Search

Graphical abstract, Highlights • Echocardiography is the first-line test to diagnose the presence and cause of AR. • Acute aortic syndromes should be excluded in patients with AR and a thickened aortic root. • Multimodal imaging with cardiac CT and MRI complement TTE and TEE to diagnose secondary causes of AR. • Aortitis is a potentially life-threatening disease, and is a rare cause of AR.

Key Clinical Message There is currently minimal clinical experience regarding retreatment options for patients failing direct‐acting antiviral combination regimens. Here, we report the outcomes of a HCV genotype 1b‐infected patient with virologic failure following treatment with daclatasvir and asunaprevir, who was successfully retreated with sofosbuvir plus simeprevir.

International audience; BACKGROUND & AIMS:We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infected patients.METHODS:This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infected patients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infected patients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12).RESULTS:For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation.CONCLUSIONS:Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infected patients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.

In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of � 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity 5 33%) without sacrificing a single SVR among 475 successes (specificity 5 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a � 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR. Conclusion: Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels � 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules—an HCV RNA level � 100 IU/mL at week 12 and detectable HCV RNA at week 24—maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation. (HEPATOLOGY 2012;56:567-575)

Background & Aims Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC) 3 program. Methods Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event. Results There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880–2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130–2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls ( P = .016). There were no new safety observations. Conclusions Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

Background & Aims EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon–alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Methods Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Results Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 ( p p p ⩽0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis ( p ⩽0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). Conclusions FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin.

Previous studies of chronic hepatitis C virus (HCV) treatment have demonstrated variations in response among racial and ethnic groups including poorer efficacy rates among African American and Hispanic patients. The individualized dosing efficacy vs flat dosing to assess optimaL pegylated interferon therapy (IDEAL) trial enrolled 3070 patients from 118 United States centres to compare treatment with peginterferon (PEG-IFN) alfa-2a and ribavirin (RBV) and two doses of PEG-IFN alfa-2b and RBV. This analysis examines treatment response among the major racial and ethnic groups in the trial. Overall, sustained virologic response (SVR) rates were 44% for white, 22% for African American, 38% for Hispanic and 59% for Asian American patients. For patients with undetectable HCV RNA at treatment week 4, the positive predictive value of SVR was 86% for white, 92% for African American, 83% for Hispanic and 89% for Asian American patients. The positive predictive values of SVR in those with undetectable HCV RNA at treatment week 12 ranged from 72% to 81%. Multivariate regression analysis using baseline characteristics demonstrated that treatment regimen was not a predictor of SVR. Despite wide-ranging SVR rates among the different racial and ethnic groups, white and Hispanic patients had similar SVR rates. In all groups, treatment response was largely determined by antiviral activity in the first 12 weeks of treatment. Therefore, decisions regarding HCV treatment should consider the predictive value of the early on-treatment response, not just baseline characteristics, such as race and ethnicity.

In addition to chronic hepatitis, many individuals infected with hepatitis C virus (HCV) suffer from fatigue, which may compromise their health-related quality of life (HRQL). To assess systematically health-related quality of life (HRQL) in patients with chronic hepatitis C and to determine if any clinical, biochemical, virologic, demographic, and histologic features are associated with HRQL status. In this cross-sectional observational study, one hundred thirty patients with chronic HCV infection (HCV RNA positive by PCR) and 61 healthy controls were enrolled from a tertiary care teaching medical center. All patients and controls completed one generic HRQL questionnaire (MOS SF-36) and one liver-disease specific instrument (Chronic Liver Disease Questionnaire, CLDQ). Ninety-five HCV patients and all the controls also completed a fatigue questionnaire (Chronic Fatigue Screener, CFS) and had immunologic markers determined (Cryoglobulin, Soluble IL-2 receptors, Rheumatoid Factor). We compared the HRQL of HCV-infected patients to the controls and, using data from other studies, to the general population, patients with diabetes, and patients with chronic low back pain. Patients with chronic HCV had greater HRQL impairment than healthy controls and those with type II diabetes. Fatigue was the most important symptom with negative impact on HRQL. Sixty-one percent of HCV-infected patients reported fatigue-related loss of activity. Additionally, other factors associated with HRQL were gender and histologic cirrhosis. Chronic HCV infection has a profound negative impact on patients' HRQL. Disabling fatigue is the most important factor that contributes to loss of well-being in this relatively young group of patients.

To evaluate safety and efficacy of long-term posaconazole in HIV-infected patients with azole-refractory oropharyngeal candidiasis and/or esophageal candidiasis.In this noncomparative, open-label study, participants received oral posaconazole 400 mg twice daily (bid) for 3 months. Enrolled patients (N = 100) included 60 from a previous 1-month acute study of posaconazole and 40 posaconazole-naïve participants. Participants with a clinical response could be followed untreated for up to 1 month afterwards. Participants who relapsed during follow-up, showed improvement at the end of 3 months of treatment (EOT), or were cured but likely to benefit from further therapy could continue on posaconazole 400 mg bid for up to 12 months.In the modified intent-to-treat population, clinical response (cure or improvement) occurred in 85.6% (77/90) at EOT. The results were similar in the previously treated participants and the posaconazole-naïve participants, 88.1% (52/59) and 80.6% (25/31), respectively. Posaconazole was well-tolerated, showing a similar safety profile during the 3-month study period and during suppressive therapy. The most frequently reported treatment-related adverse event was vomiting (4/100, 4%) during the early follow-up period (on or before day 105) and elevated hepatic enzymes (3/51, 6%) during the long-term follow-up (after day 105).Oral posaconazole 400 mg bid demonstrated long-term safety, tolerability, and efficacy, offering a long-term, suppressive treatment option for HIV-infected participants with azole-refractory mucosal candidiasis.

Invasive fungal infections are an important cause of morbidity and mortality after allogeneic hematopoietic stem-cell transplantation.In an international, randomized, double-blind trial, we compared oral posaconazole with oral fluconazole for prophylaxis against invasive fungal infections in patients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy. The primary end point was the incidence of proven or probable invasive fungal infections from randomization to day 112 of the fixed treatment period of the study.Of a total of 600 patients, 301 were assigned to posaconazole and 299 to fluconazole. At the end of the fixed 112-day treatment period, posaconazole was found to be as effective as fluconazole in preventing all invasive fungal infections (incidence, 5.3% and 9.0%, respectively; odds ratio, 0.56; 95 percent confidence interval [CI], 0.30 to 1.07; P=0.07) and was superior to fluconazole in preventing proven or probable invasive aspergillosis (2.3% vs. 7.0%; odds ratio, 0.31; 95% CI, 0.13 to 0.75; P=0.006). While patients were receiving study medications (exposure period), in the posaconazole group, as compared with the fluconazole group, there were fewer breakthrough invasive fungal infections (2.4% vs. 7.6%, P=0.004), particularly invasive aspergillosis (1.0% vs. 5.9%, P=0.001). Overall mortality was similar in the two groups, but the number of deaths from invasive fungal infections was lower in the posaconazole group (1%, vs. 4% in the fluconazole group; P=0.046). The incidence of treatment-related adverse events was similar in the two groups (36% in the posaconazole group and 38% in the fluconazole group), and the rates of treatment-related serious adverse events were 13% and 10%, respectively.Posaconazole was similar to fluconazole for prophylaxis against fungal infections among patients with GVHD. It was superior in preventing invasive aspergillosis and reducing the rate of deaths related to fungal infections. (ClinicalTrials.gov number, NCT00034645 [ClinicalTrials.gov].).

The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection.To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor).This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included.Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg.The primary study outcome was SVR12 (HCV-RNA25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort.Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea.In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir.clinicaltrials.gov Identifier: NCT01979939.

Background/Aims: Hepatitis C and nonalcoholic fatty liver disease (NAFL) are the two most common forms of liver disease in the United States. Recently, obesity and its associated risk factors have been suggested to enhance HCV-related fibrosis. The aim of this study was to assess the impact of hepatic steatosis, steatohepatitis, and its associated risk factors on HCV-related fibrosis. Methods: Patients with untreated, biopsy-proven, chronic hepatitis C (6/97–3/99) were included. Clinical and demographic data at the time of liver biopsy were obtained from chart review and verified by telephone survey. One hepatopathologist reviewed all pathologic specimens, using the modified histological activity index score and the Ishak staging for fibrosis and a NAFL pathologic protocol. Results: One hundred and seventy patients with hepatitis C were included [age: 48.7±9.33 (years), body mass index (BMI): 28.1±5.7 (kg/m2) and type 2 diabetes mellitus (DM): 14%]. Of these, 77 (45.3%) had no or mild fibrosis and 93 (54.7%) had advanced fibrosis. Hepatic steatosis was seen in 90 (52.9%) patients. The grade of steatosis was associated with markers of obesity only. Age (p=0.002), type 2 DM (p=0.04), and superimposed steatohepatitis (p=0.047) were independently associated with advanced fibrosis. Superimposed nonalcoholic steatohepatitis (NASH) was seen in 17 (10%) patients. Patients with superimposed NASH were mostly obese (76.5%), males (62%) with 16% having type 2 diabetes and a BMI 33.8±7.12. Conclusion: In patients with chronic hepatitis C, type 2 DM and superimposed steatohepatitis are independently associated with advanced fibrosis.

To compare the gross and histologic effects of bipolar and monopolar cautery, ultrasonic scalpel, and CO(2) laser on porcine ureter, bladder, and rectum.Experimental prospective study.Cleveland Clinic Foundation Animal Research Laboratory, Cleveland, Ohio.Nonpregnant adult female pigs.The rectum, bladder, and ureters of 12 female pigs were injured with four different laparoscopic energy sources.Gross measurements of injured tissue and histologic analysis of the depth of the tissue injury.Gross assessment results were that monopolar injuries of the bowel and bladder were significantly longer than ultrasonic injuries (P0.01). Injuries were generally manifest as coagulative denaturation of collagen bundles. This resulted in an eosinophilic homogenization of tissue. Nuclei were retained in the injured tissue, although in most cases they had a pyknotic, streamed appearance. The CO(2) laser caused no deep-tissue injury.Laparoscopic energy sources injure tissue differently. Monopolar cautery appears to have the most lateral spread of thermal energy. The CO(2) laser appears to cause the least deep-tissue injury.

Quantitative measures of the value patients place on the state of their health is crucial to understanding their experience, and to calculate quality-adjusted years of life for economic analyses. Patients' values in chronic liver disease remain unexplored, although experts' estimates of utilities have been examined. Our study tests the validity of a widely used utility measure in chronic liver disease and, if valid, establishes the decrement in health-related quality associated with chronic liver disease.A total of 120 patients with chronic liver disease participated in the study (age 50 +/- 10 yr; men 53%; cirrhosis 51%, chronic viral hepatitis 51%, and chronic cholestatic liver disease 30%). All patients completed three instruments: Health Utility Index Mark 2 (scores 0-1), Short Form-36 (scale scores 0-100), and a disease-specific health-related quality of life instrument (Chronic Liver Disease Questionnaire; scores 1-7).We found a moderate to strong correlation between scores on the three measures and that impairment worsened as the severity of disease worsened. Patients without cirrhosis and those with Child's A cirrhosis showed substantial decrement in utilities (0.82 and 0.83, respectively) in the range of patients surviving brain tumor. Those with Child's B and C showed a greater decrement (0.67 and 0.56) that was in the range experienced by patients who survive a stroke (0.67). Utilities assessed by Health Utility Index Mark 2 differed substantially from estimates by "expert."We conclude that utilities should be based on patient reports and that the data from this study can inform economic analyses in studies of patients with chronic liver disease.

This study is designed to measure the impact of orthotopic liver transplantation (OLT) on patients' health-related quality of life. Two types of health-related quality-of-life questionnaires were administered at baseline and after OLT: generic (Medical Outcomes Study Short Form 36) and liver specific (Chronic Liver Disease Questionnaire). We also recorded clinical, demographic, and laboratory data. Pre-OLT scores of liver transplant candidates were compared with those of the general population and patients with congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD). Thirty-seven liver transplant candidates were evaluated: 25 men and 12 women; age, 50.2 ± 12 years; Child's class A, 3 patients; class B, 30 patients; class C, 4 patients; and galactose elimination capacity, 277 ± 81. Health-related quality-of-life scores for patients awaiting liver transplants were significantly lower than those for patients with COPD and CHF and those in the general population. Sex and cause of liver disease did not affect the scores. There was a weak but significant inverse correlation between some aspects of health-related quality of life and both age ( r = –0.31 to –0.34) and worsening of the Child-Pugh score ( r = –0.32 to –0.43). All measured aspects of health-related quality of life significantly improved after OLT, and mental health scores were indistinguishable from the population norms. Similar improvements were evident in physical and disease-specific aspects of health-related quality of life, but some residual dysfunction persisted. (Liver Transpl 2000;6:779-783.)

No objective measure of the level of sedation is universally accepted. However, bispectral index monitoring is currently used to objectively measure sedation levels in several clinical settings. This study compares the temporal relationship of bispectral index levels versus the Observer's Assessment of Alertness/Sedation (OAA/S) scale for sedation during endoscopy and proposes a functional bispectral index range for endoscopic procedures.Fifty consecutive adults undergoing endoscopic retrograde cholangiopancreatography, colonoscopy, or esophagogastroduodenoscopy by a single endoscopist were studied. Intravenous sedation was achieved with diazepam and meperidine. Bispectral index levels (0 to 100) and OAA/S scores (1 to 5) were recorded every 3 minutes by a single trained observer.There were significant temporal correlations between bispectral index levels and OAA/S scores (r = 0.59, p0.0001). Bispectral index levels and OAA/S scores corresponded with the need for additional sedation as determined clinically by the endoscopist. An OAA/S score of 3 corresponded to a bispectral index level of 81.49 +/- 9.78.Bispectral index monitoring temporally correlates with the OAA/S scale and therefore provides an objective measure of sedation during endoscopy. This preliminary, observational study suggests that a bispectral index level near 82 corresponds with sufficient and functional sedation levels for endoscopy.

Background. We attempted to minimize the undesired side effects and maximize the benefit of OKT3 induction therapy in renal transplantation. Methods. One hundred and one recipients of kidney-only transplants were randomized to three groups. Each received low-dose 2.5-mg OKT3 induction for 7–14 days, but different premedication on days 0, 1, and 2. Group I was given 250 mg i.v. methylprednisolone at 1 and 6 hr, and group II received another 500 mg at 1 hr before initial OKT3. Group III received Atgam 15 mg/kg on day 0 and began OKT3 on day 1. A CD3+ T-cell cut-off of 50/mm3 was used to guide therapy. Maintenance therapy included cyclosporine and steroids for each patient. However, groups I and II were also given mycophenolate mofetil, and group III received azathioprine as a third agent. All rejections were biopsy confirmed and Banff scored. Results. No differences in demographic or transplant characteristics were noted between groups I, II, and III, and mean follow-up was 25.7 (1–38) months. There was no significant difference in actuarial patient (90%, 91%, 94%) or graft survival (83%, 88%, 84%) at 3 years between the respective groups. Mean creatinine values and infectious complications were similar for each group. No patient experienced acute rejection during induction, and eight patients required dose escalation to sustain suppression of CD3 counts. The incidence of acute rejection at 6 and 12 months was significantly (P =0.004) greater in group III (38.2, 44.1%) than in either group I (15.1, 18.1%) or group II (14.7, 17.6%); relative risk 1.988 (95% CI 1.012–3.906). Formation of anti-OKT3 antibody was significantly (P =0.006) greater in group III (26.5%) than in group I (6%) or group II (2.9%). Group I recipients enjoyed significantly (P =0.001) fewer (2.17) OKT3 side effects on days 0, 1, and 2 than group II (3.03) or group III (2.49), and contained the largest number (61%) of recipients who experienced no side effects. Group I also exhibited the most suppressed profile of OKT3-induced release of tumor necrosis factor-α (P =0.006), interferon-γ (P =NS), and interleukin-6 (P =0.01) on days 0 and 1. Conclusions. Low-dose 2.5-mg OKT3 with pretreatment of split-dose steroids on days 0, 1, and 2 provides the most effective method for OKT3 induction, which minimizes side effects for most patients. Subsequent maintenance therapy with cyclosporine, mycophenolate mofetil, and steroids provides effective rejection prophylaxis without increased complications for up to 3 years. Predepletion of T cells before exposure to OKT3 does not prevent cytokine release.

Background. Acute rejection (AR) of the transplanted kidney has been identified as the major risk factor for the development of chronic rejection and immunological graft loss. However, the clinical presentation and response to AR therapy can vary considerably between recipients. Methods. We studied the first AR episode in 201 kidney-only recipients transplanted between January 1987 and June 1998 who were biopsied between April 1993 and June 1998 and were graded using the Banff schema. All patients received cyclosporine-based immunosuppression. There were 134 cadaver donor (66.7%) and 67 live donor (33.3%) recipients followed for a mean of 46.2 (range 4-128) months. All Banff grade 1-3 and 40/78 borderline (BL) cases were treated for rejection after biopsy. These patients were compared with a contemporaneous control population who did not experience AR. Demographic risk factors associated with graft loss were identified in both univariate and multivariate analysis. Daily (0-18) serum creatinine (SCr) values during and after the AR were plotted for each patient to generate curves and calculate area under the serum creatinine versus time curve (mg/dl/day). Four response patterns to treatment were identified according to the velocity of % increase (V1) and decrease (V2) of serum creatinine. These were identified as rapid rise and fall (n=62); rapid rise and slow fall (n=43); slow rise and fall (n=55); and slow rise and rapid fall (n=41). Kaplan-Meier graft survivals were compared between the groups. Results. Any Banff grade was associated with increased risk for graft loss (P=0.0001). However, no significant differences were observed between the Banff BL and B1-3 groups, or among those BL patients who were treated or remained untreated for AR. Multivariate analysis identified a black recipient (P=0.03, risk ratio 2.0) and area under the serum creatinine versus time curve (P=0.0001, risk ratio 3.2) as significant risk factors for graft loss. The AR response pattern RS resulted in a significantly (P=0.0072) diminished 5-year graft survival (45%) compared with the other groups. Serum creatinine pattern, but not Banff grade, was also a significant (P=0.025) predictor of re-rejection. Conclusions. These data suggest that all Banff grades, including BL, carry a significant risk for graft loss, and the initial response to antirejection therapy can predict long-term graft outcome. They support the practice of treating AR promptly and definitively and suggest that the RS subgroup of rejecting grafts could be targeted for additional antirejection therapy. This subgroup can be identified by 10 days of AR therapy, and should be the subject of further study.

Background & Aims: The spectrum of nonalcoholic fatty liver disease ranges from fatty liver alone to nonalcoholic steatohepatitis. Most previous studies have short follow-up and have not carefully delineated different histological types when determining clinical outcomes. The aim of this study was to compare clinical characteristics and outcomes of patients with different types of nonalcoholic fatty liver. Methods: All liver biopsy specimens from 1979 to 1987 with fat accumulation were assessed for inflammation, ballooning degeneration, Mallory hyaline, and fibrosis. Biopsy specimens were also assessed for histological iron and hepatitis C RNA. Outcomes were cirrhosis, mortality, and liver-related mortality. Results: Of 772 liver biopsy specimens, complete data were available in 132 patients. Fatty liver (type 1) did not differ from the other three types combined with respect to gender, race, age, or obesity. Cirrhosis was more common in the other types combined (22%) than fatty liver alone (4%; P ≤ 0.001). Overall mortality, histological iron, and hepatitis C did not differ between groups. Most of the liver-related deaths were in type 4. Conclusions: The outcome of cirrhosis and liver-related death is not uniform across the spectrum of nonalcoholic fatty liver. These poor outcomes are more frequent in patients in whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis. GASTROENTEROLOGY 1999;116:1413-1419

Objective. Intracranial hemorrhage is a recognized complication in neonates and infants on extracorporeal membrane oxygenator support and various risk factors associated with this have been defined. The prevalence and risk factors associated with intracranial hemorrhage in adults on extracorporeal membrane oxygenator support are unknown and this study was performed to define these factors. Methods .A retrospective study of adults supported with extracorporeal membrane oxygenators at a single institution between January 1992 and December 1996 was performed. Age, gender, weight, body surface area, renal function, anticoagulation, coagulation variables, blood flow, arterial pressure, arterial cannulation sites, duration of support, extracranial bleeding, native cardiac function and presence of intracranial microemboli were analyzed to determine the risk factors for intracranial hemorrhage. Results. Fourteen out of 74 adults on extracorporeal membrane oxygenator support had intracranial hemorrhage (18.9%). An increased risk of intracranial hemorrhage showed a positive correlation with female gender (P = 0.02, odds ratio 6.5), use of heparin (P = 0.05, odds ratio 8.5), creatinine greater than 2.6 mg/ dl (P = 0.009, odds ratio 6.5), need for dialysis ( P = 0.03, odds ratio 4.3) and thrombocytopenia (P = 0.007, odds ratio 18.3). Diminishing renal function and the need for dialysis were associated with increasing duration of support. Multivariable logistic regression showed female gender and thrombocytopenia, especially with platelet counts less than 50 000 cells/mm 3 to be the most important predictors of intracranial hemorrhage. Intracranial hemorrhage was associated with a mortality of 92.3% compared with a mortality of 61% in those without intracranial hemorrhage (P = 0.027). Conclusion. Intracranial hemorrhage is a significant complication in adults on extracorporeal membrane oxygenator support. Judicious management of anticoagulation, prevention of renal failure and aggressive correction of thrombocytopenia may help to lower the risk of intracranial hemorrhage in adults on extracorporeal membrane oxygenator support. © 1999 Elsevier Science B.V. All rights reserved.

Background To maximize the renal donor pool, cadaveric pediatric en bloc kidneys have been transplanted as a dual unit by some transplant centers. We compared the short- and long-term outcomes of adult recipients of cadaveric pediatric en bloc renal transplants versus those of matched recipients of cadaveric adult kidneys. Methods. Thirty-three adults who received pediatric en bloc kidney transplants between April 1990 and September 1997 were retrospectively identified and were compared with 33 matched adults who received adult cadaveric kidney transplants. The groups were identical for transplantation era, immunosuppression, recipient sex, race, cause of renal failure, mean weight, and follow-up duration (37.8 vs. 37.5 months). The mean recipient age study versus control was lower (36.3 vs. 48.9 years, P=0.0003). Results. There was no difference between the en bloc and adult donor groups in the 3-year patient survival rates (95% vs. 87%, P=0.16) or the 3-year graft survival rates (87.3% vs. 84.2%, P=0.35). Further, there was no difference in en bloc patient or en bloc graft survival time stratified by recipient age (14-44 vs. >45 years, P=0.11), en bloc donor age ( 24 months, P=0.39), or recipient weight ( 75 kg; P=0.60). Differences in serum creatinine (mg/dl) for the en bloc versus the control group at the time of discharge (3.0 vs. 7.8 mg/dl, P=0.06), at 1 year (1.4 vs. 2.0 mg/dl, P=0.06), and at 2 years (1.1 vs. 1.6 mg/dl, P=0.14) had dissipated by the time of the 5-year follow-up examination (1.1 vs. 1.6 mg/dl, P=0.14). Vascular complications were more prevalent in the en bloc group: renal vein thrombosis (one case), thrombosis of donor aorta (two cases), arterial thrombosis of one renal moiety (two cases), and renal artery stenosis (two cases). There were no differences between groups in delayed graft function, acute or chronic rejection, posttransplant hypertension, posttransplant proteinuria, or long-term graft function. Conclusions. Collectively, these data indicate that transplanting pediatric en bloc kidneys into adult recipients results in equivalent patient and graft survival compared with adult cadaveric kidneys. Further, the data also suggest that pediatric en bloc kidneys need not be strictly allocated based on recipient weight or age criteria.

Purpose: The serotonin receptor antagonists effectively prevent emesis with little toxicity when employed with standard doses of emetogenic chemotherapy. The optimal approach to the prevention of the emesis associated with the high doses of chemotherapy used for autologous stem cell transplantation is not known. A randomized controlled trial was designed to assess the relative efficacy and toxicity of granisetron compared to ondansetron in the setting of autologous stem cell transplantation. Methods: A group of 48 patients with breast cancer were randomized in a double-blind fashion to receive either (1) granisetron as a 0.5-mg i.v. bolus 30 min. before chemotherapy followed by a continuous infusion of 0.04 mg/h (1 mg/day) for 7 days or (2) ondansetron as an 8-mg i.v. bolus 30 min before chemotherapy followed by a continuous infusion of 1 mg/h (24 mg/day) for 7 days. All patients also received 10 mg dexamethasone/day i.v. for 7 days. Chemotherapy consisted of 1500 mg cyclophosphamide per m2/day, 125 mg thiotepa m−2 day−1, and 200 mg carboplatin per m2/day all as a continuous infusion for 4 consecutive days. The two study arms were then compared for the incidence and severity of nausea, incidence of emesis, number of salvage anti-emetics required, cost, and toxicity. Results: A total of 46 patients were evaluable. The treatment arms were well-balanced for known risk factors for chemotherapy-induced nausea and vomiting. Compliance with self-reporting of nausea and vomiting was poor but indicated no difference between the two treatment arms. The average number of anti-emetics required was 15.8 in both treatment arms and the average time to the first dose of a salvage anti-emetic was 2.8 days in the granisetron arm and 2.9 days in the ondansetron arm. The incidence of headache was 36 % in the granisetron arm and 39 % in the ondansetron arm. None of these differences was statistically significant. The use of granisetron resulted in a cost saving of 6.5 %. Conclusion: There was no significant difference between granisetron and ondansetron in either efficacy or toxicity. At our institution, the use of granisetron resulted in a moderate cost saving.

Purpose: We conducted a psychosocial followup of living kidney donors from 1983 to 1995.Materials and Methods: A new questionnaire about donor satisfaction and the Medical Outcomes Study Short-Form Health Survey, a standardized measure of health related quality of life, were completed by 167 donors (67% response rate).Results: Of respondents 90% would make the same choice again and 83% would strongly encourage others to donate. However, 15% of respondents believed that donating had impacted negatively on their health and 23% reported negative financial consequences. Respondent health related quality of life was not impaired. The strongest correlates of donor dissatisfaction included a conflicted initial relationship with the recipient, believing that information given preoperatively had been inadequate and perceived damage to health or finances.Conclusions: Only a minority of living kidney donors suffer psychosocial morbidity. Better psychological preparation for surgery and more consistent follow...

Background & Aims Therapeutic options for patients failing hepatitis C retreatment are limited. EPIC 3 included a prospective trial assessing long-term peginterferon alfa-2b (PegIFNα-2b) maintenance therapy in patients with METAVIR fibrosis scores (MFS) of F2 or F3 who previously failed hepatitis C retreatment. Methods Patients with F2/F3 MFS who failed retreatment were randomized to PegIFNα-2b (0.5μg/kg/week, n=270) or observation (n=270) for 36months. Blinded liver biopsies obtained before retreatment and after maintenance therapy were evaluated using MFS and activity scores, and confirmatory testing was performed using FibroTest and ActiTest. Results In total, 348 patients had paired biopsies: 192 patients had missing post-treatment biopsies and were considered as having no change in fibrosis/activity scores. In total, 16% of patients receiving PegIFNα-2b and 11% of observation patients had improvement in MFS ( p =0.32). More PegIFNα-2b than observation patients had improvement in activity score (20% vs. 9%; p 0.001). Among patients treated for >2.5years, improvement in MFS or activity score was more common with PegIFNα-2b than observation (21% vs. 14%, p =0.08 and 26% vs. 10%, p 0.001). FibroTest and ActiTest evaluations indicated significant benefit associated with PegIFNα-2b in terms of reduced fibrosis progression and improved activity score. The safety profile of PegIFNα-2b was similar to previous studies. Conclusions PegIFNα-2b did not significantly improve MFS estimated by biopsy compared with observation; however, activity scores were significantly improved and MFS trended toward increased improvement with treatment durations >2.5years. Both FibroTest and ActiTest were significantly improved during maintenance therapy.

Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG-IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self-reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1%17.0%; relative risk, 1.65; 95% confidence interval, 1.46-1.87; P0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P0.001), and elevated creatinine (5% versus 1%, P0.001).Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency.

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).

Objective: To compare laparoscopic, gross, and fluorescent assessment of laparoscopic pelvic injuries. Design: Experimental prospective study. Setting: Cleveland Clinic Foundation Animal Research Laboratory, Cleveland, Ohio. Animal(s): Nonpregnant adult female pigs. Intervention(s): Pelvic organs injured with laparoscopic energy sources were assessed laparoscopically, grossly, and with a fluorescent indicator and Wood's lamp. Main Outcome Measure(s): Three different measurements of each laparoscopic injury. Result(s): Assessment of injuries by laparoscopy did not differ significantly from gross assessment of injuries. In the segments of bowel and bladder that were injured with monopolar cautery, the Wood's lamp assessment of the injuries was significantly longer than the laparoscopic assessment of the injuries. Conclusion(s): Laparoscopic assessment of injured ureters, bowel, and bladder appear to be similar to gross assessment of these tissues. In tissue where the serosal surface is intact, the use of a fluorescent dye and a Wood's lamp provides a clear margin of the injured tissue.

Background. We evaluated the efficacy and safety of oral posaconazole for human immunodeficiency virus (HIV)‐infected subjects with oropharyngeal candidiasis (OPC) and/or esophageal candidiasis (EC) who were clinically refractory to treatment with oral fluconazole or itraconazole. Methods. Subjects with confirmed OPC or EC who did not improve after receiving standard courses of fluconazole or itraconazole treatment were eligible for study enrollment. Subjects received either oral posaconazole (400 mg twice daily) for 3 days followed by oral posaconazole (400 mg once daily) for 25 days (regimen A; 103 patients) or oral posaconazole (400 mg twice daily) for 28 days (regimen B; 96 patients). The primary end point was cure or improvement after 28 days. Primary efficacy analyses were performed on the subset of treated subjects with refractory disease (e.g., baseline culture positive for fluconazole- or itraconazole-resistant Candida species or persistent or progressive clinical signs or symptoms consistent with treatment failure). Results. Of the modified intent-to-treat population, 132 (75%) of 176 subjects achieved a clinical response to posaconazole treatment. Clinical response rates were similar between regimen A recipients (75.3%) and regimen B recipients (74.7%). Clinical responses occurred in 67 (73%) of 92 subjects with baseline isolates resistant to fluconazole, 49 (74%) of 66 subjects with baseline isolates resistant to itraconazole, and 42 (74%) of 57 subjects with isolates resistant to both. Clinical response was achieved in 32 (74.4%) of 43 subjects with endoscopically documented EC. The most common treatment-related adverse events were diarrhea (11%), neutropenia (7%), flatulence (6%), and nausea (6%). Eight subjects (4%) discontinued therapy as a result of a treatment-related adverse event. Conclusions. Posaconazole offers a safe and effective treatment option for HIV-infected subjects with azolerefractory OPC and/or EC. In patients with HIV infection, oropharyngeal candidiasis (OPC) and esophageal candidiasis (EC) can be recurrent and debilitating [1‐3]. Fluconazole and itraconazole treatments are usually effective against these forms of mucosal candidiasis (MC), have a favorable safety profile, and permit oral administration [2, 4]. Refractory MC has been reported in 4%‐5% of HIV

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is reported commonly in patients with type 2 diabetes mellitus (DM), which has been suggested as a risk factor for the progressive form of NAFLD, or nonalcoholic steatohepatitis. The aim of this study was to assess the outcome of patients with NAFLD and DM. Methods: A cohort of patients with NAFLD was identified, and patients with other causes of liver disease (alcohol, medication, etc.) were excluded. Clinical, pathological, and mortality data were available for this cohort. Patients were categorized and compared according to the presence or absence of DM. Results: Of 132 patients with NAFLD, 44 patients (33%) had an established diagnosis of DM. Patients with DM were older and had greater serum glucose and triglyceride levels and a greater aspartate aminotransferase-alanine aminotransferase ratio. Liver biopsy specimens from patients with DM showed more vacuolated nuclei and acidophilic bodies. Cirrhosis (histological or clinical) occurred in 25% of patients with DM (11 of 44 patients) and NAFLD compared with only 10.2% (9 of 88 patients) of patients without DM with NAFLD ( P = 0.04). After adjusting for potential confounders (age, body mass index, and the presence of cirrhosis), both overall mortality (risk ratio [RR], 3.30; 95% confidence interval [CI], 1.76–6.18; P = 0.002) and mortality related to liver disease (RR, 22.83; 95% CI, 2.97–175.03; P = 0.003) were greater in diabetic patients with NAFLD. Markers of hepatic dysfunction (low albumin level, high total bilirubin level, and prolonged prothrombin time) were the only independent predictors of increased mortality. Conclusions: Patients with NAFLD and DM are at risk for the development of an aggressive outcome, such as cirrhosis and mortality. This study supports the potential role of insulin resistance in the development of poor clinical outcomes in patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopatholologic conditions ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), with varying risks for progression to cirrhosis. Although steatosis alone seems to be nonprogressive, some patients with NASH can progress. This study focuses on the clinical and pathological characteristics of patients with NAFLD associated with the development of histological fibrosis. Patients with an established diagnosis of nonalcoholic fatty liver were identified through our NAFLD database containing extensive clinical, demographic, and laboratory data. Liver biopsy specimens were read blindly by one hepatopathologist using a 19-item pathological protocol and by another hepatopathologist using a second pathological protocol. Clinical and pathological data were matched to the presence of different types of histological fibrosis. Univariate and multivariate analyses helped determine all of the variables independently associated with histological fibrosis. Of 132 NAFLD patients, 21.2% had advanced fibrosis (septal/bridging fibrosis or well-established cirrhosis). Sinusoidal fibrosis was present in 20.3% of patients, whereas perivenular fibrosis was seen in 17.2%. Ballooning degeneration and Mallory bodies were independently associated with both sinusoidal fibrosis and perivenular fibrosis. Aspartate aminotransferase/alanine aminotransferase ratio and ballooning degeneration were also independently associated with periportal-portal fibrosis. We conclude that the presence of hepatocyte injury in NAFLD is associated with fibrosis. These pathological features can be used to establish the pathological criteria for diagnosis of the progressive form of NAFLD or NASH.

Adherence to Assigned Dosing Regimen and Sustained Virologic Response Among Hepatitis C Genotype 1 Treatment-NaiVE and PEG/Ribavirin Treatment-Failures Treated With Boceprevir Plus Peginterferon Alfa-2B/ Ribavirin Stuart C. Gordon, Eric J. Lawitz, Bruce R. Bacon, Mark Sulkowski, Eric M. Yoshida, Mitchell N. Davis, Navdeep Boparai, Vilma Sniukiene, Margaret Burroughs, Clifford A. Brass, Janice K. Albrecht, Rajender Reddy

483 IMPORTANCE OF HCVRNA ASSAY CHARACTERISTICS AND DIFFERENCES BETWEEN ASSAYS FOR RESPONSE GUIDED THERAPY OF CHRONIC HEPATITIS C V. Weich, S. Schwendy, B. Moller, N. Dikopoulos, P. Buggisch, J. Encke, G. Teuber, T. Goeser, R. Thimme, H. Klinker, W. Boecher, E. Schulte-Frohlinde, S. Zeuzem, T. Berg, C. Sarrazin. J.W. Goethe University Hospital, Frankfurt/Main, Uniklinik TU Munchen, Munchen, Leberzentrum Checkpoint, Berlin, Uniklinik Ulm, Ulm, Uniklinik Hamburg, Hamburg, Uniklinik Heidelberg, Heidelberg, Interdisziplinares Facharztzentrum, Frankfurt, Uniklinik Koln, Koln, Uniklinik Freiburg, Freiburg im Breisgau, Uniklinik Wurzburg, Wurzburg, Uniklinik Mainz, Mainz, Uniklinik Leipzig, Leipzig, Germany E-mail: viola.weich@kgu.de

Some patients diagnosed with cryptogenic cirrhosis may have "burned-out" nonalcoholic fatty liver disease (NAFL). To test this hypothesis, we used our liver transplant database (November 1984 to November 1998) to assess the incidence of NAFL in patients with cryptogenic cirrhosis after orthotopic liver transplantation (OLT). We also examined the clinicodemographic features associated with post-OLT NAFL, obtained by chart review and telephone interviews. When available, post-OLT liver biopsy specimens were reviewed blindly by a hepatopathologist according to the NAFL pathology protocol. We identified 51 patients with cryptogenic cirrhosis (mean age, 51 +/- 12 years); 60% were women, 94% were white, and 34% had type 2 diabetes mellitus (DM). Mean pre-OLT body mass index (BMI) was 27.33 +/- 5.54 kg/m(2). Twenty-five patients underwent at least 1 post-OLT liver biopsy. Post-OLT NAFL was identified in 13 patients (25.4%), whereas post-OLT nonalcoholic steatohepatitis (NASH) was seen in 8 patients (15.7%). Features associated with post-OLT NASH were pre- and post-OLT type 2 DM (P < or =.05) and an elevated fasting triglyceride level (P

The type and severity of chronic liver disease may have different effects on health-related quality of life (HRQL). The aim of our study was to determine whether HRQL in patients with chronic liver disease differs by type and severity of disease and to identify which clinical and physiological factors affect this impairment.In this study, HRQL was measured with a generic (Short Form 36) and a liver disease-specific (Chronic Liver Disease Questionnaire) questionnaire. Clinical, demographic, and laboratory data were collected at office visits. Patient's HRQL scores were compared with the published norms and to the chronically ill populations. A total of 353 patients (mean age 50 yr, 51% men) with chronic liver disease, either viral disease (hepatitis B and C), cholestatic disease (primary biliary cirrhosis or primary sclerosing cholangitis), or hepatocellular disease were enrolled in the study.In general, HRQL in patients with chronic liver disease was lower than the normal population and was similar to that of patients with chronic obstructive pulmonary disease or congestive heart failure. In cirrhotic patients, some dimensions of HRQL were less impaired in patients with cholestatic disease than in those with hepatocellular diseases. More severe disease (higher Child's class) was associated with a lower Chronic Liver Disease Questionnaire score and the Short Form 36's physical component summary scores. Older age had a weak negative association with the physical aspects of HRQL.We conclude that chronic liver disease substantially reduces HRQL, and this impact does not differ markedly by type of disease. Older age and measures of disease severity were associated with poorer HRQL.

Background/Aims : Interferon-based regimens (alone or with ribavairin) are standard therapies for chronic hepatitis C. The aim of this study was to compare a 24-week regimen of interferon alpha-2b+ribavirin (IFN+RIBA) to interferon alpha-2b+amantadine (IFN+AMANT) in non-responders to previous interferon monotherapy. Methods : In a multi-center, double-blind clinical trial, 118 patients (non-responders to previous interferon monotherapy) were equally randomized into the two arms: interferon alpha-2b (3 MU thrice weekly) and ribavirin (800 mg daily) vs. interferon alpha-2b (3 MU thrice weekly) and amantadine (200 mg daily). Results : After 24 weeks of therapy, HCV RNA became undetectable in 34.8% (95% CI: 23.7–49.2) of IFN+RIBA and 19.6% (95% CI: 10.6–34.7) of IFN+AMANT ( P =0.10). This response was sustained in 3.9% (95% CI: 1.0–14.9) of IFN+RIBA and 0% of IFN+AMANT ( P =0.16). Ten patients from IFN+AMANT (17%) and 12 patients (20%) from IFN+RIBA were discontinued before completion of therapy. Of these, 7% in IFN+AMANT and 12% in IFN+RIBA were discontinued due to adverse effects. Conclusions : Re-treatment of interferon non-responders with a 24-week course of IFN+AMANT was not associated with any sustained viral eradication. Although IFN+RIBA in this group was associated with a reasonable end of treatment response, relapses were common and sustained responses were low.

OBJECTIVE: Symptoms associated with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) negatively affect health-related quality of life (HRQL). The aim of this study was to measure HRQL in patients with chronic cholestatic liver diseases and to determine factors associated with more severe impairment. METHODS: We conducted a cross-sectional study in which we documented patients’ demographic and clinical characteristics, and measured their HRQL using the Short Form-36 and Chronic Liver Disease Questionnaire. We assessed the association of HRQL impairment with disease severity (Child’s-Pugh class and Mayo PBC Risk Score) and compared patients’ HRQL with those of a healthy population, and patients with congestive heart failure, chronic obstructive pulmonary disease, and diabetes. RESULTS: One hundred and four patients with PBC and PSC participated, of whom 73% were women, with an average age of 55 ± 12 yr. Of these patients, 61% had cirrhosis (37% Child’s A, 23% Child’s B, and 2% Child’s C). Patients with cholestatic liver disease showed more HRQL impairment than the healthy population and were similar to patients with other chronic conditions. Additionally, patients who experienced severe itching showed profound HRQL impairment. In patients with PBC, Physical Component Summary (PCS) scores of the SF-36 and Chronic Liver Disease Questionnaire (CLDQ) scores fell from noncirrhotic to Child’s A to Child’s B/C and with worsening Mayo PBC Risk Scores. No other clinicodemographic data were associated with patients’ well-being. CONCLUSIONS: Patients with cholestatic liver disease (PBC and PSC) showed substantial impairment of HRQL, which is further affected by worsening disease severity. Disease-specific measures were better able to discriminate patients with varying severities.

Hepatitis C virus–related disease is rapidly becoming the most common indication for orthotopic liver transplant (OLT) in the United States. Although post-OLT hepatitis C viremia is universal, 40% to 60% of patients develop recurrent chronic hepatitis C. Distinguishing recurrent chronic hepatitis C infection from acute rejection may be difficult because of overlapping histopathologic features. To improve our diagnostic accuracy we undertook a study to determine interobserver and intraobserver agreement between pathologists examining post-OLT liver biopsy specimens in patients from our transplant database. Clinical data and microscopic sections from 26 patients with hepatitis C virus–related OLT were reviewed. Biopsy specimens were obtained because of abnormal liver enzymes (21/26) or routine post-OLT follow-up (5/26), representing both early (18 ± 11 days) and late (252 ± 206 days) post-OLT periods. Unidentified sections were examined by an experienced pathologist in a randomly assigned order and reexamined 6 weeks later in the same fashion by the initial reviewer and a second experienced pathologist. Interobserver and intraobserver agreement was calculated using κ statistic. The intraobserver agreement was 81% with a κ coefficient of 0.67 (P = .001). The interobserver agreement was 78% with a κ coefficient of 0.60 (P < .001). The early post-OLT biopsy specimens (18 ± 11 days) were the most difficult to interpret.