Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B.

OBJECTIVE: To determine the efficacy of tenofovir disoproxil fumarate (TDF) in adults with chronic hepatitis B virus (HBV) infection who had previously failed lamivudine (LAM) and had significant viral replication (HBV DNA >105 copies/ml if HBeAg positive, > 104 copies/ml if HBeAg negative) despite at least 24 weeks of treatment with adefovir dipivoxil (ADV). DESIGN: A prospective open-label study of TDF 300 mg daily. Patients receiving combination ADV/LAM prior to baseline were switched to TDF/LAM. SETTING: Multiple tertiary referral centres. METHODS: Sixty patients were enrolled. The median age was 48.5 years (range 21e80), 46 (77%) were male and 40 (67%) were HBeAg positive. Thirty-eight patients (63%) were switched from ADV to TDF, the remainder from ADV/LAM to TDF/LAM. At baseline, substitutions conferring resistance to LAM or ADV were present in 20 patients (33%) and 17 patients (28%), respectively. The median baseline viral load was 5.33 log10 IU/ml (range 2.81-8.04). Patients initially treated with TDF monotherapy with persistent viral replication at or after 24 weeks were switched to TDF/LAM. The main outcome measures were change in HBV viral load from baseline and percentage of patients achieving an undetectable viral load (<15 IU/ml). RESULTS: Results are reported at 96 weeks of treatment. One patient discontinued TDF at 10 days due to rash. The time-weighted change in viral load from baseline to week 12 was -2.19 log10 IU/ml overall. The median change in HBV DNA from baseline to weeks 12, 24, 48 and 96 was -2.86, -3.23, -3.75 and -4.03 log10 IU/ml, respectively. At 48 and 96 weeks, 27/59 (46%) and 38/59 (64%) patients achieved a HBV DNA <15 IU/ml. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. CONCLUSIONS: In heavily pretreated patients with a high rate of genotypic resistance, TDF retains significant activity against HBV although this appears diminished in comparison with studies of naïve patients.

Clinical trial: effects of adefovir dipivoxil therapy in Asian and Caucasian patients with chronic hepatitis B.

BACKGROUND: Two-thirds of the 350 million people infected with chronic hepatitis B virus live in the Asia-Pacific region. AIM To compare the effects of adefovir dipivoxil therapy between Asian and Caucasian patients with chronic hepatitis B. METHODS: The safety and efficacy of 10 mg of adefovir dipivoxil was compared to placebo in 501 Asian (n = 259) or Caucasian (n = 242) HBeAg+ and HBeAg- chronic hepatitis B virus patients treated for 48 weeks in two randomized, double-blind, placebo-controlled studies. RESULTS: At week 48, histological improvement was observed in 60% and 56% of Caucasian and Asian patients, respectively. Change in serum hepatitis B virus DNA from baseline to week 48 for the adefovir dipivoxil-treated patients was -3.89 and -3.70 log(10) copies/mL in Caucasian and Asian patients, respectively, while 34 per cent of Caucasian patients and 39 per cent of Asian patients had undetectable serum hepatitis B virus DNA (<400 copies/mL) at week 48. The percentage of patients achieving alanine aminotransferase (ALT) normalization at week 48 was similar in both groups (Caucasian 64 per cent, Asian 63 per cent). No patients developed resistance through week 48. No differences in adverse events or grade 3 or 4 laboratory abnormalities were observed between groups. CONCLUSIONS: There were no significant differences in treatment response between Asians and Caucasians. Adefovir dipivoxil was well tolerated and no resistance developed up to week 48 in both racial groups.

Adenosine triphosphate bioluminescence to validate decontamination of endoscopes.

The reports of outbreaks involving carbapenemase-resistant Enterobacteriaceae (CRE) associated with gastrointestinal endoscopy prompted a review and study of a novel method of assessing cleaning. This study assessed adenosine triphosphate (ATP) bioluminescence to demonstrate cleanliness prior to endoscopy. ATP testing was compared with microbiological monitoring for 127 endoscopes. Samples were taken after cleaning, reprocessing and storage, but immediately before the endoscopy procedure. We recommend implementing ATP testing prior to endoscopy procedures as an alternative to microbiological testing at periodic intervals. ATP testing provides a convenient assessment of endoscopy hygiene to demonstrate safety and quality assurance.

Cyanoacrylate in the treatment of gastric varices complicated by multiple pulmonary emboli.

Bleeding gastric varices are increasingly being obliterated with the aid of endoscopic injection of n-butyl-cyanoacrylate (histoacryl) diluted with lipiodol. This glue acts as a tissue adhesive that polymerizes on contact with blood in a gastric varix. Severe glue pulmonary embolism is a rare complication of injection therapy. This case involves a 52-year-old man with fundal gastric varices, who developed multiple pulmonary emboli following glue injection with profound hypoxia requiring hospital admission for 13 days, but with eventual recovery of normal lung function.

Now, later or never? Challenges associated with hepatitis C treatment.

BACKGROUND AND AIMS: Of the 259,000 Australians estimated to have a hepatitis C virus infection, very few have received antiviral therapy. This study identifies personal, psychological and structural barriers associated with decisions to begin treatment and the challenges associated with adhering to a demanding treatment regimen. METHODS: Between August 2003 and May 2004, 224 people living in Victoria who were hepatitis C antibody positive completed a 78-item survey instrument. Participants were recruited from a variety of settings and included those who were on treatment for hepatitis C (n=45); previously on treatment (n=65); and people who had never experienced treatment (n=114). RESULTS: The average age of the participants was 43 years. Men (n=29) were more likely than women (n=15) to be receiving treatment. Participants diagnosed in the past five years (31%) were more likely to be receiving treatment compared with those diagnosed more than five years ago (14%). Participants rated the effectiveness of treatment as the most important factor in influencing their decision to begin treatment. Side effects were rated the biggest challenge to adhering to treatment and were also rated as the most important consideration for those who decided against treatment. CONCLUSIONS: This study has shown many decisions and challenges affect the uptake of, and adherence to, hepatitis C treatment. Dissemination and promotion of information about increased effectiveness of new treatments will greatly influence decisions to begin treatment. Careful management and minimisation of side effects are also essential to improve uptake and increase adherence to hepatitis C treatment.

Pelvic endometriosis simulating colonic malignant neoplasm.

Three women had endometriosis that involved the rectosigmoid colon; their clinical presentation suggested primary colonic malignant neoplasm. Intestinal obstruction, weight loss, and, in two patients, rectal bleeding with radiologic evidence of a mass lesion that involved the rectosigmoid were present at initial evaluation. All patients eventually underwent colonic resection as definitive therapy. Endometriosis of the pelvic colon may mimic primary intestinal disease, mistakenly suggesting malignant neoplasm. Such symptoms in a young woman should prompt a search for endometriosis, which is a more likely diagnosis. Adequate therapy frequently requires surgical intervention.

The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3.

BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV-1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.

Lack of gastric mucosal protection by sucralfate during long-term aspirin ingestion in humans.

The ability of sucralfate to prevent gastric mucosal erosions caused by long-term aspirin ingestion was studied in 19 normal human subjects. A placebo-controlled, double-blind, crossover design was used to study the capacity of 4 g sucralfate daily to lessen the noxious effect on gastric mucosa of 3.6 g aspirin daily for 14 days. Gastric mucosal injury was assessed by endoscopic scoring of erosions. There was no significant difference in mean erosion scores or the degree of partial mucosal protection between the two groups. It was concluded that sucralfate lacks a mucosal protection capacity at the dosage studied in human subjects ingesting large doses of aspirin over a two-week period.

Induction interferon and ribavirin for re-treatment of chronic hepatitis C patients unresponsive to interferon alone.

BACKGROUND: The optimal treatment for hepatitis C patients unresponsive to interferon is unclear. High-dose induction interferon may enhance early viral clearance, whilst ribavirin reduces relapse; in combination, they may improve sustained virological response rates. AIM: To compare the efficacy and safety of re-treatment with interferon induction, with or without ribavirin, in interferon non-responders. METHODS: We randomized 218 biochemical interferon non-responders to 10 MU interferon alpha 2b daily for 4 weeks, followed by 5 MU thrice weekly for 48 weeks plus ribavirin (II + R), or to the same interferon regimen plus placebo (II + P). All patients were viraemic at entry. RESULTS: The sustained virological response in the II + R group was 39%[95% confidence interval (CI), 30-48%], compared with 16% (95% CI, 9-23%) in the II + P group (P < 0.002). The study drug was discontinued for intolerable symptoms during induction in 9% of the II + R group and in 5% of the II + P group. By logistic regression, a sustained virological response was more likely following II + R treatment (odds ratio, 4.4; 95% CI, 2.1-9.7) and less likely in patients with genotype 1 or 4 (odds ratio, 0.16; 95% CI, 0.07-0.36). CONCLUSION: High-dose induction interferon plus ribavirin is well tolerated and effective for patients unresponsive to interferon alone.

Alcohol consumption induces hepatocyte apoptosis in patients with chronic hepatitis C infection.

BACKGROUND: Epidemiological studies have established that heavy alcohol consumption in persons with chronic hepatitis C infection is associated with advanced liver disease, including cirrhosis. The cellular mechanisms underlying this process, which appear to occur over decades, are unknown. Increased hepatocyte apoptosis has been observed in association with hepatitis C infection. The aim of this study was to evaluate the relationship between alcohol consumption and hepatocyte apoptosis in hepatitis C-infected patients. METHODS: Liver tissue from 20 hepatitis C-infected patients with variable alcohol consumption, and 10 normal control subjects was examined for hepatocyte apoptosis, proliferation and bcl-2 expression. RESULTS: Hepatocyte apoptosis was significantly greater in hepatitis C-infected patients than in controls. In hepatitis C-infected patients, significantly more hepatocyte apoptosis was seen in those consuming at least 30 g per day of alcohol compared with those drinking less than 10 g daily. Bcl-2, an inhibitor of apoptosis, was not detected in liver tissue from patients with the highest ethanol intake and rate of hepatocyte apoptosis. In contrast, patients drinking lesser amounts of ethanol had lower rates of hepatocyte apoptosis and more frequent bcl-2 expression. CONCLUSIONS: This study confirms that both hepatitis C infection and ethanol consumption induce hepatocyte apoptosis in humans. Ethanol-induced hepatocyte apoptosis has previously been shown only in animal models of alcohol-related liver injury. The precise role of apoptosis in the pathogenesis of hepatitis C-related liver injury remains unclear, but its induction may be related to downregulation of bcl-2 expression associated with ethanol consumption.

HIV-related gastrointestinal disease.

Gastrointestinal disease is common in patients infected with HIV and can represent the first significant clinical illness. Diarrhoea, dysphagia, abdominal pain, jaundice or gastrointestinal bleeding may be the result of opportunistic infection, AIDS-related neoplasia, or infection with HIV alone. The spectrum of gastrointestinal tract and liver involvement in HIV infection is broad and has been well reviewed recently. This article is selective in that the main emphasis is placed on the variety of ways that HIV may first declare itself with symptoms in the gastrointestinal tract.

Emergencies of the biliary tract.

The traditional approach to urgent therapy of biliary tract disease has undergone significant change. Technologic advances now permit a nonoperative approach to acute cholangitis, acute gallstone pancreatitis and hemobilia. Acute cholecystitis continues to be treated surgically in most cases. The clinical use of such nonoperative therapy has been guided mainly by retrospective data. The precise indications and optimal timing for endoscopic and radiologic therapy and their relationship to traditional surgical therapy remains to be defined by careful prospective evaluation.

Gastrointestinal emergencies in the acquired immunodeficiency syndrome.

Opportunistic infection and neoplasia involving the gastrointestinal tract are common in AIDS patients. Life-threatening complications of this involvement may occur, requiring urgent diagnosis and therapy. We review the clinical presentation and approaches to management of AIDS-related gastrointestinal emergencies.

Managing HIV. Part 5: Treating secondary outcomes. 5.3 HIV, gastrointestinal and hepatobiliary disease.

Diseases of the gastrointestinal tract, biliary tree and liver are a major source of morbidity and mortality in patients with HIV infection, who may present with a complex array of signs and symptoms that require accurate diagnosis and therapy.

High prevalence of Helicobacter pylori antibodies in an institutionalized population: evidence for person-to-person transmission.

OBJECTIVE: To evaluate the prevalence of H. pylori antibodies in mentally and physically handicapped adults living together in a long-term care facility. METHODS: One hundred twenty-two institutionalized subjects from six living areas were compared to a normal representative Caucasian population obtained by random sampling from the urban population area of Melbourne. Serum samples from 1977 and 1989 from 122 subjects were tested for H. pylori antibody by an ELISA technique. The data were analyzed by Student's t test, chi 2 test and logistic regression. RESULTS: Ninety-two of the 122 subjects (75%) from whom sera was collected in 1989 were seropositive for H. pylori, compared with only 23% in age- and sex-matched control subjects (p < 0.0001). The prevalence of H. pylori antibodies in 1977 was 34% (42/122). Of the remaining 80 seronegative subjects, 51 (61.4%) converted to became positive in the 12-yr interval. The annual seroconversion rate was 7.4%, with an average of 4.25 newly positive subjects each year. The prevalence of H. pylori in 1989 was significantly higher than in 1977 after adjustment for age (odds ratio 2.39, 95% CI 1.1-5.3, p = 0.03). CONCLUSIONS: H. pylori antibodies are significantly more prevalent in institutionalized adults compared with controls from the general population. These data support the hypothesis that H. pylori is acquired by either fecal-oral or oral-oral transmission.

Fas-mediated hepatocyte apoptosis is increased by hepatitis C virus infection and alcohol consumption, and may be associated with hepatic fibrosis: mechanisms of liver cell injury in chronic hepatitis C virus infection.

Epidemiological studies have established that heavy alcohol consumption in persons with chronic hepatitis C virus (HCV) infection is associated with advanced liver disease, including cirrhosis. The aims of this study were to evaluate the relationship between alcohol consumption and hepatocyte apoptosis in HCV-infected patients and to determine the role of Fas in HCV-mediated apoptosis. Liver tissue from 44 HCV-infected patients with variable alcohol consumption, and 10 normal control subjects who did not consume alcohol was examined for hepatocyte apoptosis, proliferation and Fas expression. Alcohol consumption was assessed using the 'Lifetime Drinking History' alcohol questionnaire. HCV RNA, alanine aminotransferase (ALT) and ferritin were also assessed in addition to demographic data. Hepatocyte apoptosis was significantly greater in HCV-infected patients compared to controls. Expression of Fas (CD95) was found in HCV patients but not in controls. The degree of Fas expression correlated with hepatocyte apoptosis as detected by terminal UTP nick end labelling (TUNEL). Active ethanol consumption led to a significant increase in hepatocyte apoptosis. Fas expression correlated with fibrosis in HCV-infected patients who were not actively drinking ethanol. In summary, HCV leads to increased apoptotic cell death in hepatocytes. Programmed cell death can be further up-regulated by active ethanol consumption. The correlation between Fas expression and TUNEL supports the hypothesis that the Fas-Fas ligand interaction is the major mechanism for HCV-induced hepatocyte apoptosis.

Low-dose antacids and nonsteroidal anti-inflammatory drug-induced gastropathy in humans.

Gastroduodenal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) is common. As yet, the ideal means to prevent NSAID-related mucosal injury remains controversial. Antacids are effective agents in treating gastric and duodenal ulcers unrelated to NSAIDs. The aim of this study was to assess the ability of a low-dose antacid to prevent NSAID injury in humans. Fifty healthy human volunteers were studied using a randomized, double-blind, placebo controlled, crossover design. After initial endoscopy, subjects were randomized to either Maalox TC (1 tablet q.i.d., acid neutralizing capacity of 104 mEq/day) or identical placebo while receiving 500 mg of naproxen b.i.d. for 21 days. After this period, a second endoscopy was performed to count antral and duodenal erosions and to evaluate symptoms and compliance with study medications. A 21-day washout period ensued, followed by a third endoscopy to insure a return to endoscopically normal mucosa. Subjects then crossed over into the alternate treatment arm for a further 21 days, followed by a fourth endoscopy to assess erosions. Forty subjects completed the study. Subjects receiving Maalox TC developed a significantly greater number of gastric erosions than did those on placebo. While this result was unforeseen, it is supported by statistical analysis and may have clinical relevance in regard to short-term NSAID therapy.

Characterization of serum activin-A and follistatin and their relation to virological and histological determinants in chronic viral hepatitis.

BACKGROUND/METHODS: Hepatocyte proliferation in viral hepatitis is regulated by a number of growth factors. Activin-A inhibits hepatocyte DNA synthesis while follistatin, a potent activin-A antagonist, promotes liver regeneration. We report the first study of activin-A and follistatin in human viral hepatitis. Sera from 15 normal subjects, 22 hepatitis B and 47 hepatitis C patients were analysed for activin-A and follistatin and correlated with serological and histological markers of liver injury and with specific immunohistochemistry. RESULTS: All groups showed immunoreactivity for activin with hepatocyte localisation. Serum activin-A was significantly increased in viral hepatitis patients compared to controls, was greater in hepatitis B compared to hepatitis C, and correlated with serum aminotransferase and hepatitis B viral replication. A concurrent rise in serum follistatin was not observed in either group, but serum follistatin correlated inversely with hepatitis B DNA levels. Although hepatocyte apoptosis in hepatitis C and proliferation in both groups was significantly elevated compared to controls, there was no correlation with serum activin-A or follistatin. CONCLUSIONS: Activin-A and follistatin are constitutively expressed in human liver and serum concentrations are increased in viral hepatitis. Dysregulation of the activin/follistatin axis may be linked to hepatitis B replication but does not correlate with hepatocyte apoptosis.

Early detection of protein depletion in alcoholic cirrhosis: role of body composition analysis.

BACKGROUND: Malnutrition is common in alcoholic cirrhosis. Bedside nutritional assessment techniques may be unreliable in patients with chronic liver disease. The aim of this study was to quantify changes in body composition and compare methods for measuring body composition in alcoholic cirrhosis. METHODS: Thirty-eight men with alcoholic cirrhosis were compared with 16 age-matched healthy men. Body composition was assessed using anthropometry and bioelectrical impedance to determine fat-free mass and body fat, deuterium oxide dilution to measure total body water, in vivo neutron activation analysis to measure total body protein, and dual energy x-ray absorptiometry to measure bone mineral content and total body fat mass. RESULTS: With increasing severity of cirrhosis, total body water increased, whereas total body protein decreased with a significant decrease in serum albumin levels. Total body protein levels, expressed as an index, were a more sensitive indicator of protein depletion than serum albumin levels. When patients were assessed by anthropometry and bioelectrical impedance for fat-free mass, there was no reduction compared with controls. CONCLUSIONS: Anthropometry and bioelectrical impedance do not accurately reflect changes in body composition associated with chronic liver disease. Quantification of body composition changes in alcoholic cirrhosis requires the use of direct methods such as in vivo neutron activation analysis, dual energy x-ray absorptiometry, or deuterium oxide dilution.