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The Liver Meeting— 54th Annual Meeting of The American Association for the Study of Liver Diseases, October 24 - 28, Boston, MA—Day 2

Alan Franciscus
Editor-in-Chief, HCV Advocate


Christopher R. Shackleton, Steven D. Colquhoun, Nicholas Nissen, John M. Vierling, Paul Martin, Fred Poordad, Tram Tran, Andrea Peterson, Shannon Hogan, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA.

Accurate delineation of the scope and magnitude of peri-operative donor risk is necessary to better allow for informed consent, to maximize the potential for donor safety, for comparative outcome analysis and ultimately to serve as a key determinant of the utility of adult-to-adult living donor liver transplantation (AALDLT). However, at present, there is lack of uniformity regarding what constitutes a complication in this setting. Moreover, a system to stratify adverse events with respect to their life altering (quantity or quality) impact is lacking.

1) to define a graded, inclusive classification schema for both early (E) and late (L) adverse operation-related events in live liver donors and,
2) to apply this system to a retrospective review of events in individuals undergoing partial hepatectomy for live liver donation at our center.

From 12/07/1999 through 05/29/2003, 195 individuals underwent evaluation liver donation at our center. Of these, 31 (22%, M/F = 20/11, mean age 40 yrs, range 21-56 years) underwent partial hepatectomy and their records were reviewed. The proposed definitions of early and late complications are included in the results tables.

At a median follow-up of 507 days (range 52-1270 days), 6 of 31 (19.4%) patients had developed 8 complications, 6 early and 2 late. Median donor length of stay (LOS) was 8 days (range, 5-20).

Two patients (6.5%) suffered cut-surface bile leaks and one (3.2%) a right colon injury (Grade 3E complications). One patient (3.2%) developed a transient bilateral ulnar neuropathy (Grade 2E). Two patients (6.5%) were readmitted within 30 days of operation for nausea and dyspnea respectively (Grade 1E). One patient underwent repair of an incisional hernia 6 months post donation (Grade 2L). One patient suffered positioning-related brachial plexopathy (Grade 3L).

The definition and adoption of a graded, scale-based system of operation-related adverse events in live liver donors will allow for an inclusive, consistent and universally applicable method to collect, analyze and report donor complications. All AALDLT programs must be encouraged to fully review and report their donor related morbidity, ideally through the creation of a national donor registry

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Sandy Feng, University of California San Francisco, San Francisco, CA; Jennifer L. Bragg-Gresham, Dawn M. Dykstra, SRTR/URREA, Ann Arbor, MI; Jeffrey D. Punch, Meelie DebRoy, University of Michigan, Ann Arbor, MI; Stuart M. Greenstein, Albert Einstein College of Medicine, Bronx, NY; Robert M. Merion, University of Michigan, Ann Arbor, MI.

Recently, an expanded criteria donor (ECD) kidney was defined based upon four donor factors known to predispose to graft loss. This definition then engendered a new allocation policy designed to diminish discard and improve outcomes of valuable albeit suboptimal organs. A parallel definition of the ECD liver based upon donor characteristics is needed. The definition may then similarly facilitate consideration of alternative allocation strategies to improve the outcome and utilization of suboptimal livers.

We analyzed 12,412 recipients who underwent transplantation between 7/1997 and 3/2001 with livers from deceased donors > 18 years of age. Cox regression was used to analyze the risk of graft loss including death (adjusted for donor race and sex and recipient age, race, sex, status, BMI, NYHA functional status, PRA>10%, cold ischemia time, ventilator use, serum creatinine, and hepatitis C status).

Five donor characteristics were significantly and independently associated with the graft failure including recipient death: age, cardiac arrest after neurological event (arrest), cerebrovascular accident (CVA) as cause of death, any serum sodium > 170 mEq/L, and split or partial liver. The ideal donor was defined as an 18 - 39 year old donor without any of these characteristics. The table below identifies donor categories with a relative risk (RR) of graft failure including recipient death exceeding 1.7 compared to the ideal donor reference group (Ref.). Using a RR of > 1.7 to define the ECD liver, ECD livers accounted for 15.9% of all transplanted livers and 28.8% of all discarded livers in the analysis. During the study, 20.9% of recovered ECD livers were not transplanted, compared with 9.9% of non-ECD livers.

This study offers a definition of the ECD liver and analyzes associated discard and failure rates for these organs. The results which stratify transplantation risk based upon donor factors may be used in discussions with liver transplant candidates. In addition, the data can be further analyzed, perhaps in conjunction with recipient factors known to impact graft and patient survival, to consider whether alternative allocation policies may improve transplant outcomes and / or organ utilization of ECD livers.

Supported by HRSA, Contract # 231-00-0116

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Norah A Terrault, Mandana Khalili, Stephanie Straley, Kathy Bollinger, Nathan Bass, John P Roberts, Nancy A. Ascher, University of California San Francisco, San Francisco, CA

Recurrent and progressive HCV disease is the most common cause of graft loss in HCV-infected liver transplant (LT) recipients. Strategies to prevent or ameliorate recurrent disease are needed. Initiation of antiviral therapy in the early post-transplant period, prior to overt evidence of HCV recurrence (i.e. preemptive therapy) may enhance rates of HCV eradication.

To determine the efficacy and tolerability of preemptive IFN versus IFN/RBV in anti-HCV positive LT patients.

Consecutive and eligible LT recipients from a single center were enrolled. The goal was to initiate treatment within 6 wks of LT. Patients were randomized to IFN or IFN plus RBV (400mg daily X 2wks, then 800mg daily X 2 wks, then 1.0-1.2g daily based upon body weight 75 kg). Induction therapy with daily IFN was used for the first 8 wks (1.5MU daily X 2wks, then 3MU daily X 6 wks) followed by 3 MU TIW (N=39) or peg-IFN 1.5 ug/kg/wk (N=10) for 40 wks. Key inclusion criteria were stable clinical status, Cr45,000 and WBC>3.0. Dose reductions for side effects, especially cytopenias were standardized. Growth factors were given for neutropenia (ANC<1000) and anemia (Hgb<9.0g/dL) beginning 7/2001.

Virological (VR) and biochemical responses (BR) were evaluated at end-of-treatment (ET) and 6 mos post-treatment (sustained virological (SVR) and biochemical (SBR) responses).

Between 12/99 and 6/02, 107 LT for HCV were performed; 63 (59%) patients met eligibility criteria and 49 were enrolled (80% males, median age 50 yrs).

Treatment was initiated 5.1 wks (median, range 1.7-9.3) post-LT. A total of 24 LT patients were randomized to treatment with IFN (71% genotype 1, 48% high viral load, VL) and 25 to IFN plus RBV (68% genotype 1, 46% high VL). Five patients dropped out after randomization but prior to treatment, 19 discontinued treatment due to adverse events, and 25 patients completed 48 wks treatment. Five patients died during the treatment period of non-treatment related causes. Full doses of IFN and RBV were obtained in 84% and 23% respectively; the median dose of RBV was 360 mg/day. ET-BR and SBR were obtained in 64% and 53% of treated patients, with higher rates of ET-BR in patients completing 48 wks treatment (74% vs. 38%, p=0.02). ET-VR and SVR were obtained in 12% and 11% (2 ET-VRs still in follow-up). SVR was more frequent in patients with undetectable HCV RNA by quantitative assay (qHCVRNA) pre-treatment (67% vs 4% with measurable qHCVRNA, p=0. 0009). Neither time from LT to treatment, age, receipt of full-dose IFN or RBV, genotype, nor treatment group (table below) were associated with response. Histological disease was mild in the majority of patients at treatment end (78% stage 0 fibrosis and 72% grade 1 or less necroinflammatory activity).

Preemptive antiviral therapy was applicable to ~60% of transplanted patients. Biochemical responses were frequent but SVRs uncommon. Treatment discontinuation and lowering of RBV doses due to side effects likely reduced SVRs and may have limited our ability to detect differences between treatment groups. The only predictor of SVR was a negative qHCVRNA pre-treatment, which implies that patients with low VL early post-LT may be the best candidates for preemptive therapy. Compared to historical reports, the severity of histological disease was very mild at 1-year post-LT in the majority of treated patients, suggesting preemptive antiviral therapy may provide important histological benefits.

Response by Treatment Group

  IFN IFN+RBV P value
12/22 (55%)
1/21 (5%)
16/22 (73%)
4/22 (18%)
10/17 (63%)
1/15 (7%)
7/15 (47%)
2/13 (15%)
Stage=0 at 12 mos
Grade< or = 1 at 12 mos
15/17 (88%)

13/17 (76%)
10/15 (67%)

10/15 (67%)


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Sanaa M Kamal, Qi He, Harvard Institutes of Medicine, Boston, MA; Jutta Fehr, University of Freiburg, Freiburg, Germany; Alaa M Ismail, Ain Shams University, Cairo, Egypt; Bernd Roessler, University of Freiburg, Freiburg, Germany; Mahmoud A Massoud, Ain Shams University, Cairo, Egypt; Jens Rasenack, University of Freiburg, Freiburg, Germany.

Peginterferon alfa - 2a (40KD)/ribavirin combination therapy markedly improves the sustained virological response in chronic hepatitis C compared to conventional interferon a-2 therapy. We have previously demonstrated that Peginterferon a - 2a (40 KD) alone or in combination with ribavirin enhances HCV specific CD4+ T helper 1 responses in patients with chronic hepatitis C but the underlying mechanism by which the HCV-specific responses are restored is not yet fully understood. Dendritic cells (DCs) are the most efficient type of cells involved in antigen presentation (APC), however HCV proteins affect DC function resulting in abnormal priming of anti-HCV-specific T cells and defective antiviral immunity. We hypothesized that peginterferon activates CD4+ T cells through restoration of the DC antigen-presenting function.

Monocyte-derived dendritic cells (DCs) generation (magnatic sorting and positive selection), phenotypic analysis and allogeneic stimulatory capacity of DC (S.I.) as well as HCV-specific CD4+ T-cell proliferative responses and cytokine production to HCV proteins (ELISPOT assay using autologous DCs as APCs) were prospectively assessed in 64 patients with chronic hepatitis C (genotypes 1 and 4) before, during and after treatment with either conventional IFNa-a2/ribavirin therapy, or Peginterferon alfa - 2a (40 KD)/ribavirin combination therapy and the results were correlated to the therapy outcome.

The SVR in genotype 1 was 49% with Peginterferon alfa - 2a (40KD)/ribavirin, and 26% with conventional IFN a-2/ ribavirin while in genotype 4 the SVR was 54% in subjects treated with Peginterferon alfa - 2a (40KD) /ribavirin combination therapy vs 28% of HCV in subjects treated with conventional IFN a-2a/ ribavirin. Before induction of therapy, DCs from HCV infected subjects exhibited a pattern of incomplete activation and the stimulatory capacity of HCV-DCs was significantly lower than that of the normal-DCs (7.8± 3.9 vs. 67.2± 19.7, respectively; P < 0.001) The same pattern of incomplete activation was observed in CD4+ T cells in the form of absent or weak pre-treatment HCV specific CD4+ responses. Initiation of Peginterferon a-2a (40KD)/ ribavirin therapy markedly ameliorated the allostimulatory capacity in DCs of HCV patients and induced significant increase in the frequency, strength and breadth of HCV-specific CD4+T-h1 responses; compared to conventional IFN-a based regimen. The stimulatory capacity of HCV-DC was restored to normal in subjects who achieved SVR (62.05 ± 17.7 in SR versus 11.88 ± 2.55 in NR; P = 0.007). Sustained responders developed early restoration of DC functions and strong multi-specific persistent HCV specific CD4+T- cell responses with preferential IFN-γ production and IL-10 suppression. Interestingly patients who had breakthrough or relapse had transient increase in DC stimulatory capacity, which coincided with the absence of HCV viremia; however DC abnormalities were detected with recurrence of viremia. Viral clearance and HAI improvement but not HCV genotype correlated with the DC stimulatory capacity and HCV-specific CD4+ responses.

Peginterferon alfa - 2a (40 KD) in combination with ribavirin enhances HCV specific CD4+ T responses through restoration of the antigen presenting functions of dendritic cells. This finding has important implications for development of novel immunotherapeutic strategies.

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Lennox J. Jeffers, Miami VA Medical Center, Miami, FL; William Cassidy, Louisiana State University Health Sciences Center, Baton Rouge, LA; Charles Howell, University of Maryland School of Medicine, Baltimore, MD; K. Rajender Reddy, University of Pennsylvania, Philadelphia, PA; Susan Sheridan, Irwin Ho, Sarkis Khouri, George Harb, Roche Laboratories, Inc., Nutley, NJ.

Response rates to interferon (IFN) therapy appear to be lower in African American (AA) patients with chronic hepatitis C than in Caucasians (Ca). The lower response has been attributed, in part, to the high prevalence of infection with hepatitis C virus (HCV) genotype 1 among the AA population. However, low numbers of AA patients in prospective clinical trials has hampered meaningful evaluation of antiviral therapy.

To determine the efficacy and safety of peginterferon alfa-2a (40KD) in combination with ribavirin (RBV) in non-Hispanic AA HCV genotype 1 patients. The trial enrolled patients in a 3:1 ratio of AA to Ca patients and was designed to estimate sustained virologic response (SVR) in the AA group to within ± 10% of a 95% confidence interval.

Patients with previously untreated chronic HCV genotype 1 and elevated ALT received peginterferon alfa-2a (40KD) 180 µg sc once weekly plus RBV 1000 or 1200 mg orally based on body weight (<75 kg or >75 kg) for 48 weeks, with 24 weeks of treatment-free follow-up. High viral load (HVL) was defined as HCV RNA >1 X 106 IU/mL. Early virologic response (EVR) at 12 weeks of therapy (defined as HCV RNA <50 IU/mL, or >2-log10 drop in HCV RNA from baseline) was assessed. SVR was defined as undetectable HCV RNA at week 72; sustained biochemical response (SBR) was defined as normal serum ALT at Week 72. Histologic responses were reported as Knodell HAI scores of liver biopsies obtained prior to treatment and within 4 weeks of completion of the 24-week untreated follow-up period.

A total of 106 patients received at least one dose of study medication. Baseline characteristics of AA patients were: mean age 46 years, 56 male (72 %), mean ALT 63 U/L, high viral load 45 (58%). Baseline characteristics of Ca patients were: mean age 45 years, 17 male (61%), mean ALT 64 U/L, high viral load 12 (43%). Sixty-two of 78 (80%) AA patients and 22 of 28 (79%) Ca patients completed treatment; and 06/78 (77%) AA patients and 17/28 (61%) Ca patients returned at week 72. The table below shows an SVR rate of 26% for AA patients and 39% for Ca patients. A larger proportion, 45 of 78 AA patients had high viral loads prior to the initiation of therapy, contrasting with only 12 of 28 Ca patients. SVR was achieved by 9 (20%) and 3 (25%) of patients with HVL in each group respectively. Of 47 AA patients who had EVRs, 20 patients went on to achieve an SVR. The negative predictive value of EVR was 100% for both AAs and Cas. SBR was observed with similar frequency for both racial groups (36% for AA and 39% for Ca). Histologic analyses of a subgroup of patients for whom paired biopsies were available showed that 13 of 53 (25%) AA patients and 1 of 16 (6%) Ca patients had fibrosis improvement. No unexpected adverse events (AEs) occurred during the study. Four of 78 (5%) AA patients and 4 of 28 (14%) Ca patients withdrew prematurely for AEs or laboratory abnormalities.

The SVR of 26% in AA with genotype 1 HCV after therapy with peginterferon alfa-2a (40KD) plus RBV is the highest response to combination therapy yet reported in this population. The SVR rate in the AA population is nonetheless lower than in other studies with patients of diverse ethnic backgrounds and may be explained by the higher viral titers observed in these patients. Failure to achieve EVR has a high negative predictive value for SVR with continuing therapy. This study demonstrates that peginterferon alfa-2a (40KD) in combination with RBV is a safe and tolerable treatment for AA patients with chronic HCV genotype 1 infection. In addition, the SVR rate and histologic benefit observed in this trial provide a basis for future efforts to increase efficacy in this difficult to treat population.

Summmary of Efficacy Analyses

Response Variable African Americans
Sustained virological response (SVR)
Number (%)

95% CI for percentage with response
20 (26%)

16 - 35%
11 (39%)

21 - 57%
Sustained biochemical response (SBR)
Number (%)

95% CI for percentage with response
28 (36%)

25 - 46%
11 (39%)

21 - 57%

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Revital Kariv, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Moshe Leshno, Tel Aviv University, Tel Aviv, Israel; Ran Oren, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Anat Beth-Or, Maccabi health care services, Tel Aviv, Israel; Shira Zelber-Sagie, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Ehud Kokia, Dina Noff, Bracha Sheinberg, Maccabi health care services, Tel Aviv, Israel; Zamir Halpern, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Serum alanine aminotrasferase (ALT), is a common and valid serological parameter used for evaluation and follow up of liver diseases. The normal range for ALT has recently been challenged for several reasons: patients with chronic hepatitis C and inflammation on biopsy may have “normal” ALT levels; patients with histologically diagnosed non alcoholic fatty liver disease (NAFLD) may have “normal” to slightly elevated ALT levels; parameters as age and gender have been described as affecting ALT serum levels, nevertheless they are not always considered in the determination of the ALT normal range.

An updated valid “cutoff” for ALT serum levels may have an impact in terms of health and economy.

To reevaluate and update the upper normal limit for healthy ALT levels, and to determine modulating factors.

Patients and methods
Between January 1st and June 30, 2002, 346,530 serum ALT tests were performed in 272,273 consecutive patients in a central laboratory (Maccabi Health Care Services).
Exclusion criteria from analysis were:
 1) Abnormal values of one or more of the following parameters: Albumin, total bilirubin, ceruloplasmin, ferritin, GOT, alkaline phosphatase , GGT, total leucocytes, hemoglobin, platelets, blood glucose, cholesterol, triglycerides, antinuclear antibodies (Ab), antimitochondrial Ab, hepatitis C Ab, hepatitis B surface Antigen, and tissue transglutaminase Ab (IgA).
 2) Patients treated with hypolipidemic, antiepileptic, oral contraceptives, or certain antifungal drugs.
 3) Recorded medical diagnosis of obesity, overweight, acute or chronic liver disease, alcoholism, cirrhosis, hepatitis C, hepatitis B or liver neoplasm.

After exclusion, 17,929 patients were available for the final analysis (group 1). Two additional patients groups were identified: Group 2- Hyperlipidemia and/or diabetes group (exclusion of all parameters except high levels of cholesterol, triglycerides, glucose, HbA1C), and group 3- diabetes group (exclusion of all parameters except high glucose and/or HbA1C).

ALT 95th percentile for each patient group is shown in table 1. ALT 95th percentile was linearly correlated with triglyceride , glucose and HbA1C levels, but not with cholesterol levels. ALT 95th percentile also changed significantly with age with a peak in the 4 -5th decades. Significant difference in ALT 95th percentile was noted between males and females.

In our study population the upper limit of the healthy ALT range is far below the upper limit of “normal”, dictated by the manufacturer. Age and gender affect ALT levels. Serum triglycerides, glucose, and cholesterol modulate ALT probably via NAFLD.

Table 1

Patient group
(Patient number)
ALT 95th percentile (U/I)
"Normal upper limit"
Group 1 - total (17,929)
Group 1 - male(6304)
Group 1 - female(11,625)
Group 2-total (87,020)
Group 3-total (303)

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Dominique Thabut, Sophie Le Calvez, Vincent Thibault, Julien Massard, Cecilia d'Arondel, Joseph Moussalli, Mona Munteanu, Vincent Di Martino, Yves Benhamou, Vlad Ratziu, Thierry Poynard, Groupe Hospitalier Pitie-Salpetriere, Paris, France.

Little data is available on hepatitis C in elderly patients.

To make a comparison of patients 65 years or older (GE65) with those less than 65 (LT65) in terms of the demographic and clinical features of hepatitis C, the severity of hepatic injury, the efficacy and safety of antiviral therapy and the usefulness of biochemical markers [FibroTest-ActiTest (AT-FT)].

Two groups of patients were analyzed: group 1, a prospective cohort including all
HCV patients from our institution (n=4,182); and group 2, all consecutive patients who had had FT-AT performed in France between September 2002 and May 2003 (n=8,540).

A total of 2,410 GE65 were included, 881 from group 1 and 1,529 from group 2. In group 1, the duration of infection and age at infection were higher in GE65 than in LT65 (26 vs 20 and 50 vs 24 years, respectively, p< 0.001). Infection with Genotype 1 and history of transfusion were more frequent in GE65 than in LT65 (78% vs 57% and 51% vs 29%, respectively, p<0.001). Fibrosis stage at liver biopsy was higher in GE65 than in LT65, regardless of the duration of infection. Among the 2,169 patients who underwent liver biopsy, bridging fibrosis (F2,F3,F4) was more frequent in GE65 than in LT65 (76% vs 46%, respectively, p<0.001). In multivariate analysis, factors associated with F2,F3,F4 were age at biopsy and age at infection. The initial manifestation of HCV infection was most often a complication (jaundice, bleeding, ascites, liver cancer) in GE65 as compared to LT65 (14% vs 4%, p<0.001). In multivariate analysis, 3 factors were associated with complications: age at diagnosis, alcohol consumption >50g/day and coinfection with HIV. A total of 170 (19%) GE65 had received interferon and/or ribavirin (patients > 80 years, n=4); treatment was well tolerated (interruption of treatment: 20%; decrease of dose: 7%). In 20 GE65 treated by PEG Interferon-Ribavirin, a sustained virologic response was obtained in 45% of cases. In group 2, the prevalence of F2F3F4 estimated by FT was 73% in GE65 (1,121 of 1,529) vs 35% in LT65 (2,419 of 7,011; Armitage trend p<0.001). The prevalence of moderate or severe necrosis (AT) was also higher, 39% vs 14%, respectively (p<0.001). Cirrhosis was detected in 70% (94/148) of patients older than 80 yrs, 36% of patients between 65-80 and 14% of LT65 (p<0.001). Despite the dramatic increase in fibrosis and necrosis prevalences in GE65, the prevalence of elevated ALT (greater than 50 IU/L) was similar between GE65 (53%) and LT65 (52%). Among patients with F2F3F4, non-elevated ALT was observed in 41% of patients older than 80 years, 39% of those between 65-80 and 31% in LT65 (p<0.001); despite non-elevated ALT Cirrhosis was present in 36%, 30% and 27%, respectively (p=0.03).

In patients 65 years or older, chronic hepatitis C is more severe and presents with lower ALT levels than in younger patients. Treatment is effective and well tolerated. Biochemical markers such as FibroTest-ActiTest seem particularly useful as a non-invasive alternative to liver biopsy in this population.

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Sylvie Deuffic-Burban, INSERM U444, Paris, France; John B. Wong, Tufts-New England Medical Center, Boston, MA; Thierry Poynard, Group Hospitalier Pitie-Salpetriere, Paris, France.

In the US, hepatitis C virus (HCV) is perhaps four times more common than human immunodeficiency virus (HIV). Prior to effective therapy for HIV, AIDS-related mortality exceeded that from liver disease, but the advent of highly active anti-retroviral therapy (HAART) has greatly improved HIV survival and reduced AIDS-related mortality. Many HIV-infected individuals have been diagnosed and treated but HCV remains mostly undiagnosed and untreated. Projecting the future health burden of these two epidemics may help health policymakers plan their responses.

To compare the projected future disease burden (incidence and mortality) related to HCV and to HIV in the US.

We applied the backcalculation method to develop mathematical models of the HIV and the HCV epidemic in the US and have incorporated antiviral treatment into these estimates (proportion treated and their likely response; for HCV these estimates were only up until 1999 and did not consider the combination of peginterferon and ribavirin).

These models were based on US epidemiologic data regarding prevalence, incidence of infection, age and gender of incident cases, AIDS, hepatocellular mortality and general population mortality from the CDC, WHO and literature data. We first applied the backcalculation method to develop separate HIV and HCV models. Logistic and time-dependent lognormal model parameters were adjusted until the models resulted in the best fit or match to the reported past incidence of these two infections up to 1998. We then projected future HIV and HCV-related mortality until 2070.

In the HIV model, the time from infection to AIDS (AIDS incubation period) is assumed to be 8 years in the absence of anti-retroviral treatment or during the mono-therapy period (before 1995), 10 years during dual-therapy period (1995-6) and 20 years during HAART or triple-therapy period since 1996. These estimates were based on HIV-seropositive subjects in French hospitals.

Backcalculation of HCV Model
• Using reported HCC mortality and published natural history data, we first backcalcuated the past incidence of HCV and than projected future HCV-related mortality (i.e. deaths from liver failure and HCC)
• Logistic function model of the past incidence until 1985 and then three plateaus according to three reductions: 30% in 1985 to account for guidelines for selecting safer blood donors, 50% in 1990 to account for screening of blood donors for HCV, 50% in 1995 to account for increased public knowledge of the risks of HCV.
• HCV treatment assumptions (Year, Likelihood of SVR, % with HCV treated)
o 1991-1994: 10% among 5% = 0.5%
o 1995-1998: 20% among 10% = 2%
o 1999: 40% among 15% = 6%
• Data
o Age distribution at infection (Armstrong, Hepatology 2000)
o Prevalence of HCV: between 2.7 millions (Alter, NEJM 1999) and 3.1 millions (Davis, Liver Transpl 2003)
o Mortality from causes other than HCV set to observed rates for US population (WHO)
o HCC mortality from 1979 to 1998 (WHO)
o Proportion of HCC related to HCV: 18% in 1993-1995 and 31% in 1996-1998 assuming an exponential model (Hassan J Clin Gastroenterol 2002)

Backcalculation of HIV Model
• Using reported AIDS cases and the incubation time from HIV infection to AIDS obtained from the literature, the mathematical model backcalculated the past incidence of HIV.
• Using the backcalculated HIV incidence and reported AIDS mortality, a second model then estimated the time from infection onset to AIDS death.
• Finally, the last model used to project future AIDS mortality
• Data assumptions
o AIDS cases (CDC) from 1982 to 2000 adjusted for reporting delay (CDC) and for underreporting (15% as in France)
o AIDS death (WHO) from 1987 to 1998 adjusted for underreporting (20% as in France)
o AIDS incubation time (IT) from the French Hospital Data base on HIV (Tassie, JAIDS)
• Anti-HIV treatment effects according to three periods to account for the introduction of dual therapy and HAART: <July 1995 (median IT=8 yrs), from July 1995 to June 1996 (median IT=10 yrs), from July 1996 (median IT=20yrs)
• Age affect
• 50% of those infected with HIV remain outside of the health care system (untreated)
• Time between infection and AIDS death: 10-yr HIV-infected 30-yr olds estimated at 64%, 72% and 95% depending on the width HIV treatments were available.

Based on the HCV backcalculation model:

• The HCV epidemic peaked with a maximum annual HCV incidence in 1984 at 149,000-224,000 new infections and then fell to about 33,000-46,000 in 1998.
• Based on the HIV backcalculation model, HIV incidence reached its maximum in 1989 at 132,000-162,000 new infections and then declined to 38,000-49,000 in 1995, before rising again.
• Mortality related to HCV (death from liver failure or hepatocellular carcinoma) rose from about 3,800-4,200 in 1998 to peak at about 14,000-19,000 in 2030.
• For comparison, observed HIV-related mortality was 16,000 in 1998 and projected to be 4,200-6,700 estimated for 2030.

With the availability of effective HAART for HIV infection, mortality from HIV appears to have declined substantially. The stability of that decline will depend on epidemiologic trends and the rate of development of HAART resistance. Our model projections for hepatitis C are consistent with three other US projections that all suggest that mortality and the public health burden of HCV will rise over the next 10-30 years.

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Anna S. Lok, University of Michigan, Ann Arbor, MI; James E. Everhart, NIDDK, Bethesda, MD; Elizabeth Wright, NERI, Watertown, MA; Raymond Chung, Massachusetts General Hospital, Boston, MA; Joel K. Greenson, University of Michigan, Ann Arbor, MI; HALT-C trial investigators.

Hepatic steatosis is a common histologic feature in patients with hepatitis C and has been reported to be associated with more advanced fibrosis. The mechanisms for hepatic steatosis in hepatitis C are unclear. The aims of this study were to determine the prevalence of hepatic steatosis among patients enrolled into the HALT-C trial, to identify factors associated with steatosis, and to determine if there is a correlation between hepatic steatosis and fibrosis.

Patients and Methods
Baseline data from 1145 patients enrolled in the lead-in phase of the HALT-C trial were analyzed. All the patients had Ishak fibrosis score ≥3 and had failed to respond to prior antiviral therapy. Patients with other causes of liver disease including severe NASH were excluded. All the biopsies were scored by a committee of study pathologists without knowledge of patient information. Steatosis was graded as 0, 1, 2, 3 and 4 if fat was present in 0, 1-5%, 5-33%, 33-67% and >67% of hepatocytes.

20% of patients had steatosis grade 0, 42% grade 1, 30% grade 2, and 9% grade 3-4. Thirty-eight had Ishak fibrosis score 5-6 (cirrhosis). Steatosis was significantly correlated with BMI, truncal obesity, diabetes, hypertriglyceridemia, HCV genotype 3, younger age, high ferritin, low HCV RNA, and cirrhosis. There was no correlation between steatosis and gender, race or history of alcohol consumption. Logistic regression analysis found that age, BMI>30, genotype 3, and hypertriglyceridemia significantly correlated with hepatic steatosis.

Steatosis was a common histologic feature in HALT-C patients (39% had fat in >5% of hepatocytes) despite the exclusion of patients with severe NASH. Risk factors for steatosis in HALT-C patients were similar to that of NAFLD patients. Steatosis correlated with fibrosis in univariate but not in logistic regression analysis. Tests for insulin levels are ongoing to determine if insulin resistance plays a role in hepatic steatosis in hepatitis C patients, particularly those with genotype non-3.

Hepatic steatosis grade
  0 1 2 3&4 p value
N 214 471 344 103  
Age (years)* 51 50 49 48 0.01
BMI (kg/m2)* 28 29 31 32 <0.0001
Waist circumference (cm)* 95 99 100 103 <0.0001
Insulin Resistance 10 16 18 20 0.0001
% Diabetes 17 22 27 34 0.001
% hypertriglyceridemia 9 13 19 28 <0.0001
% HCV genotype 3 1.5 4.0 5.3 11.1 0.0003
% cirrhosis 28 39 45 30 0.04
* mean values          

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Masaru Enomoto, Shuhei Nishiguchi, Madoka Kohmoto, Akihiro Tamori, Daiki Habu, Tadashi Takeda, Shuichi Seki, Susumu Shiomi, Osaka City University Medical School, Osaka, Japan.

We reported that the dynamics of hepatitis C virus (HCV) during the first few weeks of interferon (IFN) monotherapy is predictive of sustained virological response. Combination therapy with IFN-a and ribavirin has recently become a standard therapeutic strategy, especially for difficult-to-treat patients with HCV genotype 1 and high baseline viral loads. However, previous studies did not reveal the synergistic effects of ribavirin when combined with IFN-a on viral dynamics, probably because of the short duration of observation and the limited sensitivity of quantitative assays. The aim of this study was to determine how ribavirin enhances viral decline in patients with chronic HCV infection during treatment with IFN-a. We also evaluated the relationship between viral kinetics and the pharmacokinetics of ribavirin.

Materials and Methods
The subjects were 20 patients with HCV genotype 1 and high viral loads (> 5.0x105 copies/ml) (13 men and 7 women; mean age, 55 ± 11 years) who received combination therapy with IFN-a2b and ribavirin. As historic controls, 10 patients with similar baseline characteristics (6 men and 4 women; mean age, 56 ± 9 years) who were treated with IFN-a2b alone were included. IFN-a2b (Intron A, Schering-Plough, Kenilworth, NJ) was given by intramuscular injection at a dosage of 6 MU every day for 2 weeks, followed by 6 MU three times a week. Ribavirin (Rebetol, Schering-Plough) was given orally twice a day at a total daily dose of 600–800 mg depending on body weight. Serum samples were obtained from the patients before the administration of drug(s) on the first day of therapy (day 0), and on days 1, 7, 14, 28 and 84. Serum HCV RNA was monitored by real-time quantitative polymerase chain reaction with the use of the ABI Prism 7700 sequence detection system (Perkin Elmer Corp./Applied Biosystems, Foster City, CA). The detection range of the assay was 2.0x102 to 1.0x109 copies/ml of HCV RNA. Serum ribavirin concentrations were determined at days 28 and 84 of therapy by a validated high performance liquid chromatography/tandem mass spectrometric assay using 13C-ribavirin as an internal standard.

In the study period during the first 12 weeks of treatment, no patient required reduction of the dose of IFN-a2b. The dose of ribavirin was reduced in one patient at week 10 of treatment, because hemoglobin concentrations decreased to below 10 g/dl. As previously reported, serum HCV levels decreased rapidly during the first 24 h of therapy and more slowly thereafter. For the following analysis, we tentatively defined the period between 0 h and 24 h of therapy (day 0) as “the first phase”, the period between days 1 and 14 as “the second phase”, and the period between days 14 and 84 as “the third phase”. The differences in median first-phase decay rate between the combination-therapy group and monotherapy group were not significant (1.41 log10/day vs 0.078 log10/day, p = 0.24), nor were differences in the second-phase decay rate (0.90 log10/day vs 0.081 log10/day, p = 0.68). In the third phase between days 14 and 84, the viral decay rate in the combination-therapy group (0.030 log10/day) was significantly higher than that in the monotherapy group (0.015 log10/day, p = 0.035). The correlations between the third-phase decay rate and serum ribavirin concentrations at day 28 (r = 0.040, p = 0.872) and day 84 (r = 0.063, p = 0. 806) were not significant.

In patients with HCV genotype 1 and high viral loads, long-term favorable response to combination therapy with IFN-a and ribavirin is associated with faster viral decline after the earliest phase of therapy. This finding may also mean that viral kinetics in the first few days of treatment cannot be used for prediction of long-term response to combination therapy. We did not find a clear relationship between serum ribavirin concentration and viral decline.

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Ke-Qin Hu, Loma Linda Univ and VAMC, Loma Linda, CA; Ramsey C Cheung, Palo Alto VAMC, Palo Alto, CA; Sue Currie, San Francisco VAMC, San Francisco, CA; Edmund J Bini, New York Harbor VAMC, New York, NY; Hui Shen, University of California, San Francisco, San Francisco, CA; Bhupinder Anand, Houston VAMC, Houston, TX; Lennox J Jeffers, Miami VAMC, Miami, FL; Samuel B Ho, Minneapolis VAMC, Minneapolis, MN; Norbert Bräu, Bronx VAMC, Bronx, NY; Warren N Schmidt, Iowa VAMC, Iowa City, IA; John McCracken, Loma Linda Univ. and VAMC, Loma Linda, CA; Stephen J Rossi, San Francisco VAMC, San Francisco, CA; Teresa L Wright, San Francisco VAMC, San Francisco, CA; For the VA-HCV-001 Study Group

Studies have indicated a high prevalence of hepatic steatosis in patients with chronic hepatitis C (CHC). However, the impact of steatosis on the clinical course of CHC, including hepatic fibrosis, and treatment response remains to be determined. AIMS: To determine the prevalence of and risk factors for steatosis, and the association of steatosis with clinical presentation of CHC in a large cohort of US veteran patients.

The present study was based on a large VA multicenter trial of interferon a-2b and ribavirin treatment, that was conducted at 25 VA Medical Centers over a 15 month period. The inclusion criteria for the present study were patients with a positive HCV RNA, a negative HBsAg and negative anti-HIV, a pre-treatment liver biopsy with assessment of hepatic steatosis. A total of 357 veterans were included in this study. Data collected in this study included demographics, history of alcohol use, pre-treatment biochemistries, HCV RNA load and genotyping, and pathological reports of the liver biopsy.

Of 357 patients, 97.1% were males and 2.9% were females with mean age of 48.7+6.4 years, and 184 (51.5%) had hepatic steatosis. The mean body mass index (BMI) was 29.3+5.2 kg/m2, including 46.4% being overweight (BMI > 25, but 30 kg/m2). Although 83.0% (278/335) reported a history of regular drinking, 70.9% quit drinking for > 12 months at entry to this study. Stage III/IV fibrosis was present in 111/334 (33.2%) of the patients. Univariate analysis revealed that four factors, Africa Americans (vs. Caucasian, 61.7% vs. 47.7%, p=0.031), obesity (64.6% vs. 48.2%, p=0.009), elevation of ALT (> 45 IU/ml, 53.5% vs. 34.9%, p=0.023) and AST (> 40 IU/ml, 55.3% vs. 38.5%, p=0.014) were significantly associated with hepatic steatosis, but a history of alcohol use in the past 12 months (50.0% vs. 52.6%, p=0.66) was not. A higher prevalence of stage III/IV fibrosis was seen in patients with steatosis (57.7% vs. 47.1%), but this was not significant (p=0.069). However, after adjusting for age, ethnicity, alcohol use, BMI, HCV genotype-3, and HCV load, stage III/IV fibrosis was independently associated with steatosis (p=0.0247). Lower end of treatment biochemical (46.0% vs. 58.3%, p=0.03) and virologic (41.9% vs. 56.4%, p=0.019) responses were significantly associated with steatosis, but sustained biochemical (48.0% vs. 56.3%, p=0.24) and virologic (43.6% vs. 55.8%, p=0.11) responses were not.

In our cohort of US veterans with CHC, the prevalence of hepatic steatosis is 51.5%. We found that steatosis is independently associated with stage III/IV fibrosis, but not obesity and a history of alcohol use in the past 12 months. Presence of steatosis is also associated with significantly lower end of treatment biochemical and virologic responses in these patients.

This study was funded in part by a grant from Schering-Plough Corporation.

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Inmaculada Castillo, Margarita Pardo, Javier Bartolome, Nuria Ortiz-Movilla, Elena Rodriguez-Inigo, Susana de Lucas, Fundacion Estudio Hepatitis Virales, Madrid, Spain; Clara Salas, Clinica Puerta de Hierro, Madrid, Spain; Jose A. Jimenez-Heffernan, Hospital La Zarzuela, Madrid, Spain; Arturo Perez-Mota, Javier Graus, Hospital Virgen de la Torre, Madrid, Spain; Juan Manuel Lopez-Alcorocho, Vicente Carreno, Fundacion Estudio Hepatitis Virales, Madrid, Spain.

Ten percent of patients with long-standing abnormal liver function tests have no etiology identified after rigorous exclusion of all known causes of liver diseases

We analyzed the presence of HCV-RNA in liver biopsies of 100 anti-HCV negative patients without serum HCV-RNA (sensitivity of RT-PCR: 10 IU/ml). They had persistently abnormal levels (tested every 3 months) of at least one of the three liver enzymes (AST, ALT or GGTP) of unknown etiology prior to the liver biopsy for a minimum time of 12 months. All causes of liver diseases were excluded by clinical, serologic and immunologic analysis. Intrahepatic positive HCV-RNA strand was detected by RT-PCR with primers of the 5' NC region in 57/100 of the anti-HCV and serum HCV-RNA negative patients (occult HCV infection). HCV-RNA was also tested in the liver biopsies of all cases by RT-PCR using primers from the core region of the HCV genome and 40 (70%) of the 57 patients with occult HCV infection were also positive when the core primers were used for testing HCV-RNA in the liver, while the remaining patients were negative. No significant differences were found between the epidemiological or clinical data of the patients with and without occult HCV infection By in situ hybridization, the positive HCV-RNA strand was also detected in the biopsies from the 57 patients with occult HCV infection, but no hybridization signals were observed in the liver biopsies of the remaining cases In addition, the negative HCV-RNA strand was found by in situ hybridization in the liver of 48/57 (84.2%) patients with occult HCV infection.

Genotyping of intrahepatic HCV-RNA showed that the 57 patients had HCV genotype 1b. The nucleotide sequence analysis of the HCV core region from 10 randomly selected patients confirmed the specificity of HCV-RNA detection. Forty patients (70%) with intrahepatic HCV-RNA had also viral RNA in their PBMC, as tested by RT-PCR and by in situ hybridization. Regarding liver histology, the number of patients with necroinflammatory activity (A1 or higher according to METAVIR) was significantly higher (p=0.017) in patients with occult HCV infection than in negative ones (20/57: 35% vs 6/43: 14%, respectively). In addition, fibrosis (F1 or higher) was significantly more frequent (p=0.022) in patients with occult HCV infection (10/57: 17.5%) than in patients without intrahepatic HCV-RNA (1/43: 2.3%). In a logistic regression analysis, the age of patients and the presence of intrahepatic HCV-RNA were found to be independently related with the necroinflammatory activity (p=0.003 and p=0.01, respectively) and with fibrosis (p=0.04 and p=0.03, respectively)

Patients with abnormal liver enzymes of unknown etiology may have intrahepatic HCV-RNA in the absence of anti-HCV and serum HCV-RNA. In addition, these patients with occult HCV infection present a more severe liver damage than those without intrahepatic HCV-RNA.

The authors also note:

  • The author also noted that even though all patients with occult HCV were infected with HCV genotype 1b that was due to the predominant genotype in their population.
  • These patients should be considered for treatment since 5% of those identified progressed to cirrhosis.

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Hannover, Germany; Christoph Sarazzin, University Saarland, Homburg, Germany; Hans L. Tillmann, Tim Greten, Manuela Meyer, Johannes Wiegand, Michael P. Manns, Heiner Wedemeyer, Hannover Medical School, Hannover, Germany.

Clearance of acute hepatitis C virus (HCV) infection is thought to be mediated by a multispecific immune response. HCV-specific T cells have been described in HCV-seronegative virus-exposed individuals such as i.v.-drug addicts, family members of chronic HCV-patients and lab-personnel. However, it is not known whether these individuals had recovered from previous asymptomatic acute hepatitis C. In this study, we prospectively followed 10 individuals who experienced an injury with an HCV-contaminated needle.

Between January 2001 and March 2003 we collected PBMC from 10 individuals (medical health professionals at our institution; 3 females, 7 males; age 30-45 years) who experienced an injury with an HCV contaminated needle. Blood samples were taken on the day or the day after the event and at different time points during follow-up for up to 25 months. Low levels of HCV-RNA were examined in serum by the highly sensitive transcription-mediated TMA-Assay (detection limit 5-50 IU/ML) and in RNA of PBMC. T cell-cytokine secretion (ELISPOT-assays for IFN-gamma and IL-10, flow-cytometry-based IFN-g capture assays), T cell-proliferation (3-thymidin incorporation, CFSE-staining), and T cell-cytotoxicity (51-chromium release assays) were investigated directly ex vivo and in T cell lines.

None of the individuals became positive for HCV-RNA in serum (TMA-assay) or PBMC and all of them remained anti-HCV-negative throughout follow-up. At the time of the needle stick injury, HCV-specific CD4+ T cell responses were already detectable in 2 of the individuals and became detectable thereafter in 2 additional persons. HCV-specific CD8+ T cell responses could be investigated in one HLA-A2-positive individual in more detail at several time points. He was negative for HCV-specific interferon gamma- and IL-10-producing cells on the day of the injury as determined by ELISPOT assays. However, after 18 weeks, we detected for Core-178-specific IFN-gamma producing CD8+ T cells. Out of 7 MHC-class I-restricted HCV epitopes tested, one additional peptide (NS3-1406) became positive 8 weeks later. The presence of Core-178 and NS3-1406-specific CD8+ T cells was confirmed by a second flow-cytometry-based assay. HCV-specific INF-gamma positive cells were CD8-dim and HLA-DR-negative. The frequency of NS3-1406 and Core-178-specific CD8+ T cells was about 1/4500 and 1/8500 PBMC, respectively, in the ELISPOT assay and remained constant in this subject until month 11 of follow-up. The increase of CD8+ T cell responses was accompanied by the development of an HCV-specific CD4+ response targeting predominantly the HCV-core and HCV-helicase antigens.

We here demonstrate in a prospective study the development of HCV-specific T cells in HCV-exposed individuals after needle stick injury in the absence of viremia. Surprisingly, these HCV-specific T cells became detectable rather late after the potential exposure. Our data are in line with previous studies demonstrating HCV-specific T cell responses in chimpanzees inoculated with sub-infectious doses of HCV. T cell immunity in medical health professionals against HCV may contribute to the low prevalence of HCV among doctors and nurses since HCV prevalence in medical health personnel has been shown to be equal or even lower as compared to the general population in most studies.
This study was funded by the German Viral Hepatitis Network “HEP-NET” (Project 10.2.2)

The authors all noted that certain factors may increase the risk of infection – needle size, spontaneous bleeding during episode, time between patients and the amount of HCV viral load.

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John B. Wong, Tufts-New England Medical Center, Boston, MA; Thierry Poynard, Group Hospitalier Pitie-Salpetriere, Paris, France.

The natural history of hepatitis C (HCV) remains controversial with little data beyond the first 2 decades and conflicting estimates based on study design and population characteristics, such as age and gender. Using 2313 liver biopsies from untreated patients including some with biopsies 20 to 40 years post infection, we translated a Cox proportional hazards model into a fibrosis-based Markov model.

To compare cohort simulation projections to published outcomes and to predict future outcomes.

Cox proportional hazards models estimated the likelihood of developing Metavir fibrosis stages F1, F2, F3 or F4 over time. For all models, covariates included age, gender, alcohol consumption (>50 gm/day), injection drug use, and Metavir inflammation A2 or A3. These Cox models and recent UNOS, SEER and NIH data were used to modify a previously published computer cohort simulation (Wong, JAMA 1998). Summary patient characteristics from the retrospective-prospective Kenny-Walsh (NEJM 1999) and Thomas (JAMA 2000) studies were then applied to the fibrosis-based Markov model to estimate the observed outcomes and to project future outcomes.

For the Kenny-Walsh study (n=376), the mean age of the Irish women when they received HCV-contaminated anti-D immune globulin was 28 years. After a mean of 17 years, liver biopsy revealed F0 in 49%, F1 in 34%, F2 in 10%, F3 in 5% and F4 in 2%. Markov model projections were 50% F0, 36% F1, 10% F2, 2% F3 and 1.6% F4. After 27 years of follow-up, the model predicted 20% F2, 4% F3 and 7% F4; and after 37 years of follow-up, 27% F2, 8% F3 and 20% F4. To examine the impact of selected cohort factors, the 17-year incidence of cirrhosis (base-case estimate 1.6%) was 3% if all of the women had instead acquired HCV through injection drug use and 6% if they drank >50 gm alcohol per day. If the women had been older, the 17-year cirrhosis incidence rose to 5% for 38 year-olds and 14% for 48 year-olds. Thus, age and duration of infection are the primary determinants of fibrosis progression. Despite the slow fibrosis progression, the projected life expectancy for this cohort was 41.8 years and 37.3 quality-adjusted life years compared to an expected 51.7 years for 28 year-old women. The projected lifetime medical care costs were $52,000 without antiviral treatment.

For the Thomas study (n=1667), the median age at first injection drug use was 20 years. With follow-up exceeding 15 years in over 75% of patients, cirrhosis was found in 2.4%. The Markov model predicted a 2.5% incidence of cirrhosis after 15 years. Future cirrhosis predictions were 11% after 25 years and 30% after 35 years. Again, to examine the impact of selected cohort factors, the 15-year incidence of cirrhosis (base-case estimate 2.4%) was 1.3% if all of the patients had instead acquired HCV through transfusion and 7% if they drank >50 gm alcohol per day. If the patients had been older, the 15-year cirrhosis incidence rose to 8% for 30 year-olds, 21% for 40 year-olds, and 46% for 50-year olds. Thus, age and duration of infection are the primary determinants of fibrosis progression. The projected life expectancy for this cohort was 30.4 years and 26.2 quality-adjusted life years compared to an expected 56.3 years for 20 year-olds. The projected lifetime medical care costs were $66,359 without antiviral treatment.

Our fibrosis-based Markov model predictions matched observed community cohort HCV outcomes well. The model suggests rapid fibrosis progression beyond 20 years and very rapid progression beyond 30 years. Despite the slow early progression, hepatitis C may still significantly reduce life expectancy and quality of life and induce substantial medical care costs because of the normally long life expectancy in these community cohorts and this delayed rapid progression. Although men, injection drug use, alcohol use and active hepatic inflammation all raise the likelihood of progression, increasing duration of infection and older age at infection onset are the primary determinants of fibrosis progression.

The authors also noted that they thought this was a good model because this study was consistent with other studies and the comparator was studies with slow disease progression.

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Theo Heller, Yuji Sobao, Eishiro Mizukoshi, Fareed Rahman, National Institutes of Health, Bethesda, MD; Arlene Sheets, Donna Gordon, Averell Sherker, Washington Hospital Center, Washington, DC; Ellen R. Kessler, Kathleen S. Bean, Inova Fairfax Hospital, Falls Church, VA; Steven Herrine, Thomas Jefferson University, Philadelphia, PA; James Schmitt, M'Lou Stevens, Yoon Park, Harvey Alter, Jay H. Hoofnagle, Jake Liang, Barbara Rehermann, National Institutes of Health, Bethesda, MD.

Most studies of HCV-specific cellular and humoral immune responses have been performed on patients who were exposed to a large volume of HCV-infected blood and developed HCV viremia. Here, we prospectively analyzed the humoral and cellular immune response of 25 subjects with a documented exposure to HCV that did not result in any detectable viremia. Cellular and humoral immune responses of the exposed subjects were compared to those of a control group of 29 healthy blood donors.

The cohort consisted of 13 female and 12 male subjects with percutaneous (needlestick, cut or bite; n=19), cutaneous (blood on skin; n=3) or mucosal (splash of blood into the eye, n=3) exposure to HCV. Virological and immunological analyses were performed on the day of exposure and at weeks 2, 4, 6, 12, 24 and 48 after exposure. Peripheral blood mononuclear cells were tested for HCV-specific proliferation using recombinant HCV core, NS3, NS4, NS5A and NS5B proteins. Direct, ex vivo effector functions of HCV-specific CD4+ and CD8+ T cells were assessed by IFN-γ ELISpot analysis using 228 overlapping 15-mer peptides spanning the HCV core, NS3, NS4A and NS4B proteins.

No subject tested positive for HCV-RNA (Amplicor Assay, Roche Diagnostics) or HCV antibodies (2nd generation EIA, Abbott Laborat.) at any study time point . Eight of 25 subjects (32%) had a positive proliferative T cell response at baseline (day 0 of the study) which was defined as higher than the mean response of 29 healthy blood donors plus 3 standard deviations. Three of 8 subjects (38%) with a baseline response had a further increase of their HCV-specific proliferative T cell response and 7/17 subjects (41%) without a baseline response developed a primary HCV-specific proliferative T cell response within 6 weeks after HCV exposure. The HCV-specific proliferative response was targeted against structural and nonstructural HCV proteins and in 9 of 10 (90%) cases, associated with IFN-γ production, thus indicating direct, ex vivo effector functions of the responding cells. HCV-specific T cell responses returned to baseline levels in all but 2 subjects within 12 weeks after exposure.

Summary and conclusions
Collectively, these results demonstrate that low level exposure to HCV can induce and/or boost HCV-specific T cell responses in the absence of antibody production and detectable viremia. Thus, cellular immune responses might be a more sensitive indicator of HCV exposure than humoral responses. The data also suggest that repeated exposure to HCV is sufficient to immunize the exposed individuals without causing clinically evident infection.

The authors also noted that the type of exposure may influence the response and that repeated exposure may protect those individuals.

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Norah A. Terrault, University of California San Francisco, San Francisco, CA; Michael Busch, Edward Murphy, Blood Centers of the Pacific, San Francisco, CA; Maria Tong, Jenya Dvorkin, University of California San Francisco, San Francisco, CA; Miriam J. Alter, Centers for Disease Control and Prevention, Altanta, GA.

Prior studies on sexual transmission of HCV in heterosexual couples have been limited by small sample size, failure to exclude non-sexual routes of HCV transmission, and failure to characterize anti-HCV concordant couples virologically.

To determine the potential for sexual transmission of HCV among monogamous heterosexual couples by identifying the factors (sexual and non-sexual) associated with anti-HCV positivity among partners, and the relatedness of virus strains among concordant couples.

Anti-HCV positive persons (without HIV and HBV coinfection) with a monogamous heterosexual partner for at least 3 years and no history of injection drug use (IDU) in both partners were eligible. Partners were tested for anti-HCV (EIA-2, RIBA-3), qualitative HCV RNA and HCV genotype/serotype (=type) as appropriate. HCV type concordant couples underwent sequencing and phylogenetic analysis (pending). Detailed information on HCV risk factors and sexual practices were obtained by interviewing the partners separately.

Of 2077 couples screened, 672 were eligible, 552 enrolled and 500 completed the study. The most common reasons for study ineligibility were lack of sexual partner (40%), prior organ transplant (15%), HIV or HBV coinfection (10%), partnership <3 years or non-monogamous (8%), and IDU in both partners (8%). The median age of partners was 49 yrs (range 27-79) and 75% were Caucasian. The median duration of sexual contact was 16 yrs (range 3-52); the median number of sexual contacts per month per couple ranged from 0.3 to 24.4. The proportions of couples engaging in vaginal, anal, oral active and oral receptive sex were 98.3%, 12.5%, 77%, and 76%, respectively. Use of condoms was reported by 80%, but only 17% reported frequent or regular condom use. A total of 20 (4%) partners tested positive for anti-HCV (EIA and RIBA) and 12 had detectable HCV RNA. The type and frequency of sexual contacts and frequency of sharing personal items (e.g. razors) did not differ between anti-HCV positive and negative partners (all p>0.05). Anti-HCV positive partners had higher rates of IDU (45% vs 1%, P<0.001), tattoos (45% vs 15%, P=0.007), blood brother rituals (37% vs 12%, p=0.0015), bloody needlestick injury (60% vs 14% (p=0.005), and total number of sex partners (p=0.005). In multivariate analysis, only IDU, tattoos and needlestick injury were independently associated with anti-HCV positivity in the partners. Genotypes/serotypes were discordant in 6 couples and concordant in 9 couples tested to date. Sexual contact rates of type concordant couples tended to be higher than type discordant couples (median 1 vs 0.25 contact per mos, p=0.07) but with no differences in types of sexual practices. The frequency of percutaneous risk factors for HCV in both partners tended to be higher in discordant than concordant couples (3/5 vs 1/9, p=0.09).

The prevalence of anti-HCV among sexual partners of persons with HCV was 4% (95% CI: 2.3%-5.7%) but 40% of partners had discordant types indicating lack of sexual transmission which would mean that the sexual transmission rate would be 2.2%. The majority of type concordant couples lacked percutaneous risk factors for HCV, suggesting sex may be the route of transmission but phylogenetic analysis of viral strains will ultimately determine whether sexual transmission occurred.

The author noted the following:
  • Duration of exposure was not a significant factor
  • Condom use was not shown to affect transmission
  • Gender question (male/female more susceptible to transmission) not answered
  • The next question that needs to be answered is what type of sexual contact is more likely to transmit HCV

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Sanaa M. Kamal, Harvard Institutes of Medicine, Boston, MA; Nakano Tatsarouni, CDC, Atlanta, GA; Jens Rasenack, University of Freiburg, Freiburg, Germany; Qi He, Cami Graham, Harvard Institutes of Medicine, Boston, MA; Alaa Ismail, Ahmed Al Tawil, Mahmoud Massoud, Ain Shams University, Cairo, Egypt; Margaret J. Koziel, Harvard Institutes of Medicine, Boston, MA.

The role of intrafamilial transmission (sexual and asexual) in the spread of HCV infection is still debated and the factors that increase the risk of HCV intrafamilial transmission are poorly understood.

The aim of this study was to determine the risk of intrafamilial transmission of HCV from index cases with acute hepatitis C and to identify the specific factors promoting HCV transmission.

Patients and Methods
The study cohort (n=347) included 55 index cases (health workers; M: F: 31:24) with proven acute hepatitis C following occupational exposure and their family members (n=102; 50 spouses) in addition to 60 index cases with chronic hepatitis C and 128 (55 spouses) family members who served as a control group. Subjects, controls, spouses and family members were prospectively followed for a mean of 48± 7 months. All index acute HCV cases and their family members had archived HCV negative serum specimens and were interviewed with special stress on potential sexual and asexual risk factors for HCV transmission; however no risk factors for HCV transmission were identified other than contact with the index case. Screening for HCV (ELISA) was performed at enrollment. Positive cases were confirmed by polymerase chain reaction and tested for genotype, HCV RNA viral load, HVR1 (nucleotide positions 1156 to 1234) sequence analysis, HCV specific peripheral and intrahepatic HCV specific CD4+-T cell proliferative & CTL responses and cytokines (ELISpot).

The risk of sexual transmission was higher in spouses of acutely infected subjects where seroconversion was detected in 2% of spouses of HCV-chronically infected index cases versus 14% of spouses of acutely infected index cases (p&lt;0.01). Asexual transmission was detected in 3 children of acutely infected index cases. Genotype and nucleotide sequencing of the HVR1 region showed that the index patients and their spouses and/or family members were infected by the same isolate with &gt; 95% homology. Females were at higher risk of sexual HCV acquisition than males, however 4/7 sexually infected females had self-limited disease. Viral load was significantly higher in acutely infected index cases (3.2 x 106 cop/ml) compared with chronic infection (1.2 x 10 6 cop/ml, p = 0.01). Multivariate-analysis identified acute hepatitis C, high viral load, and vaginal infections as important variables of sexual transmission. CD4+ proliferative and CTL responses were detected in index cases and HCV positive family members and was maintained indefinitely after recovery from HCV infection whereas it was weak and narrowly focused in persistently infected patients. Interestingly, CD4+ responses could be detected in 12/50 spouses of acutely infected subjects despite being seronegative with no apparent viremia.

Our data demonstrate that acute hepatitis C and high HCV RNA levels increase the risk of sexual transmission. The observation that HCV-specific CD4+ and CTL responses exist in apparently HCV negative subjects may have implications for vaccine development and epidemiological studies.

The authors noted:

  • Higher clearance in females
  • They found that the rate of sexual transmission of HCV was higher in acute (15%)
  • Presence of high viral load (more than 2,000,000 copies/mL or 800,000 IU) increased risk of HCV transmission

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Jorge Rakela, Marek Radkowski, Tomasz Laskus, Jeffrey Wilkinson, Debra Adair, Mayo Clinic, Scottsdale, AZ; Andrea Kovacs, Marek Nowicki, University Southern California, Los Angeles, CA.

Sexual transmission of HCV occurs at a low level and seems to be more prevalent among women co-infected with HIV and HCV. Mother to infant transmission of HCV is also more common in the setting of HIV/HCV co-infection and the mechanism is unclear. Genital secretions are rarely studied because of difficulties in obtaining such specimens.

To define prevalence of HCV in genital secretions among women infected with HCV.

We have studied 75 anti-HCV positive women enrolled in the Women’s Interagency HIV-1 Study (WHIS) at the Los Angeles site. We studied plasma and cervical lavage (CVL) specimens. We determined anti-HCV in plasma, HCV-RNA presence and titer in plasma and CVL. We further characterized amplified viral sequences by single strand conformational polymorphism (SSCP), cloning and sequencing.

Sixty-two of 75 women (83%) who were anti-HCV positive were also HIV positive. CVL from 18 of 62 women (28%) who were co-infected with HIV was HCV-RNA positive; none of CVL from 13 women who were anti-HCV positive only was HCV-RNA positive (p=. 03, Fisher’s exact test). Sixteen CVL specimens had HCV < 8,000 copies/ml. Two CVL specimens had HCV RNA of 8,360 and 39,667 copies/ml. The mean HCV viral load in CVL was 1.52x103 copies/ml. A multivariate analysis that included CD4 counts, CD3 counts, HIV RNA in plasma, HIV RNA in CVL, and HCV RNA in plasma, showed that the only independent predictors of HCV RNA in CVL were HCV viremia in plasma (p=0.02) and HIV viremia in CVL (p=0.03). We studied in detail plasma and CVL HCV quasispecies from 9 women. HCV-RNA was detected in both plasma and CVL in 5 of 9 women. HCV-RNA negative strand was found in CVL in one. In 4 of 5 women, SSCP, cloning and sequencing demonstrated that HCV strain present in CVL was unique to that compartment.

1) HCV-RNA in CVL is more likely to be present in HIV/HCV co-infected women; this may provide substrate to increased likelihood of HCV transmission to their respective sexual contacts and may also provide an explanation for the increased likelihood of HCV transmission to their infants
2) The presence of HCV-RNA in CVL was associated with HIV-RNA in the same compartment; this suggests a local interaction between both viruses that needs further analysis.
3) We found evidence of HCV compartmentalization in CVL; this finding supports the concept of extrahepatic HCV replication and may be consequential for sexual and mother to infant transmission of HCV. Supported by NIH grants DA13760 and RO1 AI52065.

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