Michael W. Fried

Transjugular intrahepatic portosystemic shunt for the management of severe venoocclusive disease following bone marrow transplantation.

Hepatic venoocclusive disease (VOD) is a common, life‐threatening complication of bone marrow transplantation (BMT). Portal hypertension is usually present and accounts for many of the clinical manifestations of this syndrome. We describe the results of transjugular intrahepatic portosystemic shunt (TIPS) for the management of VOD after BMT TIPS was performed in six patients with histologically confirmed VOD who had progressive jaundice and ascites. Portal hypertension was improved by TIPS in all patients (mean portal pressure gradient before TIPS, 20.2 +/‐ 4.6 vs. 6.7 +/‐ 1.9 mm Hg post‐TIPS, P < .004). Three patients who underwent TIPS late in the course of VOD did not demonstrate any clinical improvement after TIPS and expired within 2 weeks of the procedure. The remaining three patients had less advanced disease and demonstrated decreases in serum bilirubin, improvement in coagulopathy, and decreased ascites after TIPS. Two patients subsequently expired, one with persistent histological changes of VOD. The lone survivor continues to do well with resolution of ascites, jaundice, and coagulopathy as of her last outpatient visit. TIPS was an effective method for portal decompression in patients with VOD after BMT, and was associated with clinical improvement in some patients. However, these effects may be transient and may not improve overall survival.

Prospective Multicenter Clinical Evaluation of AMPLICOR and COBAS AMPLICOR Hepatitis C Virus Tests

ABSTRACT We conducted a multicenter clinical evaluation of the second versions of the manual AMPLICOR and the semiautomated COBAS AMPLICOR tests for hepatitis C virus (HCV) RNA (Roche Molecular Systems, Inc., Pleasanton, Calif.). The performance characteristics of these HCV RNA tests for diagnosis of active viral infection were determined by comparison to anti-HCV serological test results, alanine aminotransferase levels, and liver biopsy histology results. A total of 878 patients with clinical or biochemical evidence of liver disease were enrolled at four hepatology clinics. A total of 1,089 specimens (901 serum and 188 plasma) were tested with the AMPLICOR test. Sensitivity compared to serology was 93.1% for serum and 90.6% for plasma. The specificity was 97% for serum and 93.1% for plasma. A total of 1,084 specimens (896 serum and 188 plasma) were tested with the COBAS test. Sensitivities for serum and plasma were the same as with the AMPLICOR test. The specificity was 97.8% for serum and 96.6% for plasma. Of the 69 specimens with false-positive and false-negative AMPLICOR test results relative to those of serology, alternative primer set (APS) reverse transcription (RT)-PCR analysis showed that the AMPLICOR test provided the correct result relative to the specimens containing HCV RNA in 64 (92.7%) specimens. Similarly, 66 of 67 (98.5%) false-positive and false-negative COBAS test results were determined to be correct by APS RT-PCR analysis. There were no substantive differences in clinical performances between study sites, patient groups, specimen types, storage conditions (−20 to −80°C versus 2 to 8°C), or anticoagulants (EDTA versus acid citrate dextrose) for either test. Both tests showed >99% reproducibility within runs, within sites, and overall. We conclude that these tests can reliably detect the presence of HCV RNA, as evidence of active infection, in patients with clinical or biochemical evidence of liver disease.

THERAPY OF CHRONIC VIRAL HEPATITIS

Interferon alpha is effective therapy for patients with chronic hepatitis B and hepatitis C. Only 20% to 40% of patients, however, have a sustained benefit from therapy. For the majority of patients with these diseases, alternative forms of therapy are needed. Nucleoside analogues appear to be extremely promising for the treatment of chronic hepatitis B and will undoubtedly play a major role in the management of this disease. For chronic hepatitis C, prolonged therapy with interferon, improved patient selection, and combined therapy with multiple agents such as ribavirin may lead to an improved therapeutic response.

A Pilot Study of Rimantadine for Patients With Chronic Hepatitis C Unresponsive to Interferon Therapy

A pilot study of rimantadine for patients with chronic hepatitis C unresponsive to interferon therapy

Serum hyaluronic acid in patients with veno-occlusive disease following bone marrow transplantation

The development of hepatic veno-occlusive disease following bone marrow transplantation is associated with high-dose combination cytoreductive therapy. Experimental models have suggested that drug-induced injury to hepatic sinusoidal endothelial cells is involved in the pathogenesis of this syndrome. Hyaluronic acid is a polysaccharide that is metabolized, almost exclusively, by hepatic sinusoidal endothelial cells. The aim of the present study was to evaluate serum hyaluronic acid as a marker for endothelial cell injury in patients with veno-occlusive disease following bone marrow transplantation. Hyaluronic acid was measured in sera from patients with and without veno-occlusive disease using an enzyme-linked protein binding assay. Mean peak serum hyaluronic acid levels were significantly greater in patients who had a diagnosis of VOD compared to those transplant patients who did not, 1173.4 ± 982.9 vs 444.9 ± 735.6 ng/ml (P = 0.01). Serial serum samples obtained from a separate cohort of patients also demonstrated that serum hyaluronic acid levels were higher in patients with moderate or severe veno-occlusive disease compared to those with none or mild disease at days 7, 17 and 25 following transplantation (greatest difference at day 25: 366 ± 327 vs126 ± 151, P = 0.01). Serum hyaluronic acid levels are increased in veno-occlusive disease and increase over time in patients with severe disease. Further studies are required to determine if elevated serum hyaluronic acid levels are due to decreased clearance by injured hepatic sinusoidal endothelial cells or increased production from early hepatic fibrogenesis associated with the acute liver injury. Bone Marrow Transplantation (2001) 27, 635–639.

Evaluation of two methods for quantitation of hepatitis C virus RNA

Background: Accurate quantitation of hepatitis C virus (HCV) RNA in serum may provide a means to predict disease course and response to interferon-alpha therapy. Several quantitative assays are commercially available, but none have been accepted as the gold standard. Methods and Results: The branched DNA quantitative hybridization assay (Quantiplex HCV 1.0, Chiron, Emeryville, CA) and a quantitative reverse transcription polymerase chain reaction (Amplicor HCV MONITOR, Roche Diagnostic Systems, Branchburg, NJ) were compared using a panel of 53 sera from patients with chronic hepatitis C. All sera contained HCV RNA of known genotype. Overall, there was a positive correlation between the results for the 41 sera that gave discrete values in both tests (r =.81, linear regression; P <.01, Kendalls rank test); however, the mean number of HCV copies per milliliter was 13.5-fold higher with Quantiplex (P <.01). A plot of the difference between methods against their means showed poor agreement between the methods. No correlation between the results of the two tests was observed for sera with MONITOR values greater than 5.0 x 10(5) copies/mL. Discrete MONITOR values were obtained for all 12 sera that were below the lower limit of quantitation of Quantiplex (mean, 1.78 x 10(5)). Parallel testing of serial dilutions of two sera showed that each method gave linear responses over the stated dynamic ranges; however, the proportional systematic error was greater with MONITOR. The mean coefficient of variation for replicate determinations was 23% for Quantiplex and 45% for MONITOR (P =.13). Conclusions: Despite a positive correlation, systematic differences exist between the two methods for quantitation of HCV RNA and they cannot be used interchangeably.

Clinical application of hepatitis C virus genotyping and quantitation.

Genotyping and quantitation of hepatitis C virus have provided great insights into the pathogenesis of chronic hepatitis C. The assays that are currently available for characterizing HCV remain powerful research tools that will be invaluable in future studies of the next generation of antiviral agents for the treatment of hepatitis C in much the same way that they have provided information about the effectiveness of interferon. Retrospective studies have demonstrated that HCV genotype and viral burden may play some role in disease progression and response to therapy. However, their utility in daily clinical practice in making decisions about treatment regimens or monitoring therapy in an individual patient remains difficult to define. As newer, more effective treatment strategies evolve (longer duration of treatment, combination therapy), previously identified predictors of disease severity or response to treatment may no longer be applicable.

Twice Daily Dosing of Telaprevir for Treatment-Naive and Treatment-Experienced Patients with Hepatitis C Infection

Background & Aims: Twice daily dosing of telaprevir in combination with peg interferon/ribavirin has not been extensively studied in treatment-naive and treatment-experienced genotype 1 HCV patients, including a “real-world” setting. The purpose of this study was to assess the effectiveness and safety of telaprevir dosed at 1125 mg Q12 hr in treatment-naive and treatment-experienced patients with genotype 1 chronic HCV infection in both a clinical study and “real-world” setting. Methods: A total of 163 subjects were evaluated in this study, including 103 treatment-naive and treatment-experienced HCV genotype 1 patients who were treated prospectively with telaprevir 1125 mg Q12 hr along with peg interferon/ribavirin. In addition, we reviewed “real-world” data from a large multicenter longitudinal database (HCV-TARGET) of 60 treatment-naive and treatment-experienced patients who received telaprevir dosed twice daily with peg interferon/ribavirin. Results: In a clinical study setting, the SVR 12 was 73% in treatment-naive/relapsers and 41% in prior treatment-failures while in a “real-world” setting, the SVR 12 was 64% and 33%, respectively. Overall, treatment discontinuation due to adverse events occurred in 21% of treatment-naive/relapsers and 53% of prior treatment-failures. Conclusions: In our study, response rates to telaprevir taken twice daily appear to be similar to published sustained virologic rates for telaprevir taken every 8 hours for treatment of genotype 1 HCV infection for both treatment-naive and treatment-experienced patients, although a lower SVR12 was seen in a “real-world” setting.