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.

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.

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.

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.

Imatinib (Gleevec)-induced hepatotoxicity.

Imatinib (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) is widely used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. To our knowledge, only one case report of histologically proven Imatinib-induced hepatotoxicity has been reported. We describe another case of hepatotoxicity in a 22-year-old woman including the histopathologic changes and the clinical course after the discontinuation of Imatinib.

IDN-6556 Idun Pharmaceuticals Inc.

IDN-6556 is a lead compound from a class of small-molecule caspase protease inhibitors, and is currently under development by Idun as a potential treatment for acute alcoholic and infectious hepatitis. In October 2003, a phase II trial of IDN-6556 began in 100 patients undergoing liver transplantation.

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.

FIBROSpect II: a potential noninvasive test to assess hepatic fibrosis.

Many forms of liver disease may ultimately lead to fibrosis of the liver, the most advanced state being cirrhosis. Cirrhosis is a morphologic disease that eventually results in a functional change of the liver. It is generally not accompanied by signs or symptoms early in its course, and is often diagnosed late when signs of liver failure become overt. Imaging studies may suggest cirrhosis, but only if there have been gross changes in the appearance of the liver, and this is often not the case. The only way to diagnose cirrhosis reliably has been through direct histologic examination of liver tissue. The drawback to histologic diagnosis has been the risks and discomfort associated with liver biopsy. Hesitation to perform the procedure also exists due to lack of experience of many practitioners and the low reimbursement rates for a procedure that is viewed as time consuming and potentially dangerous. The search for noninvasive modalities to assess fibrosis through biochemical and other means has begun. Several markers are currently under investigation, many of which are combined with clinical assessment and other biochemical parameters, to establish the presence of liver fibrosis. FIBROSpect II is an example of a commercially available assay that employs a combination of three markers to distinguish between no, minimal and advanced fibrosis.

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.

Advances in liver transplantation. New strategies and current care expand access, enhance survival.

Liver transplantation revolutionized the management of liver disease. Although the number of patients who could benefit from a transplant far exceeds the number of available cadaveric donors, new strategies, such as splitting cadaveric organs and using living donors, have expanded access to transplantation. Here, a team of transplant physicians highlights these new strategies, as well as the long-term management issues of special relevance to primary care physicians caring for transplant recipients.

Developments in hepatitis C therapy during 2000-2002.

Hepatitis C virus (HCV) is a human hepatotropic virus with an estimated worldwide prevalence of 170 million cases, including approximately 4 million cases in the US. It is a major cause of liver disease and is the most common indication for liver transplantation in the US. The majority of infected individuals are eligible for therapy. Since it is difficult to predict who will have progressive disease, those with significant inflammation or fibrosis on histologic examination of liver biopsy are generally offered treatment. The following chapter is an overview of the patent literature during 2000-mid-2002, and discusses the potential of various treatment modalities for HCV.

Hepatitis C infection and the patient with end-stage renal disease.

Hepatitis C virus (HCV) remains common in patients with end-stage renal disease (ESRD) and is an important cause of liver disease in this population. Acquisition of HCV infection continues to occur in dialysis patients because of nosocomial spread. The natural history of HCV in dialysis patients remains controversial because the course of HCV typically extends over decades, whereas dialysis patients have higher morbidity and mortality rates than those of the general population limiting long-term follow-up. However, recent reports suggest that HCV infection affects the survival of chronic dialysis patients as well as renal transplant (RT) recipients. The severity of preexisting liver disease on pretransplantation liver biopsy may provide useful prognostic information about clinical outcome after RT; liver biopsy should be incorporated in the evaluation and management of RT candidates with HCV. Recent surveys with long-term follow-up have documented adverse effects of HCV on patient and graft survival. Use of renal grafts from HCV-infected donors in recipients with HCV does not appear to result in a greater burden of liver disease albeit with short-term follow-up. There is only limited data about interferon (IFN) therapy in chronic dialysis patients, although sustained responses are reported. Preliminary data on IFN plus ribavirin therapy in dialysis patients with hepatitis C have given encouraging results, but randomized trials are needed. Interferon remains contraindicated post-RT because of concern about precipitating graft dysfunction.