Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease.

Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct-acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment-naïve or treatment-experienced adults with Child-Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7-9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS-331007 (sofosbuvir metabolite) was 2.2-, 1.5-, 1.2- and 1.2-fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.

Interferon-free, direct-acting antiviral therapy for chronic hepatitis C.

The treatment environment for chronic hepatitis C has undergone a revolution, particularly in genotype 1. Gone are interferon-based therapy and its associated tolerability challenges, inadequate response rates and numerous baseline factors that affect response to therapy. New and emerging treatment regimens employ all-oral combinations of direct-acting antiviral agents, and results of clinical trials suggest that these regimens routinely achieve cure rates >90%, even in patients who failed prior interferon-based triple therapy. In 2015, three all-oral FDA-approved regiments will be available for genotype 1 (sofosbuvir /ledipasvir, sofosbuvir/simeprevir, and paritaprevir/r/ombitasvir/dasabuvir). Furthermore, new treatment combinations appear to be more tolerable and require shorter duration of therapy. We provide an overview of the classes of direct-acting antiviral agents (DAAs), the clinical factors affecting their integration into combination therapies and recent findings from trials of such combination therapies in patients with genotype 1 HCV infection.

Simeprevir with peginterferon/ribavirin for treatment of chronic hepatitis C virus genotype 1 infection: pooled safety analysis from Phase IIb and III studies.

This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon-α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in 'Photosensitivity' were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild-to-moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in simeprevir-treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient-reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for simeprevir due to the use of response-guided therapy. Simeprevir is well tolerated in HCV genotype 1-infected patients.

Peginterferon and ribavirin for treatment of recurrent hepatitis C disease in HCV-HIV coinfected liver transplant recipients.

Achievement of a sustained virologic response (SVR) with antiviral therapy significantly improves graft survival in hepatitis C virus (HCV) monoinfected liver transplant (LT) patients. Risks and benefits of HCV therapy in HCV-human immunodeficiency virus (HIV) coinfected LT recipients are not well established. Among 89 HCV-HIV LT recipients in the HIVTR cohort, 39 (23% Black, 79% genotype 1, 83% fibrosis stage ≤ 1) were treated with peginterferon-a2a or a2b plus ribavirin for a median 363 days (14-1373). On intent-to-treat basis, 22% (95% CI: 10-39) and 14% (95% CI: 5-30) achieved an end-of-treatment response (EOTR) and SVR, respectively. By per-protocol analysis (completed 48 weeks of therapy ± dose reductions), 42% and 26% had EOTR and SVR, respectively. Severe adverse events occurred in 85%, with 26% hospitalized with infections and 13% developing acute rejection. Early discontinuations and dose reductions occurred in 38% and 82%, respectively, despite use of growth factors in 85%. Eighteen of 39 treated patients (46%) subsequently died/had graft loss, with 10 (26%) attributed to recurrent HCV. In conclusion, SVR rates are low and tolerability is poor in HCV-HIV coinfected transplant recipients treated with peginterferon and ribavirin. These results highlight the critical need for better tolerated and more efficacious HCV therapies for HCV-HIV coinfected transplant recipients.

Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents.

Summary. During the late 1990s and early 2000s, major advances were made in the treatment of patients with chronic hepatitis C virus (HCV) infection. Interferon, combination interferon plus ribavirin (RBV) and pegylated interferon plus RBV increased sustained virologic response (SVR) rates from ~5% to ~40-80%, depending on the genotype of HCV infection. Advances in molecular biology have allowed investigators to begin to understand the mechanisms of HCV infection and replication. Advances in understanding of viral kinetics have provided tools to identify patients who are most likely to attain SVR. With the advances in the science of HCV infection, the first part of the 21st century has seen the development and early introduction of a number of direct-acting antiviral (DAA) drugs. These novel medications interfere with critical steps in HCV replication and have the potential to significantly increase SVR rates. This article will review the key elements of HCV replication and evaluate the various classes of new and investigational DAA that have the potential to create a revolution in the management of patients with chronic hepatitis C.

Standardization of terminology of virological response in the treatment of chronic hepatitis C: panel recommendations.

The treatment paradigm for hepatitis C virus (HCV) infection is at a critical point in its evolution. The addition of a protease inhibitor to peginterferon plus ribavirin has become the new standard-of-care treatment for most patients. Data from clinical trials of new antivirals have been difficult to interpret and compare, partly because of heterogeneity in trial design, and partly because of inconsistencies in terminology used to define viral responses and the populations evaluated. Present definitions of viral responses for treatment with peginterferon and ribavirin are insufficient for novel treatment paradigms. Further, categorization of prior patient treatment experience in clinical trials, particularly of nonresponders to prior therapy, is inconsistent. Existing terms and definitions must be updated, standardized and/or redefined for easier interpretation of data and effective communication among clinicians. A panel of experts in HCV infection treatment met on 3 December 2009. Goals of the panel were to evaluate terms and definitions used traditionally in treatment with peginterferon and ribavirin, to refine and clarify definitions of existing terms that have varying meanings and to propose new terms and definitions appropriate for novel treatment paradigms emerging with development of new agents. A number of recommendations were accepted unanimously by the panel. Adoption of these terms would improve communication among investigators, enhance comparability among clinical trials, facilitate development of therapeutic guidelines and provide a standardized terminology for use in clinical practice.

A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C.

The aim of this study is to review clinical trial data on the newly approved protease inhibitors boceprevir and telaprevir to develop consensus recommendations on the optimal use of these agents for the treatment of patients with chronic hepatitis C virus (HCV) infection. An expert panel of seven leading authorities in viral hepatitis was convened to establish and disseminate a practical guide on best practices for incorporating boceprevir and telaprevir into therapy for HCV infection in both treatment-naive and treatment-experienced patients. The topics covered include selecting candidates for boceprevir- or telaprevir-based treatments, predictors of response and early viral kinetics, response-guided therapy approaches, on-treatment management strategies to optimize the likelihood of response and minimize the risk of drug resistance, management of adverse effects during therapy and key considerations for special populations. The expert panel incorporated the best available clinical evidence into recommendations on how boceprevir and telaprevir should be used in the clinical setting. They indicated how treatment regimens may differ according to the baseline factors, such as presence of cirrhosis and when therapy may need to be modified or stopped altogether because of adverse events or poor virologic response. This practical guide will serve as a valuable resource for clinicians embarking on the new treatment paradigm of boceprevir or telaprevir in combination with peginterferon/ribavirin for chronic genotype 1 HCV infection.

Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate.

BACKGROUND & AIMS: Hepatitis C virus (HCV) treatment is frequently complicated by anemia from ribavirin (RBV)-related hemolysis and peginterferon-alfa (PEG-IFN)-related bone marrow suppression. We investigated the relationships among treatment outcomes, anemia, and their management with RBV dose reduction and/or erythropoiesis-stimulating agents (ESAs). METHODS: We analyzed data from a trial conducted at 118 United States academic and community centers in treatment-naïve patients with HCV genotype 1. Patients were treated for as many as 48 weeks with 1 of 3 PEG-IFN/RBV regimens. ESAs were permitted for anemic patients (hemoglobin [Hb] <10 g/dL) after RBV dose reduction. Sustained virologic responses (SVR) were assessed based on decreases in Hb, anemia, and ESA use. RESULTS: While patients received treatment, 3023 had their Hb levels measured at least once. An SVR was associated with the magnitude of Hb decrease: >3 g/dL, 43.7%; ≤3 g/dL, 29.9% (P < .001). Anemia occurred in 865 patients (28.6%); 449 of these (51.9%) used ESAs. In patients with early-onset anemia (≤ 8 weeks of treatment), ESAs were associated with higher SVR rate (45.0% vs 25.9%; P < .001) and reduced discontinuation of treatment because of adverse events (12.6% vs 30.1%, P < .001). ESAs did not affect SVR or discontinuation rates among patients with late-stage anemia. CONCLUSIONS: Among HCV genotype 1-infected patients treated with PEG-IFN/RBV, anemia was associated with higher rates of SVR. The effect of ESAs varied by time to anemia; patients with early-onset anemia had higher rates of SVR with ESA use, whereas no effect was observed in those with late-onset anemia. Prospective trials are needed to assess the role of ESAs in HCV treatment.

Tobacco and other factors have a negative impact on quality of life in hepatitis C patients.

Hepatitis C virus (HCV) is known to adversely affect general, social, emotional and mental health domains. This study was designed to identify variables that may be associated with these measurable outcomes. We conducted a cross-sectional retrospective review of demographic and clinical data from 800 patients with HCV evaluated between January 1998 and November 2007. Data were collected using a standardized questionnaire filled out by the patients at the first encounter. Variables evaluated included fibrosis stages (i.e. FS0/1/2 vs FS3/4), demographics, comorbid health conditions, tobacco and alcohol use, high-risk social behaviours and laboratory data. Variables assessed were depression, fatigue, problems sleeping and loss of interest in sex. Statistical analysis was performed using univariate and multivariate logistic regression. Depression (29.3%) in our HCV study population was associated with female gender, tobacco use, hyperlipidemia, history of heavy alcohol use and intravenous drug use. Fatigue (44.6%) was associated with end-stage renal disease, past and current tobacco use and current alcohol use. Difficulty sleeping (13.8%) was associated with past and current tobacco use, current alcohol use and diabetes. Loss of interest in sex (7.7%) was associated with current tobacco use, multiple risk factors for HCV and age at time of evaluation. Fibrosis stage (FS) also had a significant positive association with alcohol use (OR 2.61; P = 0.003) and tobacco use (OR 2.00; P = 0.002). Smoking and alcohol use have a significant negative impact on the presence of depression, fatigue, difficulty sleeping and loss of interest in sex in HCV patients. Practitioners should be aware of these associations, particularly tobacco use, which significantly and negatively impacted every variable evaluated.

Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.

Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B.

This retrospective analysis was conducted to describe the characteristics of nucleoside-naïve hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg-positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double-blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off-treatment follow-up. Through a maximum duration of 96 weeks on-treatment and 24 weeks off-treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside-naïve HBeAg-positive patients treated with entecavir, and that HBsAg loss is associated with sustained off-treatment suppression of HBV DNA.

Virological relapse in chronic hepatitis C.

Approximately one-third of all patients infected with hepatitis C virus (HCV) genotype 1 who complete pegylated interferon alpha based therapy and have undetectable serum HCV RNA at the end of treatment will experience relapse. Although relapse is a common outcome of therapy, its pathology and strategies for optimal management are poorly understood; however, optimized ribavirin dosing is recognized as pivotal in mitigating relapse. Recent data also suggest that early viral kinetics might help identify particular patient groups, such as slow responders, who are predisposed to relapse. This review provides a comprehensive overview of the importance of relapse in patients with chronic hepatitis C, including its underlying pathobiology, potential predictors and strategies to optimize the retreatment of previous relapsers.

Review article: thrombocytopenia in chronic liver disease.

BACKGROUND: Thrombocytopenia is a common finding in advanced liver disease. It is predominantly a result of portal hypertension and platelet sequestration in the enlarged spleen, but other mechanisms may contribute. The liver is the site of thrombopoietin (TPO) synthesis, a hormone that leads to proliferation and differentiation of megakaryocytes and platelet formation. Reduced TPO production further reduces measurable serum platelet counts. AIM: This paper describes the scope of thrombocytopenia in chronic liver disease and assesses the clinical impact in this patient population. METHODS: A medline review of the literature was performed pertaining to thrombocytopenia and advanced liver disease. This data is compiled into a review of the impact of low platelets in liver disease. RESULTS: The incidence of thrombocytopenia, its impact on clinical decision making and the use of platelet transfusions are addressed. Emerging novel therapeutics for thrombocytopenia is also discussed. CONCLUSIONS: Thrombocytopenia is a common and challenging clinical disorder in patients with chronic liver disease. New therapeutic options are needed to safely increase platelet counts prior to invasive medical procedures as well as to counteract therapies that further exacerbate low platelets, such as interferon. An ideal compound would be orally available and safe, with rapid onset of action.

Review article: the burden of hepatic encephalopathy.

Hepatic encephalopathy, a challenging complication of advanced liver disease, occurs in approximately 30-45% of patients with cirrhosis and 10-50% of patients with transjugular intrahepatic portosystemic shunt, while minimal hepatic encephalopathy affects approximately 20-60% of patients with liver disease. Although the total direct and indirect costs of hepatic encephalopathy have not been formally quantified, data from the Healthcare Cost and Utilization Project suggest that hepatic encephalopathy-related hospitalizations are associated with substantial costs. In 2003, there were over 40 000 patients hospitalized in the United States for a primary diagnosis of hepatic encephalopathy, resulting in total charges of approximately $932 million. Furthermore, trends over the past 10 years suggest that the burden of hepatic encephalopathy is increasing, as indicated by increases in hospital admissions and higher charges per stay. Because of inconsistencies in coding for hepatic encephalopathy, the prevalence and cost data from this data source are believed to significantly underestimate the true burden of hepatic encephalopathy. In addition, expenditures for physician fees and out-patient care, as well as indirect costs attributable to lost work days and decreased productivity, have not been quantified. Thus, there is need for future studies to more accurately define the burden of hepatic encephalopathy, including minimal hepatic encephalopathy.

Nonalcoholic fatty liver disease: a review.

Nonalcoholic fatty liver disease is an umbrella term that includes steatosis, nonalcoholic steatohepatitis and advanced fibrosis or cirrhosis. The terminology, although cumbersome, was intended to differentiate these disorders from alcohol-related liver disorders, as they are histologically similar. The term was first used by Ludwig in 1980, but has received a tremendous amount of attention in the past several years as a result of a better understanding of the scope of the problem. Although the pathogenesis has not been fully elucidated, there is a tremendous amount of research ongoing in this arena, both clinical and basic, to determine how the course of the disease can be altered. This text reviews the epidemiology of the disease, leading theories of pathogenesis, and treatment options.

Therapeutic strategies in nonalcoholic fatty liver disorders.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in developing countries. Many of the risk factors are well defined, but the underlying pathogenesis is not well understood. The demographics of the condition mirror those of the metabolic syndrome, with obesity and insulin resistance being the most commonly associated conditions. At present, therapy is aimed at correcting the risk factors, but there are no proven therapies at this point.

Cost-efficacy analysis of peginterferon alfa-2b plus ribavirin compared with peginterferon alfa-2a plus ribavirin for the treatment of chronic hepatitis C.

OBJECTIVE: Combination therapy with pegylated interferon (Peg) and ribavirin (RBV) is the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. This analysis compares the cost efficacy of treatment with pegylated interferon alfa-2b plus ribavirin (Peg-2b plus RBV) with pegylated interferon alfa-2a plus ribavirin (Peg-2a plus RBV) in hypothetical cohorts of 100 chronic HCV patients comprised 75% of genotype 1. METHODS: A decision analysis model was constructed from the viewpoint of a managed care organization to compare Peg-2b plus RBV (1.5 mcg per kilogram per week plus RBV 800 mg per day) and Peg-2a plus RBV (180 mcg per week plus RBV 1,000-1,200 mg per day) pursuant to the label dosing approved by the U.S. Food and Drug Administration. The model also included the so-called weight-based dosing regimen with Peg-2b plus RBV (1.5 mcg per kilogram per week plus RBV 10.6 mg/kg per day). Patient weight was assumed to be 80 kg. For purposes of this analysis, early virologic response (EVR), defined as viral negative or 2-log drop in viral load, was assessed at 12 weeks for only genotype 1 patients, and nonresponders were assumed to discontinue therapy. The positive predictive value (PPV) was calculated for each treatment group for genotype 1 patients, which is determined from the values for EVR and sustained viral response (SVR). Genotype 2 and genotype 3 patients were assumed to be treated for 24 weeks. Treatment duration and efficacy data were obtained from the published literature. Product pricing was based on average wholesale price, October 2004, and sensitivity analysis was performed using prices from the Federal Supply Schedule. Economic outcomes were determined from hypothetical 100-patient cohorts assumed to be comprised 75% of genotype 1 HCV. RESULTS: Taking into account both EVR and SVR, the PPV for genotype 1 patients was 0.63 and 0.57 for Peg-2b plus RBV and Peg-2a plus RBV, respectively. The proportion of treated patients achieving SVR would be nearly identical, (53.6%) and (53.8%) for Peg-2a plus RBV and Peg-2b plus flat RBV, respectively. For Peg- 2b plus weight-based RBV, the proportion of patients achieving SVR was higher (61.4%). Consequently, this leads to fewer overall treatment weeks for the Peg- 2b plus RBV cohorts. Therefore, the cost per successful treatment (defined as SVR) was 19.4% less (37,638 US dollars) for Peg-2b plus flat dosing of RBV as compared with Peg-2a plus RBV (46,717 US dollars). When Peg-2b plus RBV was dosed 1.5 mcg per kilogram per week plus RBV 10.6 mg/kg/day, then the cost per SVR was 39,045 US dollars. The cost for the 100-patient cohort was 2,024,846 US dollars for Peg-2b plus RBV, 2,397,529 US dollars for Peg-2b plus weight-based RBV, and 2,505,317 US dollars for Peg-2a plus RBV. This difference is due to a lower PPV in the Peg-2a plus RBV groups and hence more patients treated in spite of a low probability of achieving SVR. CONCLUSION: The results of this cost-efficacy analysis suggest that treating HCV genotype 1 patients with Peg-2b plus RBV may result in savings to a health care system because fewer of these patients are treated beyond 12 weeks when achieving sustained viral clearance is unlikely.

Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease.

BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease. METHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy. RESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction. CONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.

Human monocytic ehrlichiosis: an emerging pathogen in transplantation.

BACKGROUND: The spectrum of disease caused by Ehrlichia spp. ranges from asymptomatic to fatal. Awareness and early diagnosis of the infection is paramount because appropriate therapy leads to rapid defervescence and cure. If left untreated, particularly in immunosuppressed patients, ehrlichioses may result in multi-system organ failure and death. METHODS: We report the second case of human monocytic ehrlichiosis (HME) in a liver transplant recipient, and review the literature. RESULTS: The patient presented with fever and headache, had negative cultures, and despite broad-spectrum antimicrobial coverage appeared progressively septic. After eliciting a history of tick exposure we treated the patient empirically with doxycycline. The diagnosis of HME was confirmed by 1) polymerase chain reaction (PCR) for Ehrlichia chaffeensis, 2) acute and convalescent serum titers, and 3) in vitro cultivation of E chaffeensis from peripheral blood. CONCLUSION: Although human ehrlichioses are relatively uncommon, they are emerging as clinically significant arthropod-borne infections. Although epidemiological exposure is responsible for infection, immunosuppression makes patients more likely to succumb to disease. A high index of suspicion and early treatment results in a favorable outcome.

Liver transplant and recurrent disease.

Current prophylactic measures have greatly reduced recurrence rates of hepatitis B after liver transplantation. HBIG remains a critically important compound and although there is variability in dosing regimens and target anti-HBs levels, it is the backbone of recurrence prevention. Adjuvant therapies with nucleoside/nucleotide analogs alone have been limited by drug-resistant strains of HBV, but the armamentarium of these molecules continues to grow and hence the management of the post-LT HBV patient will evolve further. Currently lamivudine with HBIG remains an excellent option provided the patient has not developed resistance, especially in the pre-LT period. Adefovir is the drug of choice in that setting and perhaps the preferred drug in the pre-LT setting to allow the use of lamivudine post-LT. Further testing with tenofovir and newer compounds in development will expand these options. The use of multiple nucleoside analogs is an intriguing option, based on the HIV experience of reducing drug resistance and optimizing viral suppression, and will likely be further studied.