Hepatitis: Boston

Matthews SJ. · Division of Clinical Pharmacy, Department of Pharmacy Practice, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, 237 Mugar Hall, 360 Huntington Avenue, Boston, MA 02115, USA. · Clin Ther. · Pubmed #18201580 No free full text.

Abstract: BACKGROUND: Telbivudine (LdT) is an L-nucleoside that is structurally related to lamivudine. It is highly selective for hepatitis B virus (HBV) and inhibits viral DNA synthesis. LdT was approved by the US Food and Drug Administration on October 25, 2006, for the treatment of chronic HBV infection in adults who have active viral replication and either elevations in liver transaminases or signs of active liver disease on histologic examination. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, and therapeutic efficacy of LdT. Potential drug interactions and adverse events associated with the use of LdT are also reviewed. METHODS: Relevant publications were identified from searches of MEDLINE (1996-June 2007), the Cochrane Library, and BIOSIS (1993-June 2007). Search terms included, but were not limited to, telbivudine, beta-L-thymidine, LdT, pharmacology, pharmacokinetics, adverse events, resistance, drug interactions, hepatitis B, and therapeutic use. Additional publications were identified from the reference lists of the identified papers, meeting abstracts, and correspondence with the manufacturer of LdT. RESULTS: After 52 weeks of therapy in the Phase III GLOBE study, HBV resistance (breakthrough and resistance mutations) to LdT occurred in 3% of patients who were hepatitis B e antigen (HBeAg) positive and 2% of patients who were HBeAg negative. After 104 weeks of therapy, 17.8% to 21.6% of HBeAg-positive and 7.3% to 8.6% of HBeAg-negative LdT-treated patients had a rebound in HBV DNA associated with breakthrough and resistance mutations. After 24 weeks of treatment, the risk of resistance was greater in patients with HBV DNA titers >3 log(10) copies/mL than in those with lower numbers of copies. LdT is not active against lamivudine-resistant HBV. The proportion of HBeAg-positive patients with undetectable HBV DNA (by polymerase chain reaction assay) after 104 weeks of therapy in the GLOBE study was significantly greater with LdT compared with lamivudine (56% vs 39%, respectively; P < 0.05). After 104 weeks of therapy, the corresponding proportions of HBeAg-negative patients with undetectable HBV DNA were 82% and 57% (P < 0.05). Patients who failed lamivudine therapy in the GLOBE study showed cross-resistance to LdT. The most common adverse events associated with LdT are upper respiratory tract infection (14%-17%), fatigue and malaise (12%-14%), nasopharyngitis (11%-15%), headache (11%-12%), and abdominal pain (6%-12%). Grade 3/4 adverse events included elevations in serum creatine kinase, which were more common in patients receiving LdT than in those receiving lamivudine (9% vs 3%, respectively). Elevations in creatine kinase are typically asymptomatic; however, myopathy has been reported in 3 of 680 patients receiving LdT. CONCLUSIONS: LdT joins the increasing number of antiviral agents for the management of chronic HBV infection. Questions concerning the optimal length of therapy and long-term efficacy await the results of on-going clinical trials. Concerns about increasing resistance over time may relegate LdT to second-line status in the management of chronic HBV infection. The role of LdT in combination therapy is under investigation.

Afdhal NH, McHutchison JG. · Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. · Aliment Pharmacol Ther. · Pubmed #17958517 No free full text.

Abstract: BACKGROUND: Patients with chronic liver disease and hepatitis C virus (HCV) frequently experience thrombocytopenia that complicates the management of their disease. Traditional therapy for thrombocytopenia consists of platelet transfusion, which can be associated with significant safety and economic issues. Consequently, efforts have been directed toward developing novel approaches for the treatment of thrombocytopenia. AIM: To summarize the available data on the limitations of traditional therapies and the effects of novel therapies currently in clinical development for the treatment of thrombocytopenia. RESULTS: Recent research has begun to reveal the complex mechanisms that regulate thrombopoiesis. Cytokines and growth factors, such as interleukin-11 and thrombopoietin (TPO), play a key role in the production of platelets. A number of recent clinical studies have provided evidence that pharmacologic agents that target megakaryocyte precursors and stimulate thrombopoiesis can effectively reverse thrombocytopenia. Here, we review the regulation of thrombopoiesis, the role of TPO, and a number of novel compounds that stimulate platelet production by acting through the TPO receptor. Agents that stimulate TPO include the orally available nonpeptidic agonists eltrombopag and AKR-501, peptidic agonists AMG-531 and Peg-TPOmp, and small engineered antibodies. CONCLUSION: Results from clinical trials with these agents in healthy subjects confirm that activation of thrombopoiesis via the TPO pathway is an effective method of stimulating platelet production. This approach may provide safer, more effective treatment for thrombocytopenia in patients with chronic liver disease. Several of these agents are currently being tested in large scale trials.

Agnello V, Elfahal M. · Department of Laboratory Medicine, Lahey Clinic, Burlington, MA, USA. · Dig Liver Dis. · Pubmed #17936219 No free full text.

This publication has no abstract.

Kamal SM. · Harvard Institute of Medicine, Boston, Massachusetts 02115, USA. · Am J Gastroenterol. · Pubmed #17900328 No free full text.

Abstract: Several factors influence treatment outcomes among patients with chronic hepatitis C. A trend is growing to adapt an individualized treatment approach to optimize treatment outcomes among chronic hepatitis C patients. Hepatitis C virus (HCV) genotype is an important factor that determines treatment outcomes among patients with chronic hepatitis C. HCV has six genotypes, and genotype 4 (G4) accounts for 20% of all global HCV infections. Patients with G4 are underrepresented in clinical trials involving patients with chronic hepatitis C because most patients infected with G4 are in Egypt, Africa, and Middle Eastern countries. Therefore, there is little information about the predictors of response to standard treatment among chronic hepatitis C patients with HCV G4. Initial evidence suggested that patients with G4 HCV are as difficult to treat as patients with G1; however, recent evidence suggests that the response rates to treatment among patients with G4 may be better than those with G1 but not those with G2 or G3. This review discusses the clinical data among patients with G4 and assesses the impact of an individualized approach on improved treatment outcomes in these patients.

Rajendra A, Wong JB. · Division of Clinical Decision Making, Department of Medicine, Tufts-New England Medical Center, Tufts University School of Medicine, 750 Washington Street, NEMC 302, Boston, MA 02111, USA. · J Hepatol. · Pubmed #17697724 No free full text.

Abstract: Although not all patients develop progressive liver disease, chronic hepatitis B and chronic hepatitis C infections cause substantial morbidity and mortality worldwide. To address this need, many new antiviral treatments have become available over the past 10 years. While safety, efficacy, and therapeutic indications have been well established for these agents, the economics of antiviral treatment have become increasingly a focus of discussion for physicians, policymakers, and health payers. In this paper, we will elucidate some economic principles using examples from the treatment of hepatitis B and C. In particular, we will examine the considerations in estimating drug costs, methods for performing economic analyses and lastly summarize published cost-effectiveness analyses for antiviral treatments of chronic hepatitis B and chronic hepatitis C. This review should help clinicians understand economic issues regarding new drugs and answer questions about whether the clinical benefit provided by a medication justifies its expense.

Bataller RM. · University of Massachusetts, Boston, 35 Moreland Ave, Lexington, MA 02421, USA. · J Emerg Nurs. · Pubmed #17643793 No free full text.

This publication has no abstract.

Koziel MJ, Peters MG. · Division of Infectious Disease, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA. · N Engl J Med. · Pubmed #17409326 No free full text.

This publication has no abstract.

Farazi PA, DePinho RA. · Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. · Discov Med. · Pubmed #17234139 No free full text.

Abstract: Liver cancer is among the most common malignancies, impacting significantly across all societies worldwide. The lethal impact of this prevalent cancer is unlikely to change considerably in the near future due to a limited understanding of disease pathogenesis on the molecular, cellular, and environmental levels and how current knowledge might be converted into new preventive, therapeutic and diagnostic approaches. This article highlights the current challenges and opportunities in this critical area of unmet need.

Dienstag JL, Wei LJ, Xu D, Kreter B. · Gastrointestinal Unit (Medical Services), Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Clin Drug Investig. · Pubmed #17177578 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Lamivudine and adefovir were approved for treatment of chronic hepatitis B virus (HBV) infection based on placebo-controlled trials, and entecavir was recently approved on the basis of its superiority over lamivudine in phase II/III trials; however, to date, these three therapies have not been compared head to head. METHODS: To evaluate the relative efficacy of these therapies, we applied a predefined protocol of established statistical techniques to compare data from phase III entecavir trials with published clinical trial results with lamivudine, adefovir and placebo in nucleoside-naive hepatitis B e antigen (HBeAg)-positive and -negative populations. RESULTS: A comprehensive literature search identified 612 publications/data sources, of which 28 satisfied predefined inclusion criteria. Independent reviewers extracted week 48-52 histological, virological, biochemical and serological endpoints from these sources, which were analysed with a fixed-effects model. For each of the three histological endpoints in HBeAg-positive patients (Histological Improvement, Ranked Assessment of Necroinflammation [RA-N] and Ranked Assessment of Fibrosis [RA-F]), entecavir was superior to adefovir. Entecavir was superior to lamivudine for Histological Improvement and comparable to lamivudine for RA-N and RA-F. With respect to reducing HBV DNA levels, entecavir (-6.98 log(10) copies/mL) was more effective than lamivudine (-5.46 log(10) copies/mL, p < 0.0001) and adefovir (-3.60 log(10) copies/mL, p < 0.0001), and lamivudine was more effective than adefovir (p < 0.0001). The parallel goals of HBV DNA reduction below the limit of quantitation (LOQ) [by polymerase chain reaction] and ALT normalisation were achieved more often with entecavir (69% and 67% of patients, respectively) than with lamivudine (38% and 59%, respectively; p < 0.0001 and p < 0.05, respectively) or adefovir (21% and 48%, respectively; both p < 0.0001), and more often with lamivudine than with adefovir (p < 0.0001 and p < 0.05, respectively). HBeAg seroconversion rates were higher with entecavir (21% of patients) and lamivudine (18%) than with adefovir (12%, p < 0.01 and p < 0.05, respectively). For each of the three histological endpoints in the HBeAg-negative population, entecavir was comparable to adefovir. Entecavir was superior to lamivudine for Histological Improvement, and comparable to lamivudine for RA-N and RA-F, and all three antivirals were superior to placebo. Entecavir proved superior to lamivudine and adefovir in lowering HBV DNA levels (-5.20 vs -4.66 vs -3.91 log(10) copies/mL, respectively; p < 0.0005 and p < 0.0001, respectively) and in suppressing HBV DNA below the LOQ (91% vs 73% vs 51% of patients, respectively; both p < 0.0001); in the latter respect, lamivudine was in turn superior to adefovir (p < 0.0001). Entecavir was also superior to lamivudine in normalising ALT (76% vs 69% patients, respectively; p < 0.05). CONCLUSIONS: Over a 12-month treatment period, this analysis predicts that the antiviral efficacy of entecavir would be superior to that of lamivudine, which in turn would be superior to that of adefovir, in nucleoside-naive patients with chronic HBV infection.

Russmann S, Grattagliano I, Portincasa P, Palmieri VO, Palasciano G. · Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA. · Curr Med Chem. · Pubmed #17168855 No free full text.

Abstract: Ribavirin (RBV) is an antiviral nucleoside analogue commonly used in combination with interferon for the treatment of chronic hepatitis C. Severe anemia develops in about 10% of treated patients, and requires close monitoring of hemoglobin and often RBV dose reduction, which may compromise sustained virologic response. Anemia is likely related to extensive RBV accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. RBV exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system. Concentration-dependent toxicity and improvement of anemia upon dose-reduction point towards the importance of pharmacokinetic factors for RBV-induced anemia. On the other hand, pronounced variability in the correlation between RBV concentration and Hb reduction limits the prediction of anemia based on plasma or erythrocyte concentrations in individual patients and points towards additional factors determining individual susceptibility to RBV-induced anemia. Recent studies suggest that erythrocyte oxidative defense mechanisms may play an important role in RBV-induced anemia. Clinical risk factors for severe RBV-induced anemia include impaired renal function, high age, high dose per body weight and female gender. Determination of RBV concentrations has little value in the management of anemia. The only proven effective prevention of RBV-induced anemia is the concomitant administration of erythropoietin. Future research on RBV pharmacokinetics and pharmacodynamics, as well as erythrocyte antioxidant defense mechanisms may improve safety and efficacy of RBV therapy and guide the development of new treatments for RBV-induced anemia and alternative antiviral agents.

Shah BB, Wong JB. · Division of Clinical Decision Making, Informatics, and Telemedicine, Tufts-New England Medical Center, Tufts University School of Medicine, 750 Washington Street #302, Boston, MA 02111, USA. · Clin Liver Dis. · Pubmed #17164114 No free full text.

Abstract: Hepatitis C virus is a disease of major public health significance throughout the world in terms of overall morbidity and mortality and in its economic consequences and demands on medical resources. The global economic burden of this disease has yet to be fully realized. In this article the authors discuss the economic burden of hepatitis C, the economics of therapy, and the economics of its prevention and screening.

Qin X, Gao B. · Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139, USA. · Cell Mol Immunol. · Pubmed #17092430 links to  free full text

Abstract: The complement system plays an important role in mediating both acquired and innate responses to defend against microbial infection, and in disposing immunoglobins and apoptotic cells. The liver (mainly hepatocytes) is responsible for biosynthesis of about 80-90% of plasma complement components and expresses a variety of complement receptors. Recent evidence from several studies suggests that the complement system is also involved in the pathogenesis of a variety of liver disorders including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury. In this review, we will discuss the potential role of the complement system in the pathogenesis of liver diseases.

Andersson K, Chung RT. · Department of Gastroenterology, Blake 4, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. · Clin Liver Dis. · Pubmed #16971263 No free full text.

Abstract: Treatment of HCV in the coinfected patient poses numerous challenges to the clinician: difficult comorbidities, an increased risk of medication side effects, and a therapy with limited response rates. End-stage liver disease from HCV has become a leading cause of death in coinfected patients. Without focused disease management, the burden of chronic liver disease in this population will rise. This article discusses the major trials investigating the use of interferon and ribavirin in coinfected patients, proposes a treatment algorithm for HCV/HIV coinfection, and considers approaches to patients who do not respond to this treatment.

Pantanowitz L, Schlecht HP, Dezube BJ. · Department of Pathology, Baystate Medical Center, Tufts University School of Medicine, Springfield, Massachusetts, USA. · Curr Opin Oncol. · Pubmed #16894295 No free full text.

Abstract: PURPOSE OF REVIEW: The incidence and spectrum of non-AIDS-defining cancers has continued to grow. As HIV-infected individuals live longer due to highly active antiretroviral therapy, their risk of dying from one of these cancers is increased. The recent literature pertaining to non-AIDS-defining cancers is reviewed. RECENT FINDINGS: Recent epidemiological studies have identified higher rates of carcinoma of the anus, lung, breast, skin, conjunctiva, liver and prostate; hematopoietic malignancies such as Hodgkin's lymphoma, plasma-cell neoplasia and leukemia; and other neoplasms like melanoma and leiomyosarcoma in HIV-positive patients. The role of HIV-induced immunosuppression in the development of these non-AIDS-defining cancers appears less important than lifestyle habits like smoking and sun exposure, as well as coinfection with human papilloma, hepatitis B, hepatitis C and Epstein-Barr viruses. SUMMARY: It is unclear whether the growing number of reports on non-AIDS-defining cancers reflects a true increased incidence or merely the product of increased surveillance, detection and reporting. Highly active antiretroviral therapy not only promotes longevity in the HIV-positive population, but may increase their risk of developing cancer like Hodgkin's lymphoma. Assertive prevention strategies are needed to adequately deal with non-AIDS-defining cancers in an aging and growing HIV-positive population.

Chung RT. · Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA. · Top HIV Med. · Pubmed #16835462 links to  free full text

Abstract: Coinfection with HIV accelerates disease progression in both hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. Management of coinfected patients is complicated by a number of factors, including disease characteristics, drug-drug interactions, and augmented toxicity. Results of HCV and HBV treatment trials in HIV-coinfected patients and strategies for patient management are discussed herein.

Waseem T. · Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · J Coll Physicians Surg Pak. · Pubmed #16827966 No free full text.

Abstract: Gene therapy is the most recent face of modern biotechnology, which has shown promise of disease diagnosis and management at a newer and the most sophisticated level. The reason of enormous interest in gene therapy lies in the fact that most of lethal pathologies including hepatitis B and C, AIDS and carcinogenesis are refractory to contemporary treatments. These techniques, at least in controlled environment, allow turning on and off various genomic sequences. Relevant to this subject, RNA interference (RNAi) is the most recent, highly precise method to silence almost any gene of choice. Currently, RNAi for various disorders is being tried in humans; if this therapeutic strategy works at clinical level as well, it would be possible to design therapies against certain intractable pathologies including hepatitis C and AIDS.

Jonas MM. · Children's Hospital, and Harvard Medical School, Boston, MA 02115, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #16819403 No free full text.

Abstract: Chronic hepatitis B infection remains a significant health problem worldwide, and acquisition during infancy or childhood causes many of the chronic infections that are responsible for the morbidity associated with this disease. Some children with chronic hepatitis B are candidates for treatment. Two medications are currently licensed for use in children, and it is anticipated that others will be available in the next several years. This article describes rationale for treatment, patient selection and pros and cons of the current and expected therapeutic options.

Kausz AT, Gilbertson DT. · Division of Nephrology, Tufts-New England Medical Center, Boston, MA 02111, USA. · Adv Chronic Kidney Dis. · Pubmed #16815227 No free full text.

Abstract: Infections are a major cause of death in end-stage renal disease (ESRD) patients, second only to cardiovascular disease, and also contribute to significant morbidity in patients with earlier stages of chronic kidney disease (CKD). Vaccines are a strategy to attempt to reduce morbidity related to infections. Patients with CKD and ESRD may not respond as well to vaccines as patients without kidney failure, but adequate seroresponse with standard or augmented regimens for vaccinations against influenza, hepatitis B, pneumococcus, and varicella have been documented. Influenza, in particular, seems to provide adequate protection with standard dosing regimens. Despite somewhat reduced effectiveness of certain vaccines in patients with CKD, there is emerging evidence of benefit to vaccination in these populations. However, vaccination rates are relatively low. Given the accumulating evidence of benefit, continuing quality improvement programs focused on increasing vaccination rates in patients with all levels of CKD are needed.

Whary MT, Fox JG. · Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Ave., Bldg. 16-825A, Cambridge, MA 02139, USA. · Lab Anim (NY). · Pubmed #16807564 No free full text.

Abstract: Researchers first isolated and characterized Helicobacter hepaticus in 1994 as a cause of hepatitis that progressed to hepatocellular carcinoma in A/JCr mice. During the past decade, isolation and characterization of additional novel helicobacters from rodents has continued. In addition to causing overt disease, rodent helicobacter infections are important because intercurrent disease in select models will confound research data. Emerging evidence suggests that inflammatory responses to enterohepatic helicobacter infections may alter host responses to other experimental stimuli in unanticipated ways. Additionally, scientists have experimentally infected a variety of inbred mouse strains and genetically engineered mice with a variety of Helicobacter spp. isolated from rodents, birds, and higher mammals (including humans) to develop animal models of gastrointestinal diseases as well as idiopathic human disease syndromes. This review highlights current information about helicobacter infections in laboratory rodents and provides recommendations for the detection and eradication of these infections. The authors discuss the impact of subclinical and clinical disease and offer recommendations for managing helicobacter-free rodent colonies.

Wong JB. · Division of Clinical Decision Making, Department of Medicine, Tufts University School of Medicine, Tufts-New England Medical Center, Tupper Research Institute, Boston, Massachusetts 02111, USA. · Pharmacoeconomics. · Pubmed #16802842 No free full text.

Abstract: Chronic hepatitis C virus (HCV) infection affects 170 million individuals worldwide. As it is detected incidentally through the evaluation of liver function tests or at the time of blood donor testing, it is usually clinically silent until the advanced stages of liver disease have occurred, when treatment is less effective and shortages of donor liver organs limit the therapeutic options. Combination therapy with ribavirin and pegylated interferon has resulted in sustained viral negative response rates of 54-61%. Because treatment is expensive and not uniformly effective, and because not all chronically infected patients will develop complications, concerns have arisen regarding the cost effectiveness of combination therapy. This paper reviews the public health and individual implications of HCV infections. Because of the latency of infection, numerous country-specific population analyses suggest that HCV will cause an increasing number of liver-related deaths over the next 10 years, despite the dramatic drop in incidence over the past 10-15 years. These deaths will be related to prevalent HCV infection from transfusion and injection drug use prior to identification of the virus and availability of screening tests in the late 1980s and early 1990s. HCV can reduce life expectancy and impair quality of life, yet not all patients will develop progressive liver disease, and antiviral treatment may have associated adverse effects. Finally, to assess the value of antiviral drugs for HCV infection, this paper reviews studies examining the costs of antiviral drugs and of the disease itself along with response to antiviral therapy and the cost effectiveness of antiviral therapy. Although antiviral therapy appears to be expensive, when also considering the likelihood of sustained viral response to therapy, and the cost savings, quality-of-life improvement and prolongation of life expectancy from the prevention of HCV complications, antiviral treatment for HCV appears to be cost effective when compared with other well accepted medical interventions.

O'Leary JG, Chung RT. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · AIDS Read. · Pubmed #16795921 No free full text.

Abstract: Approximately 300,000 patients in the United States are coinfected with HIV and hepatitis C virus (HCV). More rapid progression of HCV-related liver disease is seen in coinfected patients than in HCV-monoinfected patients. Since the introduction of potent antiretroviral therapy, liver disease has become a leading cause of death in HIV-infected patients. Therefore, more aggressive management of HCV-related liver disease is essential in HIV-positive patients. Recently, several trials have established the superiority of pegylated interferon alfa in combination with ribavirin to standard interferon with ribavirin for treatment of HCV infection in HIV-HCV-coinfected patients. Sustained virologic response (SVR) rates were only 14% to 29% in genotype 1 and 43% to 73% in genotype 2 and 3 HCV with 48 weeks of combination therapy. Absence of an early virologic response determined at 12 weeks can limit treatment exposure in patients destined not to achieve an SVR. The risk of interactions between drugs used to treat hepatitis C and those for HIV, such as between ribavirin and didanosine, needs to be considered before initiating treatment in HIV-HCV-coinfected patients.

Matthews SJ. · Department of Pharmacy Practice, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts 02115, USA. · Clin Ther. · Pubmed #16678641 No free full text.

Abstract: OBJECTIVE: This article reviews the pharmacology/pharmacokinetics and therapeutic efficacy of entecavir, which was approved on March 29, 2005, for the management of adult patients with chronic hepatitis B virus (HBV) infection who have active viral replication and/or elevations in liver transaminases or signs of active liver disease on histologic examination. Potential drug interactions and adverse events associated with the use of entecavir are also reviewed. METHODS: Relevant literature was identified through searches of MEDLINE (1996-July 2005) and BIOSIS (1993-July 2005). Search terms included, but were not limited to, entecavir, BMS-200475, hepatitis B, pharmacology, pharmacokinetics, adverse events, and therapeutic use. Further publications were identified from the reference lists of the identified articles and through correspondence with the manufacturer of entecavir. RESULTS: Entecavir is highly selective for the HBV and inhibits all 3 steps of viral replication. Results of early studies indicated a 6% resistance potential after 48 weeks of therapy, although the potential may be higher in patients who harbor lamivudine-resistant mutants. The approved dosage in treatment-naive patients is 0.5 mg/d p.o., administered on an empty stomach; in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg/d p.o.. The oral tablet and solution can be used interchangeably. Entecavir is well absorbed orally, achieving a dose-related Cmax between 0.6 and 1.5 hours after administration. It is metabolized to a small extent and is not a substrate for the cytochrome P450 enzyme system. The mean elimination t(1/2) ranges from 77 to 149 hours in patients with normal kidney function. Entecavir is eliminated primarily in the urine via glomerular filtration and tubular secretion (62%-73%). No dose adjustment appears to be necessary in patients with moderate to severe liver disease alone. The potential for drug interactions with entecavir appears to be minimal, although medications that inhibit tubular secretion of drugs (eg, probenecid) may be expected to prolong serum concentrations of entecavir. One of the Phase III studies of entecavir found statistically significant benefits compared with lamivudine in terms of improvements in liver histology after 48 weeks of therapy (72% vs 62%, respectively; P<0.009), the proportions of patients with undetectable HBV DNA titers on branched DNA signal amplification assay after 48 weeks of therapy (91% vs 65%; P<0.001), and the proportion with undetectable HBV DNA on polymerase chain reaction (PCR) assay after 48 weeks of therapy (69% vs 38%; P<0.001). In another Phase III study, patients who had failed to respond to lamivudine therapy responded to entecavir: after 48 weeks of therapy, significant differences between entecavir and lamivudine were seen in histologic improvement (55% vs 28%; P<0.001) and the proportion of patients with undetectable HBV DNA on PCR assay (21% vs 1%; P<0.001). Adverse events associated with entecavir therapy were similar in character, severity, and incidence to those associated with placebo or lamivudine therapy. The most common adverse events in clinical trials of entecavir were headache (17%-23% of patients), upper respiratory tract infection (18%-20%), cough (12%-15%), nasopharyngitis (9%-14%), fatigue (10%-13%), dizziness (9%), upper abdominal pain (9%-10%), and nausea (6%-8%). CONCLUSIONS: Entecavir is a new antiviral agent for the management of chronic HBV infection. Questions concerning the ideal length of therapy, long-term efficacy, and resistance rates over time await the results of ongoing clinical trials.

Goldberg HJ, Fiedler D, Webb A, Jagirdar J, Hoyumpa AM, Peters J. · Brigham and Womens' Hospital, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Harvard University School of Medicine, PBB Clinics-3, 75 Francis St., Boston, MA 02115, USA. · Respir Med. · Pubmed #16675213 No free full text.

Abstract: Recombinant interferon-alpha (rINF-alpha) is an immunomodulator used in the treatment of various conditions, including viral infections and malignancies. The use of rINF-alpha has been associated with the development of sarcoidosis in recent case reports. In this series, we report the incidence of sarcoidosis in recipients of rINF-alpha for hepatitis C viral (HCV) infection at our institution. We also review the 57 additional cases of sarcoidosis associated with rINF-alpha described in the literature, including clinical presentation, radiographic findings, management, and outcomes, and discuss the potential mechanisms by which rINF-alpha may lead to the development of sarcoidosis.

Dienstag JL. · Massachusetts General Hospital, Harvard Medical School, Blake 4, 55 Fruit Street, Boston, MA 02114, USA. · Am J Gastroenterol. · Pubmed #16448448 No free full text.

Abstract: New antiviral agents are currently being developed to treat patients with chronic hepatitis B. Both pegylated interferon alfa-2a and entecavir are now approved for the treatment of hepatitis B while telbivudine, tenofovir, emtricitabine, and pegylated interferon alfa-2b are in clinical development. Successive advances have resulted in more profound suppression of hepatitis B replication, a reduction in breakthrough resistance, and an increase in the frequency of attainment of virologic, serologic, biochemical, and histologic clinical endpoints.

Dienstag JL, McHutchison JG. · Gastrointestinal Unit (Medical Services) Massachusetts General Hospital, Department of Medicine and Office of the Dean for Medical Education, Harvard Medical School, Boston, Massachusetts, USA. · Gastroenterology. · Pubmed #16401486 No free full text.

This publication has no abstract.