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J McHutchison

Publications and source records attributed to J McHutchison.

15 recordsLinked to original sources
PubMed2001

Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c.

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.

Adult↗
PubMed2001

Peginterferon alpha-2b: a new approach to improving response in hepatitis C patients.

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.

Animals↗
PubMed2000

Is an "a la carte" combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group.

UNLABELLED: 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.

Adult↗
PubMed2000

Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C.

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.

Adult↗
PubMed1999

Hepatitis C therapy in treatment-naïve patients.

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.

Antiviral Agents↗
PubMed1999

A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group.

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.

Adult↗
PubMed1999

Analysis of the viability of freezer stored serum samples for hepatitis C virus RNA analysis by the SUPERQUANT method: results of a 16 year retrospective study.

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.

Adult↗
PubMed1999

Changes in serum hepatitis C virus RNA in interferon nonresponders retreated with interferon plus ribavirin: a preliminary report.

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.

Adult↗
PubMed1999

Genotype does not affect pattern of HCV RNA decrease among responders during interferon treatment of chronic hepatitis C. Consensus Interferon Study Group.

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.

Antiviral Agents↗
PubMed1998

Is there an optimal time to measure quantitative HCV RNA to predict non-response following interferon treatment for chronic HCV infection?

BACKGROUND/AIMS: Current criteria to predict sustained response for a patient with chronic hepatitis C virus during interferon treatment are not consistent. The aim of this study was to determine a reliable point in time to predict non-response to therapy, as a theoretical basis for early cessation of treatment. METHODS: Sera (-70 degrees C) from 66 patients treated with interferon (3 million units three times a week for 6 months) were assayed with a quantitative polymerase chain reaction (sensitivity < or =100 copies per milliliter). Evaluations were made at baseline, during treatment at weeks 1, 2, 4, 12, and 24, and at follow-up week 48. Biochemical response was defined using standard alanine aminotransferase criteria. Virologic response was defined as: sustained if loss of HCV RNA persisted through therapy and follow-up; relapse if HCV RNA became undetectable but reappeared during treatment or follow-up; and non-response if HCV RNA remained detectable during the study period. Alanine aminotransferase and HCV RNA results were analyzed at defined time intervals to determine a predictive value for non-response and sustained response. RESULTS: HCV RNA results are a more accurate predictor than alanine aminotransferase for both non-response and sustained response. Serum HCV RNA predicted non-response better than sustained response. The optimal time to predict non-response with serum HCV RNA was treatment week 12. CONCLUSIONS: Treatment week 12 results indicate that HCV RNA was a more accurate predictor for non-response than serum alanine aminotransferase. This prediction would have theoretically permitted stopping treatment for 75% of the patients in this study at treatment week 12 allowing an overall cost savings of 28%.

Adult↗
PubMed1997

Autoimmune liver diseases.

Certain serum autoantibodies serve as useful diagnostic markers in AiLD; however, the etiology and pathogenesis of AiLD remain unknown. Although AiLD is characterized by the presence of autoantibodies and other humoral immune abnormalities, there is significant evidence that cell-mediated immune mechanisms are critical contributors to tissue injury in AiLD. The most sensitive and specific diagnostic immunologic marker for PBC is AMA. The availability of commercial kits that measure AMA directed against PDH-E2 (anti-M2) using ELISA may increase standardization of this test. AiH is characterized by the presence of ANA, SMA, and LKM. ANA are most commonly identified by IIFM using Hep-2 cells as substrate. IIFM is most commonly used to detect SMA and LKM, which, like AMA, can be identified using rodent (rat or mouse) combined kidney/stomach/liver tissue blocks as substrate. Most clinical laboratories with a capability to perform IIFMs therefore can identify the characteristic autoantibody patterns described in AiLD. As specific ELISAs become available, their widespread use in clinical laboratories also will facilitate the work-up of individuals with suspected AiLD.

Autoantibodies↗
PubMed1993

Systemic versus nonsystemic reperfusion of the transplanted liver.

Reperfusion of the orthotopically transplanted liver can result in severe hemodynamic instability. This instability can result in the postreperfusion syndrome (PRS), which includes decreases in mean arterial pressure (MAP), systemic vascular resistance (SVR), and heart rate, and increases in central venous pressure and pulmonary capillary wedge pressure. This syndrome appears to be mediated by the left ventricular mechanoreceptor reflex (LVMRR), which can be activated by changes in preload, afterload, or left ventricular contractility, and by the infusion of alkaloids or potassium into the right atrium. In an attempt to prevent activation of the LVMRR and PRS, we have inserted a cannula into the retrohepatic vena cava and have allowed the initial 500-600 cc of portal blood reperfusing hepatic allografts to be discarded. We compared this nonsystemic reperfusion (NSRP) of livers with systemic reperfusion (SRP), in which the initial portal blood reperfusing livers is allowed to enter the systemic circulation. In the NSRP group (n = 14) there was no decrease in MAP, heart rate, or SVR, and the serum potassium did not increase after reperfusion. In the SRP group (n = 14), six patients (42%) developed PRS and there were statistically significant decreases in MAP and SVR, and increases in pulmonary capillary wedge pressure and serum potassium, as compared with the NSRP group. In conclusion, NSRP results in less hemodynamic instability during reperfusion, and should be considered the preferred method for reperfusion of the transplanted liver.

Adult↗