavakoli-Tabasi S, Yoffe B.

Baylor College of Medicine, Houston, TX, USA VAMC (151B) 2002 Holcombe boulevard, Houston 77030, USA.


BACKGROUND/AIMS: Identification of factors predicting response to therapy is critical in the management of hepatitis C. This study assessed significance of lymphocytosis as a predictor of sustained virological response (SVR).

METHODS: Retrospective analysis of lymphocytosis and its correlation with virologic response was performed in 110 subjects with chronic HCV infection, who underwent interferon based therapy. Lymphocytosis was defined as ratio of lymphocytes to neutrophils (L/N) above 0.6. L/N ratios were calculated to avoid the impact of hypersplenism and constitutional leukopenia seen in African Americans (AA).

RESULTS: At baseline, L/N of HCV subjects (0.86) as compared to Hepatitis B controls (0.56) was significantly higher (P<0.01). More AA HCV subjects (81.8%) had lymphocytosis at baseline when compared to Caucasian Americans subjects with HCV (37.9%) or AA controls (39.4%). Nonresponders had a higher frequency of lymphocytosis at baseline compared to subjects that achieved SVR (61.4% vs. 36.0%, p<0.05). More HCV subjects without lymphocytosis at baseline achieved SVR (33.3%) compared to HCV subjects with lymphocytosis (15%). At week 12 of therapy, nonresponders had higher L/N (1.02 vs. 0.86) and frequency of lymphocytosis (73% vs. 48%) compared to subjects that achieved SVR (p<0.05 for both). Only 17.2% of subjects with lymphocytosis at 12 weeks achieved SVR compared to 37.5% without lymphocytosis (p<0.05). All responders exhibited significant normalization of lymphocytosis after treatment.

CONCLUSIONS: HCV induces lymphocytosis, especially in AA, and is associated with lower rate of SVR. Furthermore, lymphocytosis may serve as an inexpensive pre-treatment tool to predict poor virologic response to HCV therapy.

Copyright © 2010 Elsevier Masson SAS. All rights reserved.

PMID: 21185139 [PubMed - as supplied by publisher]


Increasing Prevalence of HCC and Cirrhosis in Patients with Chronic Hepatitis C Virus Infection

Gastroenterology. 2010 Dec 21. [Epub ahead of print]

Kanwal F, Hoang T, Kramer JR, Asch SM, Goetz MB, Zeringue A, Richardson P, El-Serag HB.

Department of Gastroenterology and Hepatology, John Cochran VA Medical Center, St. Louis, MO; School of Medicine, St. Louis University, St. Louis, MO.


BACKGROUND & AIMS: Patients with hepatitis C virus (HCV) infection are at risk for developing additional liver disorders that are costly to treat and have high rates of morbidity, although the actual prevalence of these diseases is not known. We examined time trends in the prevalence of cirrhosis and its related complications, such as hepatic decompensation and hepatocellular cancer (HCC).

METHODS: We calculated the annual prevalence of cirrhosis, decompensated cirrhosis, and HCC in a national sample of veterans diagnosed with HCV between 1996 and 2006. Patients with HCV who had at least 1 physician visit in a given calendar year were included in the analysis of prevalence for that year. We used direct standardization to adjust the prevalence of cirrhosis and related complications for increasing age of the cohort, as well as sex and changes in clinical characteristics.

RESULTS: In this cohort, the number of individuals with HCV increased from 17,261 in 1996 to 106,242 in 2006. The prevalence of cirrhosis increased from 9% in 1996 to 18.5% in 2006. Similarly, the prevalence of patients with decompensated cirrhosis doubled, from 5% in 1996 to 11% in 2006, whereas the prevalence of HCC increased approximately 20-fold (0.07% in 1996 to 1.3% in 2006). After adjustment, the time trend in the prevalence of cirrhosis (and its complications) was lower than the crude trend, although it still increased significantly.

CONCLUSIONS: The prevalence of cirrhosis and HCC in HCV-infected patients has increased significantly over the past 10 years, and could increase further. An aging cohort of HCV patients could partly explain our findings. Clinicians and healthcare systems should develop strategies to provide timely and effective care to this high-risk population of patients.

Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21184757 [PubMed - as supplied by publisher]


Insurance status and treatment candidacy of patients with hepatitis C: Analysis of population-based data from the United States

Accepted Article (Accepted, unedited articles published online for future issues)

Maria Stepanova 1,4, Fasiha Kanwal 2, Hashem B. El-Serag 3, Zobair M. Younossi 1,4,*,‡
DOI: 10.1002/hep.24131
Copyright © 2010 American Association for the Study of Liver Diseases

Author Information
1 Center for Liver Diseases at Inova Fairfax Hospital, Falls Church, VA
2 John Cochran VA Medical Center and Saint Louis University School of Medicine, St Louis, MO
3 Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX
4 Betty and Guy Beatty Center for Integrated Research, Inova Health System Falls Church, VA, USA
Email: Zobair M. Younossi (zobair.younossi@inova.org)

* Correspondence: Zobair M. Younossi, Center for Liver Diseases, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042
Conflicts of interest: There are no conflicts of interest for any of the authors.
Ph: (703) 776-2540; Fax: (703) 776-4386

Publication History
Accepted manuscript online: 17 DEC 2010 03:44PM EST
Manuscript Accepted: 9 DEC 2010
Manuscript Revised: 3 DEC 2010
Manuscript Received: 1 SEP 2010

Funded by
Liver Outcomes Research Fund of The Center for Liver Diseases
Inova Fairfax Hospital, Falls Church, Virginia

Successful treatment with antiviral therapy could potentially reduce morbidity and mortality in patients with hepatitis C virus (HCV) infection. However, at the population level, these benefits may be offset by limited number of patients who have access to antiviral treatment.

Using National Health and Nutrition Examination Survey (NHANES) conducted in 2005-2008, we analyzed health insurance status and treatment candidacy of HCV+ individuals.

Total 10,582 subjects were examined; of those, 1.16 % had detectable HCV RNA and were defined as HCV+. The HCV+ patients were less likely to be insured than HCV- individuals (61.2% vs. 81.2%, P = 0.004). Among those with health insurance, HCV+ patients were less likely to have private insurance, while the coverage by Medicare/Medicaid and other government-sponsored plans was similar to the rest of the population. In multivariate analysis, HCV infection was an independent predictor of being uninsured even after adjustment for demographic disparity of the HCV+ cohort [odds ratio = 0.43 (95% CI = 0.24-0.78)]. Of all HCV+ patients, 66.7% were eligible for anti-HCV treatment. However, only 54.3% of HCV+ treatment candidates had any type of insurance coverage. Finally, only 36.3% of HCV+ patients were potentially eligible for treatment and had health insurance.

A high proportion of HCV+ patients are currently uninsured, and many have publicly funded health insurance. Among those who could be candidates for treatment, the rate of insurance coverage is even lower. These findings can have important implications for health insurance coverage of these patients under the new healthcare reform legislation. (HEPATOLOGY 2010.)