309 Quantitative tests (QLFTS) detect impaired hepatic function in a high proportion of chronic hepatitis C patients with fibrosis or compensated cirrhosis and may predict risk of cirrhosis, splenomegally, and varices

Abstract

Rationale: Pegylation of interferon-alfa results in an improved pharmacokinetic profile by maintaining constant blood levels, resulting in higher sustained response rates (SVR). However, modification of interferon-alfa by pegylation also reduces biologic potency. Delivery of a bio-optimized alpha interferon in an unmodified form (consensus interferon, Infergen(r)) by continuous infusion can be expected to provide sustained and constant levels of a fitly potent protein. We hypothesize that such an approach may potentially result in greater antiviral activity and improved tolerability by avoiding wide swings in interferon levels. Methods:We conducted a phase 2 pilot study to assess the safety, tolerability and viral kinetics of Infergen (12 t~g/day) by continuous infusion using a subcutaneous infusion device (Medtronic MiniMed(r) pump) in combination with ribavirin (1000 mg or 1200 mg daily). The MiniMed model 508 micro infusion pump is deared for use in the treatment of diabetes. HCV RNA viral levels were measured at days 1, 3, 7, 10, 14, 21, 28 and then at weeks 6 and 12. Results: Among 10 nonresponders treated to date with Infergen by continuous infusion with available early viral kinetics data, 7 showed a substantial reduction in HCV viral levels (at least 1 logm reduction in 4, and 2 logm reduction in 3). All 7 of these patients were genotype 1 and 6 had less than 1.0 logm decrease with prior treatment while I had a 1.5 logm decrease at similar time-points with other combination therapy [either pegylated interferon/RBV (4 pts) or interferon-alfa/RBV (3 pts)]. No serious adverse events were reported and 3 patients discontinued (2 due to moderate interferon-related side effects and I due to inability to acclimate to the pump). Other patients continuing on study experienced mild adverse events that have been tolerable. Conclusions: Consensus interferon administered by continuous delivery via the Medtronic MiniMed pump shows early substantial reduction of HCV RNA levels among nonresponder patients and shows a good safety and tolerability profile. Updated data on a total of 22 patients (including 10 na/'ve genotype 1 patients) will be presented.

Factors Affecting the Quantitative Liver?Spleen Scan in Normal Individuals

“…This study demonstrates that a postprandial value of the PHM <100 is abnormal and a value <90 probably reflects cirrhosis (1)(2)(3)(4). Preliminary reports from the baseline study in the prospective HALT-C trial found the postprandial PHM as measured by the methods in this study to be the single best noninvasive test of clinical liver disease including detection of cirrhosis, varices, and splenomegaly (39).…”

Portal‐systemic shunting in patients with fibrosis or cirrhosis due to chronic hepatitis C: the minimal model for measuring cholate clearances and shunt

“…In this study, we demonstrated that cholate Cl oral , using a cut‐off of 1300 mL/min, and shunt, using a cut‐off of 30%, may be useful in detecting patients with cirrhosis and varices – both tests were more sensitive than liver biopsy in detection of patients with varices. Previously we reported that cholate shunt and cholate Cl oral correlated with Ishak fibrosis score, variceal size and grade of portal hypertensive gastropathy at endoscopy, spleen size on ultrasonography and routine laboratory tests of liver dysfunction 5 . In addition, other analyses have indicated that cholate shunt and cholate Cl oral may be useful in prediction of response to anti‐viral therapy, 6, 7 and risk of future decompensation 8 .…”

“…In HALT‐C patients, cholate Cl oral and cholate shunt compared favourably to other quantitative tests of liver function. They correlated better with cirrhosis, varices, standard laboratory tests and response to anti‐viral therapy than caffeine elimination, antipyrine elimination and clearance, galactose elimination capacity, MEGX generation from lidocaine and methionine breath test 5–7 . In a study of other patients, cholate Cl oral and cholate shunt were better than caffeine elimination or antipyrine elimination and clearance in identifying patients at risk of future decompensation 8 …”

“…For this analysis we used 548 studies of 282 patients with CHC enrolled in the Hepatitis C Antiviral Long‐term Treatment against Cirrhosis (HALT‐C) Trial 9 who participated in the quantitative liver function test (QLFT) ancillary study 5 . HALT‐C patients are characterized by hepatic fibrosis (Ishak fibrosis scores 2–4) or compensated cirrhosis (Ishak fibrosis score 5 or 6), non‐response to prior courses of anti‐viral therapy, and exhibit a broad range of functional impairment 5 and clinical manifestations 10 . These results were compared with results from 32 healthy controls.…”

“…It is defined as the percentage of orally administered cholate that escapes hepatic extraction from the portal circulation. In recent studies primarily of patients with CHC, cholate shunt correlated with clinical manifestations of portal hypertension and response to anti‐viral therapy, 5–8 and was more sensitive than standard laboratory tests in detecting fibrotic stages of liver disease 5 . However, the method for measuring cholate shunt required a sampling period of 3 h and 14 samples of blood.…”