Predictors of response to tenofovir disoproxil fumarate plus peginterferon alfa-2a combination therapy for chronic hepatitis B.

BACKGROUND: In patients with chronic hepatitis B, tenofovir disoproxil fumarate (TDF) plus pegylated interferon (PEG-IFN) for 48-weeks results in higher rates of hepatitis B surface antigen (HBsAg) loss than either monotherapy. AIM: To identify baseline and on-treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks. METHODS: A secondary analysis of data from an open-label study where patients were randomised to TDF (300 mg/day, oral) plus PEG-IFN (PI, 180 µg/week, subcutaneous) for 48 weeks (TDF/PI-48w); TDF plus PEG-IFN for 16 weeks, TDF for 32 weeks (TDF/PI-16w+TDF-32w); TDF for 120 weeks (TDF-120w) or PEG-IFN for 48 weeks (PI-48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72. RESULTS: Rates of HBsAg loss at Week 72 were significantly higher in the TDF/PI-48w group (6.5%) than in the TDF/PI-16w+TDF-32w (0.5%), TDF-120w (0%) and PI-48w (2.2%) groups (P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 (P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/PI-48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72. CONCLUSIONS: HBsAg decline at Week 24 of TDF plus PEG-IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72.

Technical note: CT-guided paravertebral adrenal biopsy using hydrodissection--a safe and technically easy approach.

The adrenal glands are an important site of both primary and secondary disease processes. Image-guided percutaneous biopsy of the adrenal gland is an accurate and safe alternative to surgical biopsy. This procedure is most often performed in patients with a suspicion of metastatic disease where an accurate pathological diagnosis plays an important role in disease staging and defining therapy. There are many different approaches to performing adrenal biopsy under CT guidance such as anterior transhepatic/transpancreatic, lateral transhepatic/transplenic or posterior transpulmonary/transpleural/paravertebral. We describe a technique in which the adrenal gland was biopsied using a CT-guided percutaneous paravertebral approach with the use of a hydrodissection manoeuver. 13 CT-guided adrenal gland percutaneous biopsies using this technique were performed at our institution between April 2009 and July 2010. All biopsies yielded sufficient material for pathological analysis and there were no complications reported after the procedure. Saline injection can expand the posterior paravertebral space and facilitate a posterior extrapleural approach with high accuracy and low complication rates, and we believe that this may be the best approach for adrenal gland biopsy.

The efficacy and safety of thymosin alpha-1 in Japanese patients with chronic hepatitis B; results from a randomized clinical trial.

Thymalfasin (thymosin alpha-1; Talpha1) is a 28-amino acid polypeptide that has shown efficacy in the treatment of chronic hepatitis B virus (HBV) infection. The objective of this study was to evaluate the long-term, dose-related efficacy and safety of Talpha1 treatment in chronic hepatitis B patients with positive HBV-DNA and abnormally high alanine aminotransferase (ALT) levels. A total of 316 patients were randomized to receive either 0.8 or 1.6 mg of Talpha1 monotherapy for 24 weeks. At the end of the 72-week observation period (12 months after cessation of therapy), 36.4% of patients in the 1.6-mg treatment group achieved normalization of ALT, 30% achieved clearance of HBV-DNA by branched DNA vs 15% by transcription-mediated amplification, and 22.8% achieved clearance of HBe-antigen. Patients in the 0.8-mg treatment group achieved similar efficacy rates, although patients with advanced fibrosis demonstrated a significantly better response rate when treated with 1.6 mg of Talpha1 monotherapy vs 0.8 mg (as determined by intragroup analysis; patients were not stratified by liver biopsy). All adverse drug reactions were mild and most involved the fluctuation of liver enzymes, which was most likely related to the positive immune effects caused by the response to Talpha1 treatment. Adverse event incidence was similar in the 1.6- and 0.8-mg treatment groups. In conclusion, Talpha1 at doses of 0.8 and 1.6 mg exhibits long-term efficacy against hepatitis B with a good safety profile.

Sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic cholestatic disease that may have an autoimmune basis. Most patients have a circulating antineutrophil cytoplasmic antibody that appears to be targeted against a 50-kD nuclear envelope protein. The clinical applications of this antibody have not yet been defined. Other autoantibodies directed against antigens, such as cathepsin G, elastase, and anticardiolipin, may also be detected in some patients. It is suggested that primary sclerosing cholangitis may have a bacterial cause. Helicobacter gene sequences have been detected in liver tissues in primary sclerosing cholangitis. The role of Helicobacter spp and other bacteria in the etiopathogenesis of primary sclerosing cholangitis remains to be determined. Primary sclerosing cholangitis may overlap with autoimmune hepatitis in some cases, although the real prevalence of this association remains to be determined. Many prognostic models have been created, but they lack cross-validation, and their clinical usefulness remains limited. Endoscopic retrograde cholangiography remains the gold standard for diagnosis, but magnetic resonance imaging may be a viable alternative in many cases. Clinical trials with cladibrine, pentoxifylline, and budesonide have failed to demonstrate benefits. Orthotopic liver transplantation remains the only effective treatment.

Sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology. Immunogenetic factors are considered important in its pathogenesis. The genetic susceptibility to primary sclerosing cholangitis is associated, in part, with the HLA HLA-DRB1, DQA1, DQB1 haplotype. Liver histology in primary sclerosing cholangitis is characterized by a portal inflammatory infiltrate mostly composed of memory T cells. Many patients eventually will develop cholangiocarcinoma, and inactivation of the p16 tumor-suppressor gene might be involved in neoplastic transformation. Alcohol consumption might be a risk factor for cholangiocarcinoma, and, in some patients, elevation of serum CA19-9 marks the neoplastic transformation. To date, no medical treatment has been proven effective. Endoscopic therapy might be useful in some patients, but controlled studies are lacking. Liver transplantation remains the only effective treatment. Posttransplant survival and quality of life are continuously improving despite the fact that the disease may recur in some patients after transplantation. Nevertheless, patient selection and timing of indication for liver transplantation remain uncertain.

Sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that progresses to death as a result of liver failure or cholangiocarcinoma. Susceptibility to PSC is associated with the HLA A1-B8-DR3 haplotype, and new associations with HLA C and tumor necrosis factor genes have been detected. A circulating antineutrophil cytoplasmic antibody is found in many patients with PSC, but its antigen or antigens have not been identified. Some studies suggest that this antigen may be an anti-nuclear membrane protein rather than cytoplasmic. Diagnosis of PSC is based on endoscopic retrograde cholangiography, but magnetic resonance cholangiography is a promising noninvasive alternative. Medical treatment remains elusive. In highly selected patients, endoscopic or even surgical treatment can be tried. Orthotopic liver transplantation remains the only effective therapy, but inflammatory bowel disease may run a more aggressive clinical course after this procedure. Sclerosing cholangitis may recur after transplantation, but this has had no clinical implications to date.

Elevation of gamma delta T lymphocytes in peripheral blood and livers of patients with primary sclerosing cholangitis and other autoimmune liver diseases.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that is possibly an autoimmune disease. Although gamma delta T cells represent a small proportion of the total T-cell population in healthy individuals, there is evidence to suggest a role for these cells in autoimmunity. Accordingly, the aim of this study was to investigate the population of gamma delta T cells in patients with PSC, compared with other chronic liver diseases. An elevation in the percentage and absolute numbers of gamma delta T cells was found in the peripheral blood of patients with PSC (8.66% and 0.13 x 10(-6)/L [P < .01 and < .05, respectively]) and autoimmune hepatitis (AIH) (8.03% and 0.13 x 10(-6)/L [both P < 0.001]) compared with controls (4.10% and 0.06 x 10(-6)/L). We also found an elevation in the percentage and absolute numbers of gamma delta T cells in the portal areas of patients with PSC (10.55% and 4.33 [P < .001 and < .001, respectively]), AIH (7.16% and 4.55 [P = .001 and < .001, respectively]), and primary biliary cirrhosis (PBC) (5.57% and 3.49 [P = .008 and < .001, respectively]) when compared with controls (2.23% and 0.81). These findings suggest a role for gamma delta T cells in the mechanism of immune damage in autoimmune liver diseases.

Biliary expression of heat shock protein: a non-specific feature of chronic cholestatic liver diseases.

AIM: To analyse the expression of heat shock protein (HSP) 60 in biliary epithelium in auto-immune liver conditions and also in chronic cholestatic and other liver diseases. METHODS: Hepatic expression of HSP-60 in frozen liver biopsy specimens from patients with primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), auto-immune hepatitis (AIH), obstructive jaundice (LDO), alcoholic liver disease (ALD), and from normal controls was studied by immunohistochemistry using the APAAP technique and confocal laser scanning microscopy. RESULTS: Increased expression of HSP-60 was demonstrated in the biliary epithelium of patients with PBC, LDO and, to a lesser extent, with PSC. Focal, weaker, biliary epithelial expression of HSP-60 was observed in AIH, ALD and normal liver tissue. Increased expression was also seen on Kupffer cells in LDO and in hepatocytes in areas of piecemeal necrosis in AIH. CONCLUSION: Enhanced biliary expression of HSP-60 is a common feature of chronic biliary disease irrespective of aetiology and is not specific to auto-immune diseases.

Superficial thrombophlebitis, dysplasia, and cholangiocarcinoma in primary sclerosing cholangitis.

Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing cholangitis. Usually, liver failure, rapidly progressing jaundice, and an increase in alkaline phosphatase levels are suggestive diagnostic features. We report two cases of patients with primary sclerosing cholangitis who developed cholangiocarcinoma without jaundice and with no changes in their serum biochemistry. Both patients were taking ursodeoxycholic acid at the time of tumor diagnosis. Initial suspicion of malignancy was based on the development of superficial thrombophlebitis. Liver histology showed evidence of bile duct epithelial dysplasia in areas free from tumor in one patient, and in the other, bile duct epithelial dysplasia preceded the appearance of cholangiocarcinoma by at least 18 months. In one of the cases, the dysplastic epithelium stained positively for carcinoembryonic antigen. The histological finding of bile duct epithelial dysplasia in patients with primary sclerosing cholangitis may suggest either imminent or actual development of cholangiocarcinoma and may thus affect consideration of orthotopic liver transplantation. In addition, the development of superficial thrombophlebitis in patients with primary sclerosing cholangitis should arouse suspicion of the presence of cholangiocarcinoma even if there is no evidence of deterioration of the liver function or a dominant stricture on endoscopic retrograde cholangiography.

[Measuring the impact of promoting breastfeeding in primary health care services in Pelotas, Rio Grande do Sul, Brazil]. / Medindo o impacto da promoção do aleitamento materno em serviços de atenção primária à Saúde em Pelotas, Rio Grande do Sul, Brasil.

All mothers with children enrolled in the Program for Child Growth and Development at primary care units belonging to the Federal University of Pelotas (UFPel) in the state of Rio Grande do Sul, Brazil, were interviewed with a standardized questionnaire. This research aimed to assess the impact of the "Groups of Expecting Mothers" in the promotion of breastfeeding. The family income of almost half of the 347 children studied was two times the minimum wage. About 1/4 of the children's mothers had spent less than four years in school, and these were the mothers who attended the Groups most frequently. Most of the mothers received prenatal care and nearly half of then participated in the Groups. In contrast, 1/3 of the children were weaned at the age of three months and almost 80% received tea in the early months of life. The results show that the Groups of Expecting Mothers suffer serious limitations in promoting breastfeeding and in postponing the introduction of foods other than breast milk in the children's diet. Data obtained in this study are intended to help strengthen action under current programs and to show that with minimum resources and a rather simple methodology it is possible to assess the quality of health services available to the population.