Hongxing Qin, Norah J. Shire, Susan D. Rouster, M. E. Eyster, James J. Goedert, Margaret J. Koziel,
Kenneth E. Sherman
Background
Patients with inherited bleeding disorders who received plasma clotting factor concentrates prior to 1987 have among the highest rates of HCV infection often associated with HIV coinfection. We evaluated the HCV core protein quasispecies evolution in longitudinally collected specimens comparing those with progression to decompensated, end-stage liver disease (ESLD) to those with compensated chronic hepatitis.
Methods
Serially collected serum samples reflecting long-term clinical outcomes were obtained from the NCI Multicenter Hemophilia Cohort Study. Index cases were derived from patients who progressed to ESLD. Nonprogressor controls were matched for age, gender, duration of infection, presence or absence of HIV coinfection, and HCV genotype. Samples from early infection (E) were compared to those obtained after onset of ESLD (L) in the index cases. The core protein coding region was amplified, subcloned and sequenced. Predicted amino acid sequences were compared for clonal variability and evolution. Complexity and diversity were determined.
Results
· Over 425 subclones derived from 10 pairs of patients followed over a mean duration of 9.3 years (S.E.= 0.69 years) were sequenced and evaluated for genetic complexity and diversity
· 80% (16/20) patients were HIV+
· At baseline, there were no statistically significant differences in complexity or diversity between progressors and nonprogressors
Summary
· Progressors demonstrated a slight increase in complexity over time compared to nonprogressors, although this change did not reach statistical significance
· Both groups of patients had dN/dS ratiors consistently <1, indicating a lack of selective pressure for this region
· Genetic distances in the core region between early and late clonal sets were likely to be greater for progressors (p=0.02), indicating greater divergence
· Mutation in the RKT motif (positions 9-11) that have been associated with NFkB activation were seen solely in progressors
Conclusions
· Differences in genetic diversity are apparent in the core region among interferon-naïve progressors and nonprogressors with inherited bleeding disorders
· None of these differences were associated with HCV or HIV viral loads, demographic factors, or CD4+/CD 8+ counts
· In progressors, the changes that occur in the core region appear to be associated more frequently with hydrophotic elements that may have important functional significance
· Further understanding of these mechanisms may help identify factors related to rate of progression in HCV-infected patients with inherited bleeding disorders
Eric
W. Dieperink, Holly Groom, Ramsey C. Cheung, Margaret
Celebreze, Barry Cohen, Samuel Ho, Mark L. Willenbring
Introduction/Objectives
The efficacy of antiviral treatment for chronic hepatitis C (HCV) has not been translated to clinical populations as most patients with HCV fail to access care. The purpose of this study was to determine patient's reasons for not seeking HCV specialty care.
Methods
We conducted seven focus groups with HCV
patients. Two groups consisted of patients actively in HCV care and five groups
who, despite extensive outreach, had failed to attend any appointments in a
specialty care hepatitis clinic.
Results
No significant differences in patient characteristics were found between groups, average age, years living with the HCV diagnosis and histories of substance use and mental illness disorders were similar in each group.
The following themes were identified as important barriers to seeking care:
· lack of perceived need for care, incorrect beliefs about progression of the illness and about treatment for HCV
· having a substance use disorder and stigma. HCV was frequently equated with HIV
Conclusions
This study identifies several potential barriers to care that may be common among veterans with HCV who do not attend appointments. Lack of knowledge regarding HCV and stigma appear to be the most important factors that influence help seeking behavior. Implications: Possible interventions to improve access include addressing logistical barriers and improving outreach by using alternative notification methods. Improved education and addressing stigma associated with HCV may improve patients help seeking and adherence with care. Efforts to improve access to care should increase the effectiveness of antiviral treatments for HCV.
Faciliators of hepatitis C care:
·
Flexibility of scheduling
· Support Groups
· Interest and knowledge of VA Staff
Possible
interventions
·
Peer resources to enhance
knowledge
·
Improved resources specifically
designed for friends or family to address concerns about stigma
·
Improved education regarding
asymptomatic disease vs. actual disease
·
Addressing logistic barriers,
in particular, improve, shorten or supplement notification of hepatitis C
testing in order to decrease delays and more closely connect patient education
with test results
Jennifer
R. Kramer, Thomas P. Giordano, Julianne Souchek, Hashem B. El-Serag
Background
It is uncertain if patients coinfected with hepatitis C virus (HCV) and HIV are more likely to suffer fulminant hepatic failure (FHF) when compared to patients with HIV-only. It is also unclear if the risk of FHF changes when coinfected patients are on highly active antiretroviral therapy (HAART).
Methods
We conducted a retrospective cohort study using national administrative databases from the Department of Veterans Affairs (172 hospitals) in patients hospitalized for the first time with HIV and/or HCV between 10/1991 and 9/2000. FHF was defined by ICD-9 code 570 (acute liver failure) occurring after the index hospitalization through 9/2001 in the absence of pre-existing liver disease. We calculated incidence rates, Kaplan Meier (KM) cumulative incidence curves, and adjusted hazard ratios (HR) in Cox proportional hazards (PH) models while adjusting for age, race, and prior diagnoses of toxic hepatitis, diabetes, and alcoholism.
Results
After excluding patients with pre-existing liver disease, we identified 11,678 patients with HIV-only and 4,761 patients with HCV-HIV coinfection.
There were 92 cases of FHF, which had a 6-week mortality rate of approximately 50%. There were 42 cases of FHF in the HIV-only group, for an incidence rate of 1.1/1000 person-years, and 50 cases in the coinfected group, for an incidence rate of 2.5/1000 person-years. In the KM analysis, the cumulative incidence of FHF in the coinfected group was higher than in the HIV-only group (p<0.0001). In a Cox PH model restricted to patients entering the cohort in the HAART era, coinfected patients had an adjusted HR for FHF of 5.86 compared to HIV-only patients (2.36-14.50). Patients with coinfection in the pre-HAART era did not have an increased risk of FHF (HR=0.99; 0.43-2.31).
Multivariate
Results
The risk of FHF with HCV Coinfection:
Hazard ratios (HR) for HCV coinfection vs. HIV-only:
· Total follow-up:
· HR=2.66 (95% CI: 1.7.-4.1), p<0.0001
o Pre-HAART era:
§ HR=0.99, (95% CI: 0.4-2.3), p=0.98
o HAART era:
§ HR=5.86, (95% CI: 2.4-14.5), p=0.0001
· HR of interaction term (HAART era HCV coinfection status) from total follow-up:
§ HR=3.96, (95% CI: 1.5-10.5
· Interpretation: The risk of FHF in patients with HCV confection compared to HIV-only during the HAART era was almost four fold higher than that calculated during the pre-HAART era.
Conclusions
·
The risk of FHF in patients
with HCV coinfection compared to HIV-only during the HAART era was several
folds higher than that during the pre-HAART era.
·
There is no question that
patients with HCV-HIV coinfection should be receiving HAART therapy, but since
FHF is associated with high mortality these patients should be monitored more
closely.
·
This is the first study of
HIV-infected patients to examine the risk of FHF in relation to coinfection
with HCV in the HAART era.
·
The overall risk of FHF is low
in HIV and HCV-HIV coinfected patients.
Carol
Christensen, Steve Livingston, Dana Bruden, Heike Dubner, Katie M. Smith, Jason Do, Esther Oh, Brian J
McMahon
Background
Methods less invasive to distinguish
between mild and moderate/severe fibrosis in patients with chronic hepatitis C
are desirable. We previously reported on 75 interpretable specimens tested with
a panel of serologic markers for fibrosis (FIBROSpectSM:
Prometheus Laboratories,
Purpose
To evaluate the performance of FIBROSpectSM II in detecting severe fibrosis (Knodell and Ishak systems in stored sera of Alaska Natives participating in a Hepatitis C outcome study.
Methods
142 specimens were tested for serum hyaluronic acid, tissue inhibitor of metalloproteinase and alpha-2 macroglobulin, proteins involved in extracellular matrix remodeling. FIBROSpect II is a logistic regression model established for this panel of fibrosis markers to detect significant fibrosis (Metavir F2-4) in chronic HCV. Using the algorithm-derived index, all specimens were classified either as consistent with no/mild (Knodell 0-1) or severe fibrosis. Blinded liver biopsies were read and scored for fibrosis by a study pathologist. Clinical performance of the two FIBROSpec algorithms was compared.
Results
Using FIBROSpect II, sensitivity for detecting Knodell fibrosis 3-4 increased to 92% (95% CI: 82-98%) with a specificity of 64% (95% CI: 54-74%), PPV of 60% and NPV of 94%. Sensitivity for Ishak 4-6 was 100% (95% CI: 89-100%) and specificity was 56% (95% CI: 46-65%), PPV of 41%, and NPV of 100%.
Conclusions
FIBROSpect II was clinically useful in ruling out severe fibrosis (Ishak 4-6). Comparing these results to our previous study with FIBROSpectSM, sensitivity improved but specificity decreased. The authors also noted that a longer biopsy length was associated with higher concordance between the FRIBOSpect II test and the Knodell biopsy score, indicating that biopsy sample size is important for an accurate assessment.
Limitations
· Relating FIBROSpect II to the Knodell scoring system present problems because a Knodell score of 1 includes persons with mild and moderate fibrosis, which could account for the decrease in specificity.
Future
Directions
· Evaluate the FIBROSpect II index score (range 0-100) in predicting the individual fibrosis, which could account for the decrease in specificity in this retrospective study cohort.
· Prespective studies evaluating FIBROSpect II test results with liver biopsy scores on patients with hepatitis B and C.
Carla
Kuiken, Russell Richardson, Karina
Yusim
Purpose
Providing web-based tools to retrieve and analyze annotated publicly available HCV sequence data.
Methods
The Los Alamos Hepatitis C virus (HCV) sequence database became publicly accessible in September 2003 (hcv.lanl.gov or hcv-db.org). It is based on the HIV sequence database (www.hiv.lanl.gov), which is used by thousands of researchers weekly.
Scientists who are familiar with that database will find it easy to navigate the HCV site. The database offers access to sequences using a flexible, user-friendly search interface that can retrieve aligned sequences based on the genomic region and a number of epidemiological and biological criteria like genotype, sampling country, risk group, and study. Alignments of all available complete-gene sequences are provided along with a large number of tools to process and analyze sequences. Using the website, researchers can obtain synonymous/non-synonymous calculations, multidimensional scaling of sequence data, primer and epitope alignments, BLAST searches of the HCV database, simple tree construction, and analysis of glycosylation sites. The sequences are annotated based on the literature and on phylogenetic analyses by the database staff.
Results
Currently the database contains 22,000 sequences, of which 19,000 are annotated with genotype and 14,800 with country information. Annotation of sequences in the database currently includes host data (host species, health status at time of sampling, therapy history and response, sampling date and location, likely infection route, date and location), virus data (genotype and subtype, sequenced region), linkage data (transmission clusters, other sequences obtained from a host), and publication data (including publication links not annotated in GenBank). Sequences from patent applications, non-human hosts, and short sequences can easily be excluded from the results. Links to retrieve all sequences from a study are provided, as are links to GenBank and to external analysis tools.
Conclusions
The HCV sequence database has the potential to become a very powerful tool in HCV genetic research and vaccine design, just like the HIV database is now indispensable for HIV scientists. Future plans include building tools for automatic tree building, optimal tree selection, distance matrix analysis, and automatic alignment of user sequences to database sequences. A database of HCV immunological epitopes will be ready for release in the spring or summer of 2004.
John
B. Wong, Thierry Poynard, Michael P. Manns, John G. McHutchison, Joann Harvey, Jamice K. Albrecht
Introduction
Although not all patients with histologically mild chronic hepatitis C progress, prior studies suggest that antiviral treatment should be cost-effective, but those studies were based on mild inflammation and involved interferon alone or with ribavirin.
Aim
To determine the cost-effectiveness of peginterferon α-2b+ribavirin for histologically mild F1 fibrosis.
Methods
Using data from Manns Lancet 2001, we compared no antiviral therapy to peginterferon α-2b+>10.6 mg/kg ribavirin. Lifelong clinical and economic outcomes were based on Cox proportional hazard models estimating the likelihood of developing Metavir fibrosis stages F1-F4 over time (using 2313 liver biopsies), and on recent UNOS, SEER and NIH data (Wong, AASLD 2003). Drug costs applied the 12-week stopping rule. Cost-effectiveness results are presented as incremental cost per discounted (3%) quality-adjusted life year gained. Cost-effectiveness ratios below $50,000 per discounted quality-adjusted life year gained were considered to be cost-effective.
Results
Observed sustained viral response rates for peginterferon α-2b+ribavirin treatment of F1 were 63% overall, 52% for genotype 1 and 91% for genotype 2/3.
Antiviral treatment reduced the 20-year incidence of cirrhosis from 20% to 7.6% overall, to 9.7% for genotype 1 and to 1.8% for genotype 2/3. Antiviral treatment extended life expectancy by 2.3 years overall, 1.9 years for genotype 1 and 3.4 years for genotype 2/3. Quality-adjusted life expectancy benefits of treatment were 4.7 years overall, 3.9 years for genotype 1 and 6.8 years for genotype 2/3.
Antiviral treatment reduced the future cost of hepatitis C complications by $27,500 overall, $22,900 for genotype 1 and $40,100 for genotype 2/3. Compared to no antiviral treatment, cost-effectiveness ratios for treatment were $5100 per discounted quality-adjusted life year gained overall, $9000 per discounted quality-adjusted life year gained for genotype 1 and $400 per discounted quality-adjusted life year gained for genotype 2/3.
Conclusion
Weight-based peginterferon α-2b+ribavirin should be cost-effective for patients with F1 fibrosis. Cost effectiveness improved in the presence of risk factors associated with more rapid fibrosis progression: advanced age, men, IVDA, A23 inflammation.
Joel Kertznus, Arie Regev, Enrique Molina, Jonatan
Konfino, Patricia Mendez, Adriana Arcila, Eugene R. Schiff
Background
Previous cross sectional studies suggest that patients with chronic hepatitis C (HCV) and superimposed NAFLD, or its risk factors, may be at increased risk of developing advanced fibrosis. Risk factors associated with NAFLD include: obesity, type II diabetes mellitus (DM), hyperlipidemia and hypertension (HTN). Previous studies were limited, as they did not assess the progression of fibrosis over time. Furthermore, none of the studies included hypertension as an independent risk factor for progression of fibrosis.
Aim
To asses the impact of body mass index (BMI), type II DM, hyperlipidemia, HTN and hepatic steatosis on the progression of HCV related fibrosis.
Methods
We retrospectively reviewed the medical records of 60 patients diagnosed with HCV, who underwent liver biopsies on two different occasions. Obtained data included demographics, BMI and medical history. All the pathology specimens were reviewed by a liver pathologist using the Scheuer fibrosis score. Extent of steatosis was graded based on the grading system proposed by Brunt et al. The rate of progression was assessed using the calculated difference between stages divided by the period of time elapsed between biopsies. Analysis of variance for repeated measures was used to study the variables.
Results
Sixty patients (41 males, 19 females) were reviewed. The mean ages were 57 and 53 respectively, and the mean BMI was 27.8 ± 4.6 (Kg/m2). The mean time between biopsies was 3.72 ± 2.53 (years). 16 pts (27%) had HTN, 7 (11.7%) type II DM and 17 (28%) hyperlipidemia. None of the patients were active alcohol drinkers, but 13 (22%) reported a past history of alcohol >50g/day and 14 (23%) <50 g/day. Steatosis was documented in 38% of the cases. HCV genotype was 1 in 88%, 2 in 5%, 3 in 5% and 4 in 2% of the patients. Patients with HTN showed a mean stage of fibrosis progression of 1.1, compared to a mean stage of progression of 0.18 in the normotensive patients (p<.0125), determining a significant interaction between HTN and progression of fibrosis. There was no significant association between the presence of type II DM, hyperlipidemia, high BMI and the progression of liver fibrosis.
Conclusions
Hypertension was an independent predictor for the progression of HCV related fibrosis . However, none of the other NAFLD risk factors independently predicted a progression of fibrosis. In addition, steatosis was not identified as an independent risk factor for progression of fibrosis in HCV patients. Larger prospective studies are needed to clarify the association between NAFLD risk factors and the progression of HCV related fibrosis.