Austrian clinical practice with anidulafungin in 2008: a multicenter survey.

Anidulafungin had demonstrated favorable efficacy versus fluconazole in a randomized trial on invasive Candida infections. Since patient characteristics in the post-approval use of antifungals likely deviate from clinical trials, we surveyed the use of anidulafungin in clinical routine. We performed a retrospective survey of the post-approval use of anidulafungin in 9 Austrian clinical centers. Anidulafungin was used in 129 critically ill patients with severe comorbidities and multiple risk factors. Indications were suspected invasive fungal infections (IFI) (61%), proven candidemia (19%), and at risk for IFI (prophylaxis, 20%). Candida colonization in conjunction with other risk factors prompted treatment in many patients. predominant pathogens were C. albicans, C. glabrata and C. krusei. Anidulafungin was mostly used for pre-emptive (69%) and first-line treatment (17%) of invasive candidiasis. Treatment response, i.e. complete response/stabilization as determined by investigators (89% in the overall population; 87% for documented candidemia) and survival rates (81% and 75%, respectively) were similar to previous trial data. No breakthrough IFI and few adverse events were reported. Overall, favorable clinical experiences were documented with anidulafungin in the clinical routine setting.

Combination of interferon induction therapy and ribavirin in chronic hepatitis C.

The initial clearance of hepatitis C virus (HCV) during interferon-alfa therapy is dose-dependent. Therefore, higher initial interferon doses (induction therapy) may improve treatment results. This concept was tested in a prospective, randomized controlled trial. Previously untreated patients with chronic hepatitis C were randomized to receive 3 different interferon doses during the first 14 weeks of therapy (Group A, n = 130: 10 MU IntronA [AESCA-Schering Plough, Traiskirchen, Austria]/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; Group B, n = 124: 5 MU/day for 14 weeks; Group C, n = 119; 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. Throughout the whole study all patients received 1 to 1.2 g ribavirin/day. On treatment, no differences in viral clearance rates were observed. Sustained response rates were also not different among the groups (A: 48.5%, B and C: 41.3%, intent to treat). When data were analyzed according to genotypes, sustained response was almost twice as high in patients with genotype 1 receiving high-dose interferon induction therapy (A: 44.2%, B: 28.6%, C: 27%, P <.05). In contrast, results were not different in genotype 3a patients (A: 61.3%, B: 75.9%, C: 56.3%; P >.1). These data indicate that high-dose interferon induction therapy may improve the outcome of interferon/ribavirin combination therapy in genotype 1 patients.

Transjugular intrahepatic portosystemic shunt (TIPS) augments hyperinsulinemia in patients with cirrhosis.

BACKGROUND/AIMS: Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinemia. Both increased insulin secretion and decreased insulin clearance appear to contribute to hyperinsulinemia in cirrhotic patients. A decrease in hepatic insulin extraction rate may be due either to hepatocellular dysfunction or to portosystemic shunting with decreased first-pass insulin clearance. METHODS: To specifically address the contribution of portosystemic shunting to the pathogenesis of hyperinsulinemia in cirrhotic patients, we analyzed glycemic control and insulin levels in fasting serum in 23 cirrhotic patients before and after transjugular intrahepatic portosystemic shunt (TIPS). RESULTS: Compared to respective values in healthy controls, C-peptide, insulin and proinsulin concentrations at baseline were increased by 340%, 120% and by 100% in cirrhotic patients (all p<0.05). In cirrhotic patients insulin levels before TIPS averaged 104+/-73 pmol/l and increased by more than 50% to 163+/-118 pmol/l after TIPS (p<0.01), whereas levels of C-peptide and proinsulin showed no significant change. Glucose and fructosamin levels also remained unchanged after TIPS. CONCLUSION: Our data demonstrate that TIPS does not impair glycemic control in cirrhotic patients and that an increase in portosystemic shunting augments hyperinsulinemia, most likely by decreasing hepatic insulin clearance.

European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group.

BACKGROUND & AIMS: Liver transplantation for hepatitis C virus (HCV)-related liver disease is characterized by frequent graft infection by HCV. The prognosis and risk factors for morbidity and mortality in this condition were determined. METHODS: A retrospective study of 652 consecutive anti-HCV-positive patients undergoing liver transplantation between 1984 and 1995 in 15 European centers was conducted; 102 patients coinfected with hepatitis B virus (HBV) received immunoglobulin prophylaxis for antibody to hepatitis B surface antigen. RESULTS: Overall, 5-year survival was 72%. Five-year actuarial rates of hepatitis and cirrhosis were 80% and 10%. Genotypes 1b, 1a, and 2 were detected in 214 (80%), 24 (9%), and 24 (9%) of 268 patients analyzed. The only discriminant factor for patient or graft survival was hepatocellular carcinoma as primary indication. Independent risk factors for recurrent hepatitis included the absence of HBV coinfection before transplantation (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2-2.6; P = 0.005), genotype 1b (RR, 2; 95% CI, 1.3-2.9; P = 0.01), and age > 49 years (RR, 1.4; 95% CI, 1.1-1.8; P = 0.01). CONCLUSIONS: The results of transplantation for HCV-related disease are compromised by a significant risk of cirrhosis, although 5-year survival is satisfactory. Genotype 1b, age, and absence of pretransplantation coinfection by HBV are risk factors for recurrent HCV.

Acute renal failure complicating non-fulminant hepatitis A.

Hepatitis, A is usually a mild and self-limiting infection of the liver. Whereas the clinical course is usually benign in children, complications such as prolonged cholestasis and fulminant liver failure have been reported in adults. Acute functional renal failure is an uncommon event in the absence of fulminating liver disease. So far, only cases of acute hepatitis A with biopsy-proven interstitial renal disease or tubular necrosis have been reported [Geltner et al. 1992. Kramer et al. 1986]. We present the case of a 35-year-old, previously healthy male with non-fulminant cholestatic viral hepatitis A, who developed progressive oliguric renal failure requiring dialysis therapy. Kidney biopsy ruled out glomerular disease and tubular necrosis. In the absence of bleeding and other causes of fluid depletion this case may be another variant of hepatorenal syndrome whose etiopathogenesis is only poorly understood.

Life-threatening gastrointestinal bleeding after liver transplantation due to hepatic artery pseudoaneurysm perforating into the common bile duct. A case report.

A 54-year-old male presented with acute rejection and life-threatening gastrointestinal bleeding 2 months following orthotopic liver transplantation. Since no bleeding was identified in the entire gastrointestinal (GI) tract, hematobilia was first suspected and an arteriocholedochal fistula angiographically confirmed. Two days after resection of a pseudoaneurysm of the hepatic artery (HA) with primary repair and closure of the bile duct fistula, hepatic artery thrombosis (HAT) occurred. Various attempts to revascularize the HA eventually failed. Two weeks later, a CT scan showed necrotic areas within the two left lateral segments. At relaparotomy, major parts of the bile duct were found to be necrotic, and the biliary anastomosis was therefore abandoned and necrotic tissue removed. HAT was otherwise well tolerated by the graft and, at a further relaparotomy some weeks later, a hepaticojejunostomy was performed. Two years after transplantation the patient is well with a normally functioning graft.

[After-care by the internal medicine physician following liver transplantation]. / Internistische Nachsorge nach Lebertransplantation.

Orthotopic liver transplantation offers the only therapeutic option for many patients with end-stage liver disease. In adults, the overall five-year survival following transplantation has increased dramatically from approximately 30% a decade ago to nearly 70% currently. Cyclosporine A became available in the 1970s and substantially improved immunosuppressive therapy. It is now the mainstay of the therapeutic approach to prevent graft rejection. The postoperative care of liver transplant recipients is one of the most exciting challenges in clinical medicine. On the basis of the experience and results of the Innsbruck liver transplant programme the management of liver transplant recipients will be discussed with regard to the typical time frame of complications. We present data of 87 liver transplantations in 84 patients during a 10-year observation period. At present, intraoperative mortality is fortunately close to zero. Most of the deaths occur in the immediate postoperative period. Major complications are haemorrhage, hepatic artery or portal vein thrombosis, biliary leakage or graft dysfunction. In addition, side-effects resulting from high-dose immunosuppressive therapy or from antibiotic and antiviral therapy add to problems in this early period. Opportunistic infections, chronic graft failure, disease recurrence and nephrotoxicity related to Cyclosporine A therapy are complications seen during long-term management of liver transplant patients. The differential diagnosis and the adequate management of these complications are a great challenge to every hepatologist.

In-vitro and in-vivo studies on the induction of neopterin biosynthesis by cytokines, alloantigens and lipopolysaccharide (LPS).

Recently we presented evidence that cellular immune responses are associated with increased in-vitro and in-vivo excretion of neopterin (Huber et al., 1983) and that, in vitro at least, macrophages and IFN-gamma play a key role in the induction of this phenomenon (Huber et al., 1984). Although this marker is increasingly applied for monitoring of human disease, there is limited knowledge about the mechanism(s) responsible for its increased biosynthesis during inflammatory states. To further elucidate this question we evaluated neopterin and IFN-levels in culture supernatants of human blood cells and in patients' sera. Cells or patients were exposed to a panel of recombinant cytokines, alloantigens or lipopolysaccharide. To investigate indirect stimulation by induction of production of endogenous IFNs, the impact of neutralization of IFNs by addition of specific antibodies was also studied. The data confirm our previous results which identified the monocyte/macrophage as the main producer cell among human blood cells. They further demonstrate that, at least in vitro, IFN-gamma, IFN-alpha and LPS can all stimulate neopterin release independently from each other. Thirdly, they indicate that stimuli such as alloantigens or TNF-alpha can indirectly enhance neopterin release by their capacity to induce production of endogenous IFN-gamma. On the basis of these data we conclude that enhanced neopterin biosynthesis does not necessarily relate to activation of T cells but can also be caused by non-immune stimuli.

Cytokines in the control of beta-2 microglobulin release. I. In vitro studies on various haemopoietic cells.

The role of cytokines in the control of beta-2 microglobulin release from various haemopoietic cells was studied in vitro. Cell types investigated were resting cells or blasts of the T cell, B cell or monocyte-macrophage lineage. Mediators used in these experiments were r-IFN-alpha 2c, r-IFN-gamma, r-TNF-alpha, r-TNF-beta, r-IL1, r-IL2 and r-GM-CSF. Nanogram amounts of some of these mediators strongly affected beta-2 microglobulin release in vitro. r-IFN-gamma, r-IFN-alpha 2c and r-IL2 strongly enhanced and r-TNF-alpha and r-TNF-beta occasionally increased shedding of beta-2 microglobulin. r-IL1 and high concentrations of r-IFN-alpha 2c were inhibitory, whereas r-GM-CSF was ineffective. The impact of antigenic stimulation on beta-2 microglobulin release in mixed lymphocyte culture (MLC) was also studied. Stimulation with alloantigens in MLC greatly enhanced beta-2 microglobulin shedding, and this enhancement could be inhibited by a monoclonal antibody neutralizing human IFN-gamma. Among the various cell types studied, macrophages derived from peripheral blood monocytes were most susceptible to cytokine-induced alterations of beta-2 microglobulin shedding. From these data, we conclude that cytokines not only control the static expression of beta-2 microglobulin on the surface of haemopoietic cells but also largely affect their shedding.

Cytokines in the control of beta-2 microglobulin release. II. In vivo studies with recombinant interferons and antigens.

The influence of in vivo application of recombinant interferon-alpha 2c (IFN-alpha 2c) and recombinant interferon-gamma (IFN-gamma) on beta-2 microglobulin levels was studied in eight patients with chronic myelogenous leukaemia or advanced renal cell carcinoma. Data indicated enhanced beta-2 microglobulin biosynthesis in close temporary association with injection of both types of interferons. The influence of in vivo stimulation by allogenic leukocytes and the influence of renal allografts or cytomegalovirus infection on serum beta-2 microglobulin and IFN-gamma levels were also studied. Increased beta-2 microglobulin concentrations were observed again in each of these clinical situations and were closely associated with enhanced endogenous interferon production. From these in vivo data and the in vitro data presented in the preceding publication, (1) we conclude that endogenous interferon levels are crucial for the regulation of beta-2 microglobulin release in vivo.

Interferon-gamma for the treatment of metastatic renal cancer: dose-dependent stimulation and downregulation of beta-2 microglobulin and neopterin responses.

Considering rIFN-gamma as a potent biological response modifier (BRM), we started an open phase II trial with rIFN-gamma in patients with advanced renal cell carcinoma (RCC). For optimization of the dose and schedule of rIFN-gamma, two biochemical serum markers, neopterin and beta-2 microglobulin, were chosen to monitor the biological response. In order to test the magnitude and kinetics of rIFN-gamma-induced neopterin and beta-2 microglobulin release in the serum, rIFN-gamma was administered thrice at three different dose levels in a randomly assigned order (0.01; 0.1; 0.5 mg). Neopterin and beta-2 microglobulin were assessed by means of commercially available radioimmunoassays. The results revealed: 1) strong, reproducible and dose-dependent increments of both markers after the first injection 2) downregulation of the magnitude of neopterin responses with repeated injections at each of the three dose levels tested, and 3) a dose-dependent downregulation of the magnitude of beta-2 microglobulin responses and of serum baseline values at the highest dose level tested. From these data, we conclude that both the dose and schedule might be of importance for optimization of biological responses to exogenously applied rIFN-gamma.

A biological approach to optimize interferon treatment in hairy cell leukemia.

Progress with the clinical application of interferons to neoplastic diseases has been slow and complicated by the need for attention to a new spectrum of therapeutic and toxic effects manifested by the interferons. In this report, we present a new approach to define clinically effective but atoxic doses of interferon-alpha for treatment of hairy cell leukemia. In order to find in vivo biologically active interferon doses, the biochemical marker neopterin was selected as a means to assess a cellular interferon response in vivo. Subcutaneous administration of minimal doses of recombinant interferon-alpha-2 (5-8 X 10(5) U/day), which induced maximum neopterin release in serum and urine, proved to be clinically effective: Eight of nine patients responded to this dose regimen. This response rate was comparable to that of a conventional dose schedule (3 X 10(6) U/sqm/day) which was also applied to nine patients (eight responders). Whereas no difference in the clinical efficacy between the two therapeutic strategies could be established, toxicity was clearly confined to the conventional dose regimen. These preliminary results suggest that at least in hairy cell leukemia the therapeutic dose range of interferon can be separated from the toxic.