Hepatitis: McHutchison J

Pianko S, McHutchison J. · No affiliation provided · Am J Gastroenterol. · Pubmed #10811315 No free full text.

This publication has no abstract.

Afdhal N, McHutchison J, Brown R, Jacobson I, Manns M, Poordad F, Weksler B, Esteban R. · Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. · J Hepatol. · Pubmed #18433919 No free full text.

Abstract: Thrombocytopenia (platelet count <150,000/microL) is a common complication in patients with chronic liver disease (CLD) that has been observed in up to 76% of patients. Moderate thrombocytopenia (platelet count, 50,000/microL-75,000/microL) occurs in approximately 13% of patients with cirrhosis. Multiple factors can contribute to the development of thrombocytopenia, including splenic platelet sequestration, bone marrow suppression by chronic hepatitis C infection, and antiviral treatment with interferon-based therapy. Reductions in the level or activity of the hematopoietic growth factor thrombopoietin (TPO) may also play a role. Thrombocytopenia can impact routine care of patients with CLD, potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy, antiviral therapy, and medically indicated or elective surgery. Therapeutic options to safely and effectively raise platelet levels could have a significant effect on care of these patients. Several promising novel agents that stimulate TPO and increase platelet levels, such as the oral platelet growth factor eltrombopag, are currently in development for the prevention and/or treatment of thrombocytopenia. The ability to increase platelet levels could significantly reduce the need for platelet transfusions and facilitate the use of interferon-based antiviral therapy and other medically indicated treatments in patients with liver disease.

Di Bisceglie AM, McHutchison J, Rice CM. · Saint Louis University, St. Louis MO 63110, USA. · Hepatology. · Pubmed #11786980 No free full text.

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Patel K, McHutchison J. · Scripps Clinic, Division of Gastroenterology and Hepatology, La Jolla, California 92037, USA. · Expert Opin Pharmacother. · Pubmed #11584999 No free full text.

Abstract: Chronic hepatitis C infection affects approximately four million Americans. Over the last decade, Type 1 interferons (IFNs) have been the mainstay of therapy for suitable patients. Recently, the combination of IFN plus ribavirin, with enhanced response rates, has replaced IFN monotherapy for treatment of these patients. The addition of a polyethylene glycol (peg) moiety to IFN alpha-2b has provided a drug with reduced clearance whilst retaining biological and antiviral activity. This formulation allows once-weekly dosing and enhances sustained response rates, without significantly changing the safety and tolerability of IFN. Clinical trials indicate a doubling of sustained virological response rates for regimens utilising pegIFN alpha-2b, compared with standard IFN-alpha 2b. The combination of pegIFN alpha-2b and ribavirin further increases the sustained virological response rates to > 50% for suitable patients. Future pegIFN alpha-2b studies will need to examine drug profiles in patients with co-morbid conditions (e.g., renal impairment, liver transplantation), as well as safety and efficacy issues in different ethnic groups. Further clinical trials are also required to determine the benefits of pegIFN alpha-2b in previous non-responders or relapse patients and as maintenance therapy to prevent disease progression. Finally, careful cost effectiveness analyses will need to be performed.

McHutchison J, Sulkowski M. · Division of Gastroenterology, Duke Clinical Research Institute, Duke University, Durham, NC 27715, USA. · J Viral Hepat. · Pubmed #18363672 No free full text.

Abstract: Current standard-of-care antiviral treatment for patients with chronic hepatitis C is combination therapy with pegylated interferon (PEG-IFN) alfa plus ribavirin. Two large clinical trials determined that each PEG-IFN alfa compound, when given in combination with ribavirin, results in overall sustained virological response (SVR) rates of approximately 50%; SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 are typically lower (42-46%). Differences in study design, treatment regimens, and patient populations preclude comparison of the data across trials; therefore, the most effective use of PEG-IFN alfa in combination with ribavirin is unclear. The Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study is a phase 3b, randomized, parallel-group, US multicentre trial in treatment-naive genotype 1 patients with chronic hepatitis C. Initially, this study was undertaken to evaluate the efficacy and safety of weight-based ribavirin dosing (800-1400 mg / day) and PEG-IFN alfa-2b dosing (arm 1: PEG-IFN alfa-2b 1.5 microg / kg / week; arm 2: PEG-IFN alfa-2b 1.0 microg / kg / week). However, because a clinical trial directly comparing the efficacy and safety of PEG-IFN alfa-2a and alfa-2b in combination with weight-based ribavirin dosing has not been performed, an additional arm (arm 3: PEG-IFN alfa-2a 180 microg / week plus ribavirin 1000-1200 mg / day) was included to address this important issue. IDEAL is fully enrolled (>3000 patients) and complete study data, including SVR rates, are expected in early 2008. Herein, we present the scientific rationale and study design, discuss key data from other trials, and summarize our expectations of this study.

Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J. · Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Université Paris VI, Paris, France. · Hepatology. · Pubmed #12883493 No free full text.

Abstract: Liver fibrosis and activity indexes were validated in patients infected by hepatitis C virus (HCV) nontreated and treated by interferon. The aim was to validate their usefulness as surrogate markers of histologic features using the data of a randomized trial of combination peginterferon alfa-2b and ribavirin. Three hundred fifty-two patients who had had 2 interpretable liver biopsies and stored serum sample before and after treatment were selected. Two hundred eight patients received peginterferon alfa-2b 1.5 mcg per kg and ribavirin and 144 patients interferon alfa-2b 3 MU three times a week and ribavirin for 48 weeks. A fibrosis and an activity index combining 5 and 6 biochemical markers were assessed at baseline and at end of follow-up (24 weeks after treatment). The biochemical markers have significant predictive values both for the diagnosis of fibrosis and for activity. For the diagnosis of bridging fibrosis and/or moderate necroinflammatory activity, the area under the receiver operating characteristics curve of the activity index was 0.76 +/- 0.03 at baseline and 0.82 +/- 0.02 at end of follow-up. A cutoff of activity index at 0.30 (range, 0.00-1.00) had 90% sensitivity and 88% positive predictive value for the diagnosis of bridging fibrosis or moderate necroinflammatory activity. Sensitivity analyses with biopsy specimens of size greater than 15 mm suggest that a part of discordances between biochemical markers and histology were due to biopsy specimen sampling error. In conclusion, these biochemical markers of fibrosis and activity could be used as surrogate markers for liver biopsy in patients with chronic hepatitis C, both for the initial evaluation and for follow-up.

Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S, Younossi Z, Albrecht J. · Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Université Paris VI, Paris, France. · Hepatology. · Pubmed #12829989 No free full text.

Abstract: It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis. We assess the effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis. We analyzed 1,428 naïve patients included in a randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment. At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes (P <.001). The variables associated with steatosis in logistic regression were genotype 3 (P <.001), triglycerides greater than 1.7 mmol/L (P <.001), body mass index greater than 27 (P <.04), age greater than 40 years (P <.001), and septal fibrosis (P =.007). In genotype 3-infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors (P <.001). Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively (P <.001 both comparisons). In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment (P <.001). Steatosis was associated with HCV genotype 3, triglycerides, high body mass index, age, fibrosis stage, and lower virologic response to treatment. In conclusion, sustained disappearance of the virus is associated with reduction of steatosis in genotype 3 as well as a correction of baseline low serum cholesterol.

Keeffe EB, Dusheiko GM, Tong MJ, Hollinger FB, Heathcote EJ, McHutchison J, Albert D. · Stanford University Medical Center, Palo Alto, CA 94304-1509, USA. · Cytokines Cell Mol Ther. · Pubmed #10850385 No free full text.

Abstract: We assessed differences in the pattern of HCV RNA decrease for HCV genotypes 1, 2, and 3 during interferon treatment to determine if the lower response rates observed among genotype 1 patients were related to a slower decrease in HCV clearance. Serum HCV RNA values of 472 chronic hepatitis C patients treated with either consensus interferon (CIFN) or interferon alfa-2b (IFN alfa-2b) were evaluated. Neither virological sustained responders nor relapsers differed in the pattern of serum HCV RNA decrease based on genotype. Virological sustained responders infected with genotype 1 cleared HCV RNA as rapidly as sustained responders who were infected with genotype 2 or 3. Relapsers had a slower rate of serum HCV RNA decrease than did virological sustained responders. Nonresponders differed in the pattern of serum HCV RNA decrease based on genotype: HCV genotype 3 patients had the greatest decrease in serum HCV RNA; genotype 2 patients had an intermediate decrease; and genotype 1 patients had the least serum HCV RNA decrease. HCV genotype 1 patients treated with CIFN had a greater decrease in serum HCV RNA during therapy than did patients treated with IFN alfa-2b. However, there was no difference in the magnitude of serum HCV RNA decrease between the two interferon treatments for patients infected with genotype 2 or 3. In summary, both genotype and ultimate response to treatment are determinants of the pattern and rate of serum HCV RNA change during interferon therapy of chronic hepatitis C.

Nyberg L, Albrecht J, Glue P, Gianelli G, Zambas D, Elliot M, Conrad A, McHutchison J. · Division of Gastroenterology/Hepatology, Scripps Clinic and Research Foundation, La Jolla, California 92037, USA. · J Clin Gastroenterol. · Pubmed #10372927 No free full text.

Abstract: Ribavirin, a nucleoside analogue, inhibits replication of RNA and DNA viruses and may control hepatitis C virus (HCV) infection through modulation of anti-inflammatory and antiviral actions. Ribavirin monotherapy has no effect on serum HCV RNA levels. In combination with interferon, this agent appears to enhance the efficacy of interferon. The aim of this study was to monitor serum HCV RNA levels early during therapy with interferon and ribavirin compared with that previously seen in the same patients during interferon monotherapy. Five patients who previously showed no response to therapy with interferon alfa 3 MU three times weekly for 6 months were retreated with the identical dose of interferon alfa 2b in combination with oral ribavirin 1,000 mg/day. Serum HCV RNA levels were monitored at baseline, week 4, week 8, and week 12 of therapy by a quantitative multicycle polymerase chain reaction assay. In the first 8 to 12 weeks, serum HCV RNA levels showed a greater decrease in all patients when retreated with combination therapy compared with interferon alone. Mean (+/- SEM) serum HCV RNA levels for interferon therapy alone were 3.3 +/- 0.95, 1.2 +/- 0.95, 1.6 +/- 1.2, and 2.3 +/- 1.2 x 10(6) copies/ml at week 0, 4, 8, and 12, respectively. This was compared with 3.3 +/- 0.83, 0.3 +/- 0.2, 0.03 +/- 0.02, and 0.15 +/- 0.14 x 10(6), respectively, for the interferon and ribavirin group (p < 0.07 at week 8). Two of five patients had undetectable serum HCV RNA during combination therapy. Combination therapy with interferon and ribavirin in prior interferon nonresponders reduces serum HCV RNA levels compared with interferon alone. This may suggest some additional antiviral effect of ribavirin when given with interferon.

Jhaveri R, McHutchison J, Patel K, Qiang G, Diehl AM. · Division of Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. · J Infect Dis. · Pubmed #18177246 links to  free full text

Abstract: BACKGROUND: Steatosis is a common histological finding and a poor prognostic indicator in patients with hepatitis C virus (HCV) infection. In HCV genotype 3-infected patients, the etiology of steatosis appears to be closely correlated with unknown viral factors that increase intracellular lipid levels. We hypothesize that specific sequence polymorphisms in HCV genotype 3 core protein may be associated with hepatic intracellular lipid accumulation. METHODS: Using selected serum samples from 8 HCV genotype 3-infected patients with or without steatosis, we sequenced the HCV core gene to identify candidate polymorphisms associated with increased intracellular lipid levels. RESULTS: Two polymorphisms at positions 182 and 186 of the core protein correlated with the presence (P= .03) and absence (P= .005) of intrahepatic steatosis. Transfected liver cell lines expressing core protein with steatosis-associated polymorphisms had increased intracellular lipid levels compared with non-steatosis-associated core isolates, as measured by oil red O staining (P= .02). Site-specific mutagenesis performed at positions 182 and 186 in steatosis-associated core genes yielded proteins that had decreased intracellular lipid levels in transfected cells (P= .03). CONCLUSIONS: We have identified polymorphisms in HCV core protein genotype 3 that produce increased intracellular lipid levels and thus may play a significant role in lipid metabolism or trafficking, contributing to steatosis.

Jhaveri R, Grant W, Kauf TL, McHutchison J. · Division of Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC 27705, USA. · J Pediatr. · Pubmed #16615966 No free full text.

Abstract: OBJECTIVE: To quantify the burden of pediatric hepatitis C virus (HCV) disease over the coming decade. STUDY DESIGN: Using national Census results and published and unpublished data, we constructed estimates of HCV prevalence, incidence, rate of vertical transmission, sustained viral response (SVR), and severe complications of infection. Using these figures, we generated a projection model for pediatric HCV outcomes, and we then performed a sensitivity analysis by altering the rates of fibrosis development and SVR. RESULTS: A prevalence of 23,048 to 42,296 pediatric patients with chronic HCV combined with 7200 new cases from vertical transmission was used for further calculations. Over the next decade, estimated screening costs were 26 million US dollars, monitoring costs ranged from 117 million US dollars to 206 million US dollars, and treatment costs ranged from 56 million US dollars to 104 million US dollars. CONCLUSIONS: To date, pediatric HCV has received relatively little attention, but it will have a significant economic impact over the next 10 years if changes in practice are not made.

Powers KA, Ribeiro RM, Patel K, Pianko S, Nyberg L, Pockros P, Conrad AJ, McHutchison J, Perelson AS. · Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA. · Liver Transpl. · Pubmed #16447184 links to  free full text

Abstract: Improved understanding of hepatitis C virus (HCV) dynamics during and after liver transplantation can be useful in optimizing antiviral therapy in transplant recipients. We analyzed serum HCV ribonucleic acid (RNA) levels during and after cadaveric liver transplantation in 6 HCV patients. After removal of the liver and before the new liver started producing virions, HCV RNA levels dropped with an average half-life (t(1/2)) of 0.8 hours. Viral loads then continued to drop up to 23 hours postimplantation (t(1/2) = 3.4 hours), and began to rise (doubling-time = 2.0 days) as soon as 15 hours after the anhepatic phase. In 3 patients the viral load reached a plateau before rising, suggesting that a nonhepatic source supplied virions and balanced their intrinsic clearance. However, from the decline in viral load over the first 24 hours of the postanhepatic phase, we estimate that nonhepatic sources can at most correspond to 4% of total viral production, 96% of which occurs in the liver, even after we corrected for fluid exchanges during surgery. As the new liver was reinfected, production increased and viral load rose to a new steady state. Using nonlinear regression, we were able to fit the patients' HCV RNA data to a viral dynamic model and estimate the de novo infection rate (mean 1.5 x 10(-6) mL/virion/day), as well as the average percentage of hepatocytes infected at the posttransplantation steady state (19%). In conclusion, we have quantified liver reinfection dynamics in the absence of posttransplantation antiviral therapy. Our findings support the notion that early antiviral therapy may delay or prevent reinfection.

McHutchison J, Zekry A. · Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27705, USA. · Nat Clin Pract Gastroenterol Hepatol. · Pubmed #16265063 No free full text.

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Terrault NA, Pawlotsky JM, McHutchison J, Anderson F, Krajden M, Gordon S, Zitron I, Perrillo R, Gish R, Holodniy M, Friesenhahn M. · Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143-0538, USA. · J Viral Hepat. · Pubmed #16108760 No free full text.

Abstract: SUMMARY: Both absolute viral load and log decline in viral load from baseline were found clinically useful in predicting sustained virological response and lack of sustained virological response (non-sustained virological response, NSVR) to treatment. We assessed the clinical utility of hepatitis C virus (HCV) RNA quantitation and changes in viral load using the VERSANT HCV RNA 3.0 Assay (bDNA) in 351 HCV-infected individuals treated with interferon plus ribavirin. We show that viral load decision thresholds provided negative predictive values (NPVs) of >95% at week 4 using a 100 000 IU/mL cut-off and at weeks 8 and 12 using 10 000 IU/mL cut-offs. A 2-log decline from baseline provided NPVs >95% at weeks 8 and 12. Combinations of absolute viral loads and changes in viral load from baseline did not enhance the performance of the decision rules for predicting NSVR. The positive predictive values (PPVs) at weeks 8 and 12 were 59.1 and 67.3%. This study highlights the critical importance of viral quantitation in gauging therapeutic response in patients with chronic HCV infection on antiviral therapy. Early changes in viral load, measured as absolute viral loads or change in viral load from baseline, are highly predictive of NSVR at 8 and 12 weeks. PPVs are modest but these data may provide encouragement to patients who are in the early phases of treatment when side effects are frequent. Additionally, we demonstrated the need for cautious interpretation of stopping rules when the values are at or near the decision thresholds.

Pockros PJ, Duchini A, McMillan R, Nyberg LM, McHutchison J, Viernes E. · Division of Gastroenterology and Hepatology, Scripps Clinic, La Jolla, California 92037, USA. · Am J Gastroenterol. · Pubmed #12190174 No free full text.

Abstract: OBJECTIVE: Hepatitis C virus (HCV) infection has been associated with the production of autoantibodies and the development of several autoimmune disorders. Immune thrombocytopenic purpura (ITP) is an immune-mediated syndrome of unknown etiology characterized by the presence of autoantibodies against platelet membrane proteins. METHODS: Retrospective chart review. RESULTS: Seven patients with chronic HCV infection (five with cirrhosis and two with chronic active hepatitis) developed thrombocytopenia, out of proportion to their liver disease, and were diagnosed with ITP based on the presence of anti-platelet antibodies and their response to treatment. The number of patients with ITP which occurred in a population of 3440 HCV patients seen over this time interval is much greater than would be expected by chance (p < 0.00001). Six patients required treatment and four required hospitalization. Four of the six responded to corticosteroids alone. Both of the patients who failed to respond to corticosteroids responded to cyclophosphamide. No mortality occurred from complications of thrombocytopenia. CONCLUSIONS: ITP occurs more commonly in patients with chronic HCV infection than would be expected by chance. This should be considered in patients with liver disease and unexplained thrombocytopenia, as well as in patients with newly diagnosed ITP. Evaluation of antiplatelet antibodies, using an antigen-specific assay, was useful in supporting this diagnosis. Therapy with either corticosteroids or cyclophosphamide was successful in the six patients who required treatment.

Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, Ling MH, Albrecht J. · Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Université Paris VI, Paris, France. · Gastroenterology. · Pubmed #11984517 No free full text.

Abstract: BACKGROUND & AIMS: Liver fibrosis is an important prognostic factor in patients with hepatitis C. The effect of pegylated (PEG) interferon alone or its combination with ribavirin on fibrosis has not been established. METHODS: We pooled individual data from 3010 naive patients with pretreatment and posttreatment biopsies from 4 randomized trials. Ten different regimens combining standard interferon, PEG interferon, and ribavirin were compared. The impact of each regimen was estimated by the percentage of patients with at least 1 grade improvement in the necrosis and inflammation (METAVIR score), the percentage of patients with at least 1 stage worsening in fibrosis METAVIR score, and by the fibrosis progression rate per year. RESULTS: Necrosis and inflammation improvement ranged from 39% (interferon 24 weeks) to 73% (optimized PEG 1.5 and ribavirin; P < 0.001). Fibrosis worsening ranges from 23% (interferon 24 weeks) to 8% (optimized PEG 1.5 and ribavirin; P < 0.001). All regimens significantly reduced the fibrosis progression rates in comparison to rates before treatment. The reversal of cirrhosis was observed in 75 patients (49%) of 153 patients with baseline cirrhosis. Six factors were independently associated with the absence of significant fibrosis after treatment: baseline fibrosis stage (odds ratio [OR] = 0.12; P < 0.0001), sustained viral response (OR = 0.36; P < 0.0001), age < 40 years (OR = 0.51; P < 0.001), body mass index < 27 kg/m(2) (OR = 0.65; P < 0.001), no or minimal baseline activity (OR = 0.70; P = 0.02), and viral load < 3.5 millions copies per milliliter (OR = 0.79; P = 0.03). CONCLUSIONS: PEG-interferon and ribavirin combination significantly reduces the rate of fibrosis progression in patients with hepatitis C.

Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht J. · Service d'Hépato-gastroentérologie, Groupe Hospitalier Pitié-Salpêtriére, Paris, France. · J Hepatol. · Pubmed #11434620 No free full text.

Abstract: BACKGROUND AIMS: In hepatitis C there is controversy over the linearity of the rate of progression and the significance of gender, mode of infection and viral factors. METHODS: 2313 untreated patients with a reliable estimated duration of infection and liver fibrosis were included. Fibrosis progression was calculated using the Kaplan-Meier method and the rate of fibrosis progression using the hazard function. Seven risk factors were assessed: age at biopsy, gender, alcohol consumption, mode of infection, activity grade, hepatitis C virus genotype and RNA level. RESULTS: The percentage of patients without cirrhosis was 91% after 20 years of infection (95% CI:90-92%) and 56% after 40 years (95% CI:48-64%). Three independent factors were associated (P < 0.001) with a faster progression rate: age at infection, alcohol consumption of 50 g or more per day, and male gender. The mode of infection, histologic activity, genotype and viral load were not independently associated with fibrosis. Fibrosis progression was mainly dependent on age and the duration of infection and can be divided into four successive periods with very slow, slow, intermediate and rapid progression rates. CONCLUSION: In patients infected with hepatitis C, the majority of fibrosis progression occurred in those aged fifty years or older.

Poynard T, McHutchison J, Davis GL, Esteban-Mur R, Goodman Z, Bedossa P, Albrecht J. · Service d'Hépato-Gastroentérologie Groupe Hospitalier Pitié-Salp etrière, Université Paris VI, Paris, France. · Hepatology. · Pubmed #11050066 No free full text.

Abstract: The extent of liver fibrosis is an important prognostic factor in patients infected with hepatitis C virus. Administration of a combination of interferon and ribavirin produces a superior viral clearance response rate than interferon alone. The effect of this combination regimen on hepatic fibrosis has not been established. To determine the impact of combination regimen or interferon alone on the progression of liver fibrosis we pooled individual data of 1,509 patients with pretreatment and post-treatment biopsies from 3 randomized trials. Fibrosis progression and regression rates between biopsies were calculated by the Kaplan-Meier method and by the fibrosis progression rate per year. The percentage of patients without significant fibrosis (stage 0 or 1) at 96 weeks was 68 +/- 4% (mean +/- SE) when treated by combination regimen for 48 weeks, 64 +/- 4% by interferon alone for 48 weeks, 42 +/- 7% by combination regimen for 24 weeks (lower than both 48-week regimens P <.001), and 24 +/- 9% interferon alone for 24 weeks (lower than the combination regimen for 24 weeks; P =.02). Three factors were independently associated with fibrosis reduction: sustained viral response, duration of treatment, and baseline fibrosis stage (all P <.001 in proportional hazards regression model). These results show that interferon and ribavirin combination therapy significantly reduces the rate of fibrosis progression in patients with hepatitis C. This effect was most prominent in patients who achieved a virologic response, those receiving 48 weeks of therapy, and in patients with significant fibrosis at baseline.

McHutchison J. · Division of Gastroenterology/Hepatology, Scripps Clinic and Research Foundation, La Jolla, California, USA. · Health News. · Pubmed #11019670 No free full text.

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Schmid P, Tong M, Conrad A, McHutchison J, Blatt LM. · National Genetics Institute, Los Angeles, CA, USA. · J Virol Methods. · Pubmed #10894636 No free full text.

Abstract: Prior to the discovery of the hepatitis C virus (HCV), virological analysis of serum from patients with non-A non-B hepatitis was not possible. Since the finding that HCV is the causative agent of most non-A non-B hepatitis, several reliable methodologies have been developed that allow for quantification of HCV RNA. To determine the viability of stored serum samples for HCV RNA analysis. 256 samples were examined for HCV RNA using a multi-cycle RT-PCR assay. All samples were stored unopened in a -70 degree C freezer until the time of testing. Collection years ranged from 1981 to 1995. To examine the integrity of stored serum samples, the distribution of quantitative HCV RNA values for each year was compared: year-to-year; and, to the distribution of HCV RNA concentrations from 1510 chronic HCV patients determined by the same assay in 1996 and 1997. Pairwise year-to-year analysis revealed that samples collected prior-to-and-including 1991 had significantly lower HCV RNA concentrations as compared to samples collected after 1991 (P < 0.001). Likewise, comparison of the stored samples to the 1510 fresh samples demonstrated that samples collected prior-to-and-including 1991 had significantly lower HCV RNA concentrations as compared to samples collected after 1991 (P < 0.001). The results demonstrate a method for determination of the integrity of stored serum samples from chronic HCV patients. The mechanism of RNA degradation is unknown but it is most likely to be due to poor sample collection procedures in place prior to 1991.

McHutchison J. · Scripps Clinic and Research Foundation, Division of Gastroenterology/Hepatology, La Jolla, California 92037, USA. · Am J Med. · Pubmed #10653459 No free full text.

Abstract: Until recently, interferon was the only approved therapy for previously untreated patients with chronic hepatitis C. Unfortunately, the majority of patients do not respond to this regimen, and rates of sustained virologic response were a disappointingly low 15% to 20%. Clearly, more effective treatment for this infection was needed. The nucleoside analogue ribavirin is now approved for administration in combination with interferon to treatment-naïve individuals with hepatitis C (HCV) infection as well as HCV-positive patients who have relapsed after interferon monotherapy. Results of a recent US multicenter trial in treatment-naïve patients with chronic hepatitis C demonstrate that combination therapy with interferon plus ribavirin produces sustained virologic response rates that are two to three times higher than those obtained with interferon alone. Rates of sustained virologic response (defined as undetectable serum HCV-RNA levels 24 weeks after completion of treatment) were 6% vs 31% after 24 weeks of interferon alone vs interferon plus ribavirin, respectively. For 48 weeks of treatment, rates of sustained virologic response were 13% and 38% with monotherapy and combination therapy, respectively. These results, which are consistent with those obtained in smaller preliminary trials and in a recently completed international multicenter trial, suggest that combination therapy with interferon and ribavirin may be preferable to monotherapy as first-line treatment for patients with chronic HCV infection.

Poynard T, McHutchison J, Goodman Z, Ling MH, Albrecht J. · Service d'Hépato-Gastroentérologie Groupe Hospitalier Pitié-Salpêtrière, Université Paris VI, Paris, France. · Hepatology. · Pubmed #10613748 No free full text.

Abstract: Randomized trials have shown the enhancement of efficacy with interferon alfa-2b and ribavirin (IFN-R) in comparison with interferon monotherapy (IFN) as first line treatment of chronic hepatitis C. Further definition of response based on disease, patient, and treatment characteristics is needed to determine the degree of benefit for the various patient subgroups. The aim of this study was to answer this question by analyzing the data from 1,744 naive patients included in trials that compared 24- or 48-week IFN-R treatment. Response factors were identified by logistic regression and receiver operating characteristics curves. Five independent characteristics were associated with a sustained loss of hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment: genotype 2 or 3, baseline viral load less than 3.5 million copies/mL, no or portal fibrosis, female gender, and age younger than 40 years. There was a significant advantage for IFN-R in comparison with IFN alone whatever the combination of factors. The most efficient strategy is to treat all patients for 24 weeks. If the 24-week polymerase chain reaction (PCR) is positive, treatment can be stopped. If the 24-week PCR is negative, patients with fewer than 4 favorable factors should be treated for an additional 24 weeks. Conclusion: The combination of IFN-R is better as first line treatment than IFN monotherapy. For patients who are PCR negative after 24 weeks of treatment, genotyping and baseline viral load, fibrosis stage, gender, and age are useful predictive factors in determining whether to continue an additional 24 weeks of treatment.

Pianko S, McHutchison J. · Division of Gastroenterology/Hepatology, Scripps Clinic and Research Foundation, La Jolla, CA 92037, USA. · Lancet. · Pubmed #10568564 No free full text.

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Heathcote J, McHutchison J, Lee S, Tong M, Benner K, Minuk G, Wright T, Fikes J, Livingston B, Sette A, Chestnut R. · Toronto Hospital, Western Division, Toronto, Ontario, Canada. · Hepatology. · Pubmed #10421664 No free full text.

Abstract: Clinical observations suggest that eradication of the hepatitis B virus (HBV) is immune-mediated. Vigorous cytotoxic T lymphocyte (CTL) activity directed at HLA class I-bound viral epitopes are detected during acute hepatitis B, but not in chronic hepatitis B carriers. A CTL epitope derived from the hepatitis B core protein amino acids 18-27 has been incorporated into a vaccine also comprised of a T-helper cell epitope and 2 palmitic acid residues (CY-1899). The aim of this study was to determine whether repeated doses of CY-1899 given to patients with chronic hepatitis B could initiate in vivo CTL activity and viral clearance. Patients with chronic hepatitis B received up to 4 doses (ranging from 0.05 mg to 15 mg) 6 weeks apart. Following vaccination, patients were monitored for hepatitis B surface antigen and "e" status, HBV-DNA levels, liver biochemistry, CTL activity, and any adverse events. Ninety patients with chronic hepatitis B infection received CY-1899. Mean CTL responses were all low but were maximal following vaccination with 5 mg CY-1899. Peak CTL responses never exceeded 10 lytic units (LU) regardless of vaccine dose, this value being well below that seen following resolution of acute hepatitis B. No significant changes in liver biochemistry or viral serology were observed during follow-up. No serious adverse events were noted. Administration of the single-epitope vaccine, CY-1899, initiated CTL activity, but of a magnitude lower than that observed during spontaneous HBV clearance. This low-level CTL activity was not associated with viral clearance.

Tillmann H, Patel K, McHutchison J. · No affiliation provided · Hepatology. · Pubmed #19177581 No free full text.

This publication has no abstract.