Treatment of hepatitis D: an unmet medical need.

BACKGROUND: Therapy of chronic hepatitis D (CHD) is still based on interferon alpha (IFNα), introduced in clinical practice 30 years ago: results are modest and better therapies are an urgent medical need. AIMS: This article provides a critical overview of the new therapies under investigation for CHD. SOURCES: Review of the recently published medical literature. CONTENT: New therapeutic efforts aim to deprive the hepatitis D virus (HDV) of functions provided to its life cycle by the hepatitis B Virus (HBV) or by the host. Three therapeutic strategies are in evaluation: a) Myrcludex B, a myristolated lipopeptide of the pre-S1 domain of the HBsAg that blocks the entry of the HDV into hepatocyes and controls infection by preventing the spreading of the virus to liver cells not infected by the HBV; b) Lonafarnib, an inhibitor of a host farnesyl-transferase that hinders morphogenesis of the HDV by preventing the farnesylation of the large HD-antigen, necessary for virion assembly; c) REP 2139, a nucleic acid polymer that prevents export of the mature HDV by the presumed inhibition of the synthesis of subviral HBsAg particles with which the virion is coated. Myrcludex B and Lonafarnib increase therapeutic efficacy in combination with Peg-IFNα. In a pilot study, REP 2139 in combination with Peg-IFNα induced the clearance of serum HDV RNA and of the HBsAg in about half of 12 treated patients. IMPLICATIONS: Long-term therapies with either Myrcludex B or Lonafarnib in combination with Peg-IFNα are required to achieve clinical control of CHD. However, with prolonged therapies tolerance becomes a problem; studies are on the way to determine whether Peg-IFN lambda may be better tolerated that Peg-IFNα. The promising preliminary data of REP 2139 in combination with Peg-IFNα await confirmation of the original pilot study.

HBsAg kinetics in chronic hepatitis D during interferon therapy: on-treatment prediction of response.

BACKGROUND: Therapy of chronic hepatitis D with Interferon is successful when testing for HDV-RNA turns negative. This end-point is disputed. AIM: To assess the role of serum hepatitis B surface antigen (HBsAg) in the clearance of HDV-RNA in pegylated interferon (Peg-IFN)-treated chronic hepatitis D (CHD). METHODS: Sixty-two patients with CHD, treated with Peg-IFN, were considered. The patients belonged to three groups: 14 patients cleared the HBsAg and HDV-RNA (responders, R), 12 cleared the HDV-RNA remaining positive for HBsAg (partial responders, PR) and 36 cleared neither the HBsAg nor the HDV-RNA (nonresponders, NR). RESULTS: In responders, at baseline the median value (mv) of HBsAg and HDV-RNA was 1187 and 188 663 IU/mL. By month 6 of therapy, HBsAg declined to less than 1000 IU/mL and HDV-RNA was undetectable in 12 patients. In NR, the pre-therapy median value of HBsAg and HDV viremia was 6577 and 676 319 IU/mL. There was no significant reduction of antigen at month 6; after a decline, HDV-RNA rebounded to baseline levels. In PR, the median value of baseline HBsAg was 7031 IU/mL; it declined at month 6 in the majority. HDV-RNA progressively declined from an initial median value of 171 405 IU/mL. HBsAg <1000 IU/mL at month 6 discriminated responders and PR from NR (P < 0.001). By ROC curve, the threshold of 0.105 log reduction of HBsAg associated with 1.610 log reduction of HDV-RNA from baseline to month 6 predicted the clearance of this marker. CONCLUSIONS: A reduction of serum HBsAg is mandatory for the definitive clearance of the HDV-RNA. Quantitative HBsAg may predict the long-term response to Peg-IFN therapy and provide a guide to prolong or stop treatment.

Reasons for nonuse of antiviral treatment in patients with chronic hepatitis C infection and thrombocytopaenia: a retrospective chart review from five European countries.

Antiviral therapy has been shown to reduce the risk of disease progression, liver damage and death in patients with chronic hepatitis C virus (HCV) infection. While interferon labels recommend that patients with platelet counts below 50 × 10(3) /µL not receive interferon-based therapy, it is unknown to what extent thrombocytopaenia influences treatment decisions in practice. This study profiles the reasons for withholding antiviral treatment in HCV patients with thrombocytopaenia in five European countries. Medical records of 466 patients who had HCV infection and thrombocytopaenia (platelet count <100 × 10(3) /µL) in 2006 were retrospectively reviewed for clinical characteristics. Collected data included use of antiviral therapy and reasons for withholding therapy. In total 184 of 466 patients (39.5%) did not receive interferon-based therapy during the study period, with treatment withheld most frequently due to multiple clinical characteristics including hepatic cirrhosis (16.3%), thrombocytopaenia (16.3%) and age >60 years (10.9%). The reasons for lack of treatment varied among countries, with thrombocytopaenia as a reason being more common in Italy (10.9%) and Spain (20.0%), and less common in France, Germany and the UK (3.2-7.1%). Overall, thrombocytopaenia was reported as the only reason for withholding treatment in 4.9% of untreated patients. This study demonstrates that thrombocytopaenia is one of many factors, indicative of the poor clinical state of the patient, that contributes to withholding antiviral treatment. In 4.9% of untreated patients, thrombocytopaenia can be considered as a modifiable factor to enable more HCV patients to receive guideline-recommended therapy and thus improved clinical outcomes.

Endoscopic ultrasound in the 2013 preoperative evaluation of gastric cancer.

The capacity of endoscopic ultrasound (EUS) to distinguish the different wall layers of the gastrointestinal (GI) tract and the possibility to obtain samples of suspicious lesions or lymph nodes by means of EUS-guided fine-needle aspiration (EUS-FNA), make EUS an ideal staging modality for GI cancers. After an endoscopic and histological diagnosis of gastric cancer (GC), an accurate preoperative evaluation is essential to choose the correct management decision, because for this malignancy various and radically different stage-oriented therapies can be performed. Even if EUS is inserted in the last guidelines for the management of GC as an essential pretherapeutic staging modality, in the literature the reported accuracy, the imaging features and the performances of the technique are variable. In this review, we synthesize the current status and the imaging findings of EUS when describing and staging GC, with a particular attention to the early GC that represents till today a diagnostic and therapeutic challenge. Currently, the EUS study is mandatory for the preoperative staging, to assess with a good accuracy the tumor depth of wall invasion, the presence of suspicious lymph-nodes and of ascites (predictive of peritoneal involvement). The main limitations for a correct EUS staging remain some features of the lesion or its localization, so more attention should be paid when these characteristics are present.

Inflammatory bowel diseases and primary sclerosing cholangitis: hepatic and pancreatic side effects due to azathioprine.

BACKGROUND AND OBJECTIVES: In up to 80% of cases primary sclerosing cholangitis (PSC) is associated with inflammatory bowel diseases (IBD). The efficacy of azathioprine (AZA), in the maintenance of remission of IBD has been suggested by several studies. However, AZA tends to exter varied well-known toxicity. Since the rate of hepato-pancreatic side-effects in patients with IBD and PSC is still unclear, we investigated this issue. MATERIALS AND METHODS: Consecutive subjects who underwent Outpatient Clinic admission for both IBD and PSC were included. Both conditions were diagnosed according to International Guidelines. RESULTS: Data of 43 patients were elaborated. Twelve of them underwent therapy with AZA. Five (41.7%) presented hepatic (n=4) or pancreatic toxicity. Eighty percent of the patients with hepato-pancreatic reactions versus 28.6% of those without (p < 0.001) were males, with 60% affected by ulcerative colitis and 40% by Crohn's disease versus 57% and 43%, respectively. Forty percent of patients with reactions versus 43% of those without needed an operation for IBD, and the same percentage underwent orthotopic liver transplantation, with a 100% versus 66.7% (p < 0.001) need of second transplantation. Colonic neoplasia (20%) was detected only in the former group while cholangiocarcinoma (28.6%) only in the latter. CONCLUSIONS: The occurrence of hepato-pancreatic reactions from AZA in our caseload is higher (41.7%) compared to that reported in literature (4%). Therefore, the presence of PSC, in association to IBD, may strongly affect AZA tolerability compared to presence of IBD only.  

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa-2a/ribavirin.

It is unclear whether the current threshold for 'high' hepatitis C virus (HCV) RNA level (800,000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono-infected and 176 HIV-HCV co-infected patients treated with peginterferon alfa-2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono-infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400,000 IU/mL was used and 16% (59%vs 43%) when 800,000 IU/mL was used. In HIV-HCV genotype 1 co-infected patients, the difference was 51% (71%vs 20%) when 400,000 IU/mL was used and 43% (61%vs 18%) when 800,000 IU/mL was used. A lower threshold (200,000 IU/mL) was identified for genotype 1 mono-infected patients with 'normal' alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400,000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1-infected individuals with elevated ALT.

Thymosin alpha-1 with peginterferon alfa-2a/ribavirin for chronic hepatitis C not responsive to IFN/ribavirin: an adjuvant role?

This study was conducted to determine whether the adding thymosin alpha-1 to standard of care for re-treatment of nonresponding hepatitis C infections can improve sustained viral response (SVR) rates. Patients (n = 552) with hepatitis C infections not responding to the combination of Peginterferon alfa-2a or 2b with ribavirin (RBV)were randomized to receive peginterferon alfa-2a 180 mg/week with RBV 800-1200 mg/daily plus either thymosin alpha-1 1.6 mg SC twice weekly (n = 275) or placebo (n = 277) for 48 weeks. Eighty-eight per cent of patients had HCV genotype 1, 6.6% type 4, 2.2% type 2 and 3.6% type 3. SVR rates in the intention to treat population were similar between thymosin alpha-1 and placebo (12.7%vs 10.5%; P = 0.407). Among patients who completed all 48 weeks of therapy, the SVR rate was significantly higher in the thymosin alpha-1 group at 41.0% (34/83) compared with 26.3% (26/99) in the placebo group (P = 0.048). No significant difference was observed between treatment groups in the incidence of adverse events. The addition of thymosin alpha-1 to the standard of care did not increase the on-treatment HCV viral response. Thymosin alpha-1 seems to play no role in the primary therapy of the disease. This study raises the hypothesis that thymosin alpha-1 may have a secondary therapeutic role as an adjuvant in the prevention of relapses in patients achieving a virologic response during therapy.

Diagnosis of deep-seated lymphomas by endoscopic ultrasound-guided fine needle aspiration combined with flow cytometry.

OBJECTIVE: Although endoscopic ultrasound combined with fine needle aspiration (EUS-FNA) is rapidly becoming the preferred diagnostic approach for the sampling and diagnosis of gastrointestinal and mediastinal malignancies, there are limited data as to its use in the diagnosis of lymphoproliferative disorders. Therefore, we carried out a retrospective evaluation of the performance of EUS-guided FNA combined with flow cytometry (FC) as a tool to improve overall sensitivity and specificity in the diagnosis of lymphoma. METHODS: Of 1560 patients having EUS-guided FNA during the period of the study, a total of 56 patients were evaluated by cytology with FC after EUS-FNA. There was adequate material to perform FC analysis for all but one case. RESULTS: EUS-FNA-FC gave a diagnosis of lymphoma in 11 cases and of reactive lymphadenopathy in 20. A specific histological type was defined by FC alone in eight cases. The remaining cases were diagnosed later by cytology and cell block sections: 13 carcinomas, nine granulomatous lymphadenopathies and one mediastinal extramedullary haematopoiesis. One case was considered only suspicious for lymphoma on cytology and FC but was not confirmed on molecular analysis and one had insufficient material for FC. CONCLUSIONS: Our results show that a combination of EUS-FNA-FC is a feasible and highly accurate method, which may be used for the diagnosis and subtyping of deep-seated lymphoma, providing a significant improvement to cytomorphology alone both for diagnosis and treatment planning, as long as immunocytochemistry is available for non-lymphoma cases.

Epilepsy and celiac disease: review of literature.

Celiac disease (CD) is a chronic, immune-mediated disorder, characterized by small intestinal malabsorption of nutrients after the ingestion of gluten by genetically susceptible individuals. The discovery of the wide variations in the nature and intensity of clinical presentation of CD has transformed its status, long considered a rare disease, to that of a common health problem. As patients with CD get older, they tend to present with complaints not directly referable to the gastrointestinal tract. Neurologic symptoms, caused by lesions of the central or peripheral nervous system occasionally occur in patients with CD and are poorly understood. This review focalizes on the present knowledge of the potential relationship between CD and epilepsy. The prevalence of CD among patients with epilepsy is not homogeneously distributed, probably because epilepsy encompasses a heterogeneous group of disorders. In fact, the clinical spectrum of epilepsy related to CD ranges from benign syndromes to intractable epilepsy. The precise mechanism of the potential association between CD and epilepsy is also still under discussion.

The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*.

Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600,000 and 350,000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under-represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost-effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.

Negative predictive value of endoscopic ultrasound in patients referred for fine-needle aspiration.

AIM: Endoscopic ultrasound (EUS) is a valuable diagnostic tool in pancreatic diseases and its high negative predictive value (NPV) in excluding malignancies is universally recognized. Moreover, EUS with fine-needle aspiration (EUS-FNA) can significantly impact on diagnosis and management of many clinical conditions. However, there are circumstances in which EUS-FNA cannot or should not be performed. We evaluated the factors that prevented us from performing or induced us not to perform FNA. METHODS: The study was conducted in a tertiary university hospital. A total of 211 patients suspected of having solid pancreatic malignancy on the basis of clinical presentation and computed tomography and/or magnetic resonance imaging was included. When FNA was withheld because not deemed necessary by the operator, the NPV of EUS was calculated. RESULTS: In 9 patients (4.3% of the procedures), FNA was withheld because of contraindications that should have been foreseen by the referring physician. In 30 subjects, FNA was not accomplished as no lesions requiring biopsy were actually found at EUS exploration. In this group, EUS reached a NPV of 96.7% in excluding malignancy, but it reached 100% in patients without chronic pancreatitis. CONCLUSION: In a cohort of patients with high pre-test probability of malignancy, the high NPV of EUS was confirmed. False negative results should be expected in patients with chronic pancreatitis and they need a strict follow-up.

Endoscopic banding for esophageal variceal bleeding: technique and patient outcome.

AIM: Endoscopic variceal ligation (EVL) is recommended for the treatment of esophageal variceal bleeding. The aim of this study was to assess the most cost-effective timing of endoscopic follow-up after variceal eradication. METHODS: Cirrhotics with esophageal varices treated between January 2008 and January 2009 until reached variceal obliteration were retrospectively analyzed for technical aspects and for outcomes. RESULTS: Out of 127 patients treated with EVL, 103 were included. Number of sessions to achieve variceal obliteration and number of bands for each session were 2.8±1.3 (range 1-7) and 4.6±1 (range 2-7), respectively. The placement of >5 bands per session was not associated with higher incidence of complications (19.6% vs. 17.8%, P=ns). Esophageal ulcers were observed in 42% of patients when the interbanding interval was <20 days (versus 15% for interval >20 days, P<0.05). Once obliteration was achieved, varices reappeared in 28% of patients; the early appearance of small varices was not associated with bleeding. CONCLUSION: A longer interbanding interval reduces the incidence of procedural-related complications. After variceal obliteration an early endoscopic control is not useful because it does not influence the approach and does not change the patient outcome.

Role of endoscopy in the management of gastroenteropancreatic neuroendocrine tumours.

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) represent in clinical practice a diagnostic dilemma because they are often very small, located deeply within the retroperitoneum or in an extramucosal site in the gastrointestinal (GI) tract and, lastly, because they may be multi-sited. Modern digestive endoscopy offers a myriad of techniques, useful for localization, diagnosis and treatment (therapeutic endoscopy). The available tools include upper digestive endoscopy (esophagogastroduodenoscopy, endoscopic retrograde cholangiopancreatography), lower digestive endoscopy (ileo-colonoscopy), enteroscopy (push-type, intra-operative, capsule, double or single balloon), for examining the small intestine, diagnostic and interventional echo-endoscopy (EUS), with radial, linear and miniprobe equipment. This narrative review offers scientific support to affirm that endoscopy and EUS give imaging and diagnostic possibilities that are unbeatable in the localization of GEP-NETs both of the GI tract and the pancreas. Endoscopy is useful for localization, bioptic diagnosis and curative resection of small neuroendocrine lesions of the stomach, duodenum, colon-rectum and more recently of the jejuno-ileum. EUS associated with dedicated instruments, particularly high frequency miniprobes, is a valuable procedure in locoregional staging of lesions of the GI wall and can supply information which has a clinical impact on therapeutic options and prognostic value. EUS is still today the sole technique in a certain number of cases which provides a definitive diagnosis of pancreatic insulinoma and to detect and follow subcentimetric lesions of the pancreas in patients with MEN-1 syndrome. It should be used in all those cases where results from radiographic imaging or nuclear medicine techniques show negative or dubious.