Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study.

GOALS/BACKGROUND: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality. STUDY: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared. RESULTS: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%. CONCLUSIONS: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.

On-Treatment Elevation in Hepatic Transaminases during HCV Treatment with Ombitasvir, Paritaprevir, Dasabuvir, Ritonavir, and Ribavirin: A Case Series.

Eradication of chronic hepatitis C virus (HCV) infection is now possible with all oral antiviral medications, including the combination of ombitasvir, paritaprevir, dasabuvir, and ritonavir (PrOD) with or without ribavirin. While high rates of sustained virologic response (SVR) can be achieved, a small subset of patients experience on-treatment liver enzyme elevations, in particular women using concurrent estradiol-containing oral contraceptive medications (OCPs). Herein, we describe four cases of liver enzyme elevations within 2-3 weeks of PrOD initiation in African-American men infected with HCV genotype 1a or 1b. Three patients with varying degrees of hepatic fibrosis received a full treatment course without medication modification, achieved SVR, and experienced resolution of liver enzyme abnormalities. One patient with cirrhosis was switched mid-treatment to an alternate HCV regimen, experienced subsequent resolution of liver enzyme abnormalities, and achieved SVR. In summary, these cases suggest that all HCV patients treated with PrOD, independent of gender or concurrent medications, should have laboratory monitoring for liver enzyme elevations, with a particular emphasis on early monitoring in cirrhotic patients.

Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus.

UNLABELLED: Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus (HCV) have used, as their primary efficacy endpoint, a sustained virological response (SVR)­defined as HCV RNA levels below a designated threshold of quantification­24 weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun to accept SVR at 12 weeks post-treatment (SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However, the concordance between SVR12 and SVR24 has not been systematically assessed with new regimens of recently approved direct-acting antiviral agents. The aim of this study was to assess the concordance between SVR at various post-treatment time points in phase III clinical trials of sofosbuvir (SOF)-containing regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected with HCV genotypes 1-6. The concordance between SVR at 4 weeks post-treatment (SVR4) and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%) with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed post-therapy, 77.6% did so within 4 weeks of completing therapy. CONCLUSION: Data from phase III studies demonstrate that with SOF-based regimens, with or without interferon, SVR12 and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine "cure" rates in trials and in clinical practice.

Predictive value of FIB-4 and APRI versus METAVIR on sustained virologic response in genotype 1 hepatitis C patients.

PURPOSE: Advanced liver fibrosis is a negative predictor of virologic response in genotype 1 chronic hepatitis C (CHC) patients. Biopsy, however, is invasive, costly, and carries some risk of complications. METHODS: Using data from the prospective, international cohort study PROPHESYS, we assessed two alternative noninvasive measures of fibrosis, the FIB-4 and AST-to-platelet ratio index (APRI), to predict virologic response in CHC patients. RESULTS: CHC genotype 1, monoinfected, treatment-naive patients prescribed peginterferon alfa-2a (40 KD)/ribavirin in accordance with country-specific legal and regulatory requirements and who had baseline METAVIR, FIB-4, and APRI scores (N = 1,592) were included in this analysis. Patients were stratified according to the baseline METAVIR, FIB-4, or APRI score to assess virologic response [hepatitis C virus (HCV) RNA <50 IU/mL] by week 4 of treatment (rapid virologic response) and 24 weeks after untreated follow-up ]sustained virologic response (SVR)]. Baseline predictors of SVR were explored by multiple logistic regression, and the strength of the association between each fibrosis measure and SVR was evaluated. Both FIB-4 and APRI scores increased with increasing levels of biopsy-assessed fibrosis. The association between FIB-4 and SVR (p < 0.1 × 10(-30)) was stronger than that between METAVIR (p = 3.86 × 10(-13)) or APRI (p = 5.48 × 10(-6)) and SVR. Baseline factors significantly associated with SVR included male gender, lower HCV RNA, lower FIB-4 score, no steatosis, and higher alanine aminotransferase ratio. CONCLUSION: The FIB-4 index provides a valuable, noninvasive measure of fibrosis and can be used to predict virologic response in patients treated with peginterferon alfa-2a (40  KD)/ribavirin.

Evaluation of pharmacokinetics, user handling, and tolerability of peginterferon alfa-2a (40 kDa) delivered via a disposable autoinjector device.

BACKGROUND: Peginterferon alfa-2a (40 kDa) is currently administered using a prefilled syringe. The peginterferon alfa-2a disposable autoinjector is a new safety-engineered device designed to facilitate injection and reduce the risk of needlestick injuries. The analysis of two open-label Phase I trials evaluated the pharmacokinetics, successful administration, and tolerability of peginterferon alfa-2a when using the autoinjector. The studies were performed to support the filing and registration of the autoinjector device. METHODS: In trial 1, 50 healthy adult subjects received one 180 µg dose of peginterferon alfa-2a via the autoinjector. Serial blood samples were collected predose, up to 336 hours following drug administration, and at follow-up (28 ± 3 days post-dosing) for noncompartmental pharmacokinetic analysis. Trial 2 randomized 60 adult patients with chronic hepatitis C to 180 µg peginterferon alfa-2a once weekly by the autoinjector or prefilled syringe for 3 weeks followed by the alternative device (prefilled syringe or autoinjector, respectively) for 3 weeks. Patients also received ribavirin. Administration by the devices was evaluated under direct observation by a study staff member and by patient subjective assessment. RESULTS: In trial 1, following a single dose of peginterferon alfa-2a, the maximum plasma concentration was 16.1 ± 5.3 ng/mL (mean ± standard deviation), and area under the concentration time curve (0-168 hours) was 1996 ± 613 ng · hour/mL, similar to that reported using a vial/syringe or prefilled syringe. In trial 2, few patients showed handling difficulties with either device. Generally, patients were observed to be more satisfied and confident, followed instructions better, and successfully initiated injection with the autoinjector versus the prefilled syringe. Patients reported the autoinjector to be more convenient and easier to use. No pain or discomfort was experienced using the autoinjector. The autoinjector safety profile was consistent with that known for peginterferon alfa-2a/ribavirin. CONCLUSION: These results indicate that peginterferon alfa-2a can be successfully and safely delivered via the autoinjector and that the device is easy to handle.

Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine.

BACKGROUND: We previously established furanocoumarins as mediators of the interaction between grapefruit juice (GFJ) and the model CYP3A4 substrate felodipine in healthy volunteers using a GFJ devoid of furanocoumarins. It remains unclear whether furanocoumarins mediate drug-GFJ interactions involving CYP3A4 substrates that are also P-glycoprotein substrates. OBJECTIVE: The effects of furanocoumarin-free GFJ on drug disposition were further characterized by using the dual CYP3A4/P-glycoprotein substrate cyclosporine. DESIGN: By randomized crossover design, 18 healthy volunteers received cyclosporine (5 mg/kg) with 240 mL orange juice (control), GFJ, or furanocoumarin-free GFJ. Blood was collected over 24 h. Juice treatments were separated by > or = 1 wk. The effects of diluted extracts of each juice and of purified furanocoumarins on [3H]cyclosporine translocation in Caco-2 cells were then compared. RESULTS: The median (range) dose-corrected cyclosporine area under the curve and the maximum concentration with GFJ (P < or = 0.007), but not with furanocoumarin-free GFJ (P > or = 0.50), were significantly higher than those with orange juice [15.6 (6.7-33.5) compared with 11.3 (4.8-22.0) x 10(-3) h/L and 3.0 (1.6-5.8) compared with 2.4 (1.1-3.1) mL(-1), respectively]. The median time to reach maximum concentration and terminal elimination half-life were not significantly different between the juices (2-3 and 7-8 h, respectively; P > or = 0.08). Relative to vehicle, the GFJ extract, orange juice extract, and purified furanocoumarins partially increased apical-to-basolateral and decreased basolateral-to-apical [3H]cyclosporine translocation in Caco-2 cells, whereas the furanocoumarin-free GFJ extract had negligible effects. Reanalysis of the clinical juices identified polymethoxyflavones as candidate P-glycoprotein inhibitors in orange juice but not in GFJ. CONCLUSIONS: Furanocoumarins mediate, at least partially, the cyclosporine-GFJ interaction in vivo. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein.

A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction.

BACKGROUND: Grapefruit juice (GFJ) enhances the systemic exposure of numerous CYP3A4 drug substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. Furanocoumarins have been identified as major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear. OBJECTIVE: To ascertain whether furanocoumarins mediate the GFJ-felodipine interaction, a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine. DESIGN: With the use of food-grade solvents and absorption resins, furanocoumarins were removed (approximately 99%) from whole GFJ, whereas other major ingredients (flavonoids) were retained. In an open, 3-way, randomized crossover design, 18 healthy volunteers ingested felodipine (10 mg) with 1 of the 3 juices (240 mL). Blood was collected over 24 h. At least 1 wk elapsed between juice treatments. RESULTS: The median and range of the area under the curve and the maximum concentration of felodipine were significantly (P < 0.001) greater with consumption of GFJ [110 (range: 58-270) nmol . h/L and 21 (7.6-50) nmol/L, respectively] than with that of orange juice [54 (29-150) nmol . h/L and 7.6 (3.4-13.9) nmol/L, respectively] or furanocoumarin-free GFJ [48 (23-120) nmol . h/L and 8.3 (3.0-16.6) nmol/L, respectively]. GFJ, orange juice, and furanocoumarin-free GFJ did not differ significantly (P > 0.09) in median time to reach maximum plasma concentration [2.5 (1.5-6), 2.8 (1.5-4), and 2.5 (2-6) h, respectively] or terminal half-life [6.6 (4.2-13.6), 7.8 (4.4-13.2), and 6.8 (2.6-14.4) h, respectively]. CONCLUSION: Furanocoumarins are the active ingredients in GFJ responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism.

Impact of donor age and year of transplant on graft survival in liver transplant recipients with chronic hepatitis C.

Studies suggest donor age and year of transplantation are associated with low graft survival in liver transplant recipients with hepatitis C. We sought to determine if advanced donor age and recent year of transplantation are associated with graft survival in hepatitis C recipients and to determine if the effect of donor age on graft survival is specific to hepatitis C. We analyzed the United Network for Organ Sharing liver transplant database from 1994 to 2002. Six thousand four hundred and four subjects transplanted for end-stage liver disease from chronic hepatitis C met our criteria. One-year graft survival in hepatitis C recipients with organs from donors <40 years old and >or=60 years old was 84% and 73%, p = 0.003, respectively. These rates in recipients with cholestatic liver disease and alcoholic liver disease were 85% and 82%, respectively, p = 0.11 and 82% and 78%, respectively, p = 0.14. Three-year graft survival in hepatitis C recipients transplanted from 1994 to 1995 and 1996 to 1999 was 67% and 69%, respectively, p = 0.10. Graft survival in hepatitis C recipients has not declined in recent years. Older donor age is associated with lower short-term graft survival in recipients with hepatitis C, but not in recipients with cholestatic or alcoholic liver disease.

Practice patterns for long-term follow-up of adult-to-adult right lobectomy donors at US transplantation centers.

Protocols used by transplant centers to care for donors after right hepatectomy for living donor liver transplantation are not well described in the medical literature. Our goal is to describe practice patterns for the long-term follow-up of adult-to-adult right lobectomy donors at US transplantation centers. All adult liver transplantation centers listed with the United Network for Organ Sharing were surveyed between October and November 2002. A transplant coordinator, hepatologist, or surgeon from each center completed a 10-item telephone questionnaire. Of 97 adult liver transplantation centers, 90 centers (92.8%) completed the survey. Ninety-six percent of participants were transplant coordinators; 2%, hepatologists; and 2%, surgeons. One thousand forty-four right lobectomies have been performed by 51 (56.7%) transplant programs (range, 1 to 101 per center). Thirty-eight percent of active programs have performed fewer than 10 donation right lobectomies. Fifty-one percent of programs have a transplant coordinator who works specifically with donors. Thirty-five programs (68.3%) have a formal follow-up protocol, and an additional 13 centers (14.4%) reported their usual follow-up patterns. Protocols ranged from no formal follow-up to visits every few weeks in the early postoperative period followed by evaluation every 6 months. Evaluation beyond 12 months is typically on an as-needed basis. Personal psychosocial support services after donation were unusual and included regular phone calls from the coordinator (5 centers), quality-of-life instruments (3 centers), scheduled follow-up with the psychologist (1 center), or a satisfaction survey (1 center). Several centers provided newsletters, combined donor-recipient support groups, recognitions parties, and certificates. There is significant variability in the long-term care of donors. Formal psychosocial support after donation is rare.

MR imaging features of primary sclerosing cholangitis: patterns of cirrhosis in relationship to clinical severity of disease.

PURPOSE: To evaluate the spectrum of magnetic resonance (MR) imaging appearances of the liver in primary sclerosing cholangitis (PSC) and to examine their correlation with clinical stage of disease. MATERIALS AND METHODS: Fifty-two patients (25 female, 27 male; mean age, 43 years; age range, 11-87 years) with PSC underwent nonenhanced and gadolinium-enhanced MR imaging. Two abdominal radiologists retrospectively reviewed all images (independently and then in consensus) for the imaging pattern of the liver parenchyma, presence and grade of intrahepatic biliary ductal dilatation, and presence of areas of parenchymal atrophy or abnormal signal intensity and/or gadolinium enhancement. Imaging findings were correlated with Child class, Child-Turcotte-Pugh score, and Mayo end-stage liver disease (MELD) score. Statistical analyses (kappa scoring for interobserver agreement, McNemar test, Mann-Whitney U test, multiple regression analysis, Spearman correlation) were performed. RESULTS: Of 52 patients, seven (13%) had no imaging findings of cirrhosis, 17 (33%) had a diffuse pattern of cirrhosis, and 28 (54%) had a large macronodular pattern (with nodules >or=3 cm) (kappa = 0.84). Intrahepatic biliary ductal dilatation was observed in 44 (85%) patients and was general in 18 (35%) and segmental in 26 (50%). Peripheral wedge-shaped areas of parenchyma were observed with atrophy in 23 (44%) and 25 (48%) patients by the two readers (kappa = 0.76) and without atrophy in 18 (35%) patients by both readers (kappa = 1.00). No correlation was found between imaging findings and clinical scores (P >.05, multiple regression analysis; P =.25-.75, Mann-Whitney U test; Spearman correlation coefficients between -0.33 and 0.33). CONCLUSION: The spectrum of MR imaging appearances of PSC is diverse and comprises distinct patterns that do not appear to correlate with severity of disease. Large regenerative nodules are a frequent finding and may help to establish the diagnosis.

Donor morbidity associated with right lobectomy for living donor liver transplantation to adult recipients: a systematic review.

The aim if this study is to determine donor morbidity associated with right lobectomy for living donor liver transplantation (LDLT) to adult recipients through a systematic review of the published literature. Data sources were English-language reports on donor outcome after LDLT. MEDLINE (1995 to June 2001) was searched using the MeSH terms "living donors" and "liver transplantation." Limits were set for human only and English language only. Bibliographies of retrieved references were cross-checked to identify additional reports; 211 reports were obtained. Population studies and consecutive and nonconsecutive series were included. All studies reported at least one of the following outcomes specific to living donors (LDs) of right hepatic lobes to adult recipients: surgical and hospital complications, length of hospital stay, readmissions, recovery time, return to predonation occupation, health-related quality of life, or mortality. Abstracts of relevant articles were reviewed independently using predetermined criteria, and appropriate articles were retrieved. Study design and results were summarized in evidence tables. Summary statistics of combined data were performed when possible. Twelve studies met the inclusion criteria. Data on donor morbidity associated with right lobectomy are limited. On the basis of reported data, morbidity associated with LD right lobectomy ranges from 0% to 67%. In conclusion, reported morbidity associated with right lobe donation for LDLT varies widely. Standardized definitions of morbidity and better methods for observing and measuring outcomes are necessary to understand and potentially improve morbidity. Future studies assessing LD outcomes should report donor outcome more explicitly.