U.S. multicenter pilot study of daily consensus interferon (CIFN) plus ribavirin for "difficult-to-treat" HCV genotype 1 patients.

BACKGROUND: Patients with chronic hepatitis C genotype 1 (HCV-1) and difficult-to-treat characteristics respond poorly to pegylated interferon alfa and ribavirin (RBV), and could benefit from an interferon with increased activity (consensus interferon or CIFN), favorable viral kinetics from daily dosing, and a longer duration of therapy. The purpose of this pilot study was to determine the efficacy and safety of daily CIFN + RBV for initial treatment of patients with HCV-1 infection. METHODS: Patients with difficult-to-treat characteristics (92% male, 33% African American, 78% Veterans Affairs [VA]; 67% high viral load, 59% stage 3-4 fibrosis, and mean weight of 204 lbs) were enrolled at seven VA and two community medical centers. They were randomized to daily CIFN (15 mcg/day SQ) and RBV (1-1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52-72 weeks (from time of viral response +48 weeks) (group B, n = 31). RESULTS: Intention to treat analysis for treatment groups A and B demonstrated 33% (11/33) and 32% (10/31) sustained virologic response (SVR), respectively. Only 2/31 patients in group B received more than 52 weeks of treatment. The overall group demonstrated a 31% (20/64) rapid virologic response rate (RVR), 54% (34/64) end of treatment virologic response and a 33% (21/64) SVR. Patients with RVR at 4 weeks, early virologic response from 8-12 weeks, and late virologic response from 16-24 weeks demonstrated SVR of 75% (15/20), 31% (4/13), and 22% (2/9), respectively. Overall early non-protocol discontinuation occurred in 26/64 (40%) patients. CONCLUSION: Daily CIFN and ribavirin for initial treatment of HCV-1 patients has potential for achieving a relatively high RVR rate, but discontinuations are frequent and successful use of this regimen is highly dependent on adequate patient support to maintain adherence.

Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis.

BACKGROUND/AIMS: Although the antiviral and histological benefits of peginterferon/ribavirin therapy are well established, the effects on health-related quality of life (HRQOL) and sexual health are less certain. This study assessed HRQOL and sexual health in patients with advanced fibrosis or cirrhosis in the HALT-C Trial. METHODS: Subjects completed SF-36 and sexual health questionnaires prior to and after 24 weeks of peginterferon/ribavirin therapy (n=1144). Three hundred and seventy-three (33%) subjects were HCV RNA negative at week 20 and continued therapy through week 48; 258 were seen at week 72. One hundred and eighty achieved sustained virological responses (SVR) and 78 relapsed. RESULTS: At baseline, patients had poorer scores for all eight SF-36 domains compared to healthy controls. Patients with cirrhosis had lower HRQOL scores than those with bridging fibrosis, as did patients with higher depression scores. SVR patients had significant improvements in seven domains, whereas relapsers had significant worsening in one domain. Sexual scores improved in SVR patients and decreased in relapsers (p=0.03). In multivariate analyses, improvements in HRQOL and sexual scores were significantly associated with SVR but were less striking in patients with lower depression scores. CONCLUSIONS: Achievement of SVR after peginterferon/ribavirin therapy improves HRQOL and sexual health in chronic hepatitis C patients with advanced fibrosis or cirrhosis.

Antiviral therapy for hepatitis C in the setting of liver transplantation.

Hepatitis C viremia after liver transplantation for hepatitis C virus (HCV) liver disease is universal. Progressive HCV disease after transplantation is the leading cause of death, graft failure, and retransplantation. Whether to treat, with which agents, and timing of therapy are unanswered questions. Timing options include pretransplantation, prophylactic, post-transplantation preemptive, and post-transplantation recurrence-based therapy. The latter is most commonly utilized. There are little data for each of these, much less comparisons. Pegylated interferon-alpha has supplanted standard interferon-alpha due to increased efficacy and is generally used in combination with ribavirin (RBV). Efficacy is less than in nontransplant settings due to immunosuppression, an increased prevalence of genotype 1 HCV, patient comorbidities, and decreased functional status. Administration of HCV therapy to cirrhotic patients prior to transplantation may eradicate or suppress HCV and prevent or reduce severity of recurrence. Sustained virological response (SVR) as high as 50% was attained in genotypes 2 or 3 HCV. Comparison of preemptive and histology-based post-transplantation HCV therapy should be done, and more data will be available on pretransplantation therapy. Post-transplant patients are less tolerant of therapy, particularly RBV. SVR, the primary goal of therapy, likely halts disease progression, but only 20% to 30% of treated patients achieve SVR. Preemptive therapy early after transplantation may have advantages due to the potential to delay or blunt severity of graft infection and recurrent hepatitis. In post-transplant therapy, RBV toxicity is attenuated in relation to decreased renal function, and side effects of interferon are more prominent. An ongoing trial will assess preemptive therapy with treatment after histologic recurrence. Novel anti-HCV therapies such as protease and polymerase inhibitors are emerging. These must be tested with urgency in the transplant setting. Retransplantation for progressive HCV disease is more controversial due to poor outcomes, graft shortage, and disease recurrence.

Rapid, accurate, and sensitive fatty acid ethyl ester determination by gas chromatography-mass spectrometry.

BACKGROUND: Fatty acid ethyl esters (FAEEs) are useful markers of ongoing alcohol use and may be associated with alcohol-induced damage to the liver and pancreas. In this article, we describe a novel method for rapid determination of the three major FAEEs found in human plasma. METHODS: Internal standard, ethyl heptadecanoate, was added to plasma samples, and FAEEs were isolated by acetone precipitation, hexane lipid extraction, and amino-propyl silica solid phase extraction. FAEEs were quantitated by gas chromatography-mass spectrometry (GC-MS) using a nonpolar dimethylpolysiloxane column. The accuracy, precision, specificity, and sensitivity of the assay were defined from plasma samples from recently drinking and abstinent persons, with and without the addition of FAEEs. RESULTS: Individual FAEE peaks demonstrated excellent resolution. Instrument time was reduced by more than 60%. The lower limit of detection was 5 to 10 nM, and the lower limit of quantitation for each FAEE was 60 nM (for 22 samples with known concentration 60 nM, x +/-SD: 61 +/- 5.7, 57 +/- 5.7, and 57 +/- 5.9 nM, for ethyl palmitate, ethyl oleate, and ethyl stearate, respectively). Instrument precision (coefficient of variance, CV) for these three FAEEs was 0.3%, 0.4%, and 0.7%, respectively. Intra-assay precision (CV) for total FAEEs was less than 7%. FAEEs were absent in 49 samples from abstinent persons. FAEEs were detected in all 76 samples with associated positive blood alcohol levels. CONCLUSIONS: Our method of FAEE analysis is rapid and potentially useful in research and clinical studies. FAEE determination using this method is precise, accurate, sensitive, and specific and deserves broader application.

Hepatitis C in alcohol dependence:drinking versus disulfiram.

Hepatitis C virus (HCV) infects alcohol dependent (AD) individuals disproportionately. Disulfiram for timely abstinence in HCV + AD cases remains controversial. Our literature review suggests that (1) active drinking accelerates HCV-related liver damage and that abstinence is associated both (2) with a slower course of HCV+ hepatic deterioration and (3) with enhanced response to antiviral HCV treatment. Further, (4) the risk of disulfiram liver injury appears much lower than that from alcohol, (5) HCV+AD individuals require close monitoring during the first 6 months of disulfiram treatment, and (6) early discontinuation of disulfiram usually reverses harmful effects when these occur. Although systematic data are sparse, continued drinking appears much more liver toxic than does disulfiram in this group. Disulfiram therapy may allow (1) prolonged abstinence leading to successful antiviral therapy for HCV, and (2) time to begin behavioral treatments that facilitate long-term abstinence. Sizeable prospective studies of HCV + AD treatment are badly needed.