Sequential therapy with adefovir dipivoxil and pegylated interferon alfa-2a for HBeAg-negative patients.

To assess the impact of sequential therapy with adefovir dipivoxil (ADV) and pegylated interferon alfa-2a (PEG-IFN) on virological (serum HBV-DNA) and serological (serum HBsAg) response in 20 consecutive HBeAg-negative patients. Patients received ADV for 20 weeks, then ADV and PEG-IFN for 4 weeks and lastly PEG-IFN for 44 weeks. Serum HBV-DNA and HBsAg were assessed at baseline, during therapy (weeks 20, 44 and 68) and follow-up (weeks 92 and 116). Sustained virological response (SVR) was defined as serum HBV-DNA <10 000 copies/mL (partial) or <70 copies/mL (complete) 24 weeks after stopping treatment. A serological response was defined as a serum HBsAg decrease ≥1 log(10) IU/mL at the end of treatment. Baseline median serum HBV-DNA and HBsAg levels were 7.6 log(10) copies/mL and 3.8 log(10) IU/mL, respectively. Ten patients (50%) achieved SVR, six of them had partial response and four complete response. Four patients (20%) achieved serological response. Complete SVRs showed a major and steep decline in HBsAg level with a median decrease of 0.5, 1.6 and 2.0 log(10) IU/mL at treatment week 20, 44 and 68, respectively. Partial SVRs showed a slight and slow decline in serum HBsAg level (0.1, 0.4, and 0.6 log IU/mL at weeks 20, 44 and 68, respectively). On-treatment serum HBsAg decrease had a high accuracy to predict SVR (AUROC = 0.88). Our results suggest that sequential therapy might be an interesting strategy for HBeAg-negative patients. Serum HBsAg kinetics seem to be an accurate tool to predict SVR. Large clinical trials are needed to explore this strategy with more potent analogues.

Polyarthritis and anemia in a hemodialysis patient: systemic lupus erythematosus following treatment with interferon alpha.

Autoimmune manifestations may occur with interferon alpha (IFNalpha) therapy. However IFNalpha-induced systemic lupus erythematosus is a rare event. We report a 33-year-old hemodialysis patient who presented polyarthritis and anemia 4 months after initiation of IFNalpha for chronic hepatitis C. Systemic lupus erythematosus was diagnosed. Clinical symptoms improved rapidly with interruption of the treatment and a low-dose steroid therapy. This is the first case of IFN-induced SLE in a hemodialysis patient to confirm the major role of IFNalpha in the lupus physiopathology. Treatment with steroid therapy does not seem to worsen the HCV infection.

Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) genotype 4 (HCV-4) is increasing in prevalence in Western countries. However, little is known about the severity of the disease and response to treatment. The aim of this study was to assess the predictors (logistic regression) of severe fibrosis (METAVIR score F3-F4), and sustained virological response (SVR) to peginterferon and ribavirin in 226 consecutive HCV-4 patients (Egyptians 40%, Europeans 35% and Africans 24%). PATIENTS AND METHODS: Insulin resistance was assessed using the homeostasis model (HOMA-IR). Serum HCV-RNA level (bDNA) and subtypes of HCV (LiPA) were determined for all patients. RESULTS: Insulin resistance (HOMA-IR >3) was present in 105 patients (46%), and was associated with: age >45 years (OR, 2.614; 95% CI, 1.316 to 5.194), body mass index (BMI) >25 kg/m(2) (OR, 2.105; 95% CI, 1.048 to 4.229), serum HCV-RNA >800 000 IU/ml (OR, 3.143; 95% CI, 1.503 to 6.574), severe fibrosis (OR, 2.657; 95% CI, 1.214 to 5.818), and steatosis >30% (OR, 2.488; 95% CI, 1.105 to 5.602). Severe fibrosis was present in 67 patients (29%) and was associated with Egyptian origin (OR, 5.872; 95% CI, 2.747 to 12.553), excessive alcohol intake (OR, 5.311; 95% CI, 1.287 to 21.924), and HOMA-IR >3 (OR, 3.864; 95% CI, 1.859 to 8.034). 108 patients received a 48 week course of peginterferon plus ribavirin. SVR (undetectable serum HCV-RNA (TMA) 24 weeks after treatment stopping) was achieved in 59 patients (55%) and was associated with Egyptian origin (OR, 13.119; 95% CI, 3.089 to 55.706), HOMA-IR <2 (OR, 5.314; 95% CI, 1.953 to 14.459), and non-severe fibrosis (OR, 8.059; 95% CI, 2.512 to 25.855). CONCLUSION: Insulin resistance and geographical origin are major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4 patients. Insulin resistance is frequently encountered in these patients, and correlated independently with serum HCV-RNA.

Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C.

BACKGROUND AND AIMS: The gold standard treatment of chronic hepatitis C (CHC) is combined pegylated interferon and ribavirin. Considering side effects and treatment cost, prediction of treatment response before therapy is important. The aim of this study was to identify a liver gene signature to predict sustained virological response in patients with CHC. METHODS: Group A (training set) comprised 40 patients with CHC including 14 non-responders (NRs) and 26 sustained virological responders (SVRs). Group B (validation set) comprised 29 patients including 9 NRs and 20 SVRs. Eleven responder-relapsers were also included. A total of 58 genes associated with liver gene expression dysregulation during CHC were selected from the literature. Real-time quantitative RT-PCR assays were used to analyse the mRNA expression of these 58 selected genes in liver biopsy specimens taken from the patients before treatment. RESULTS: From the Group A data, three genes whose expression was significantly increased in NRs compared with SVRs were identified: IFI-6-16/G1P3, IFI27 and ISG15/G1P2. These three genes also showed significant differences in their expression profiles between NRs and SVRs in the independent sample (Group B). Supervised class prediction analysis identified a two-gene (IFI27 and CXCL9) signature, which accurately predicted treatment response in 79.3% (23/29) of patients from the validation set (Group B), with a predictive accuracy of 100% (9/9) and of 70% (14/20) in NRs and SVRs, respectively. The expression profiles of responder-relapsers did not differ significantly from those of NRs and SVRs, and 73% (8/11) of them were predicted as SVRs with the two-gene classifier. CONCLUSION: NRs and SVRs have different liver gene expression profiles before treatment. The most notable changes occurred mainly in interferon-stimulated genes. Treatment response could be predicted with a two-gene signature (IFI27 and CXCL9).

Management of chronic hepatitis C.

Chronic hepatitis C is a major cause of cirrhosis and primary liver cancer (hepatocellular carcinoma). Decompensated cirrhosis or hepatocellular carcinoma secondary to hepatitis C is the first cause of liver transplantation in Europe and in the United States. The prognosis of chronic hepatitis C depends on the progression of fibrosis which determines the risk of developing cirrhosis and its complications. Knowledge of the natural history and the factors associated with the progression of fibrosis is essential for the patient's management. The risk of the progression of fibrosis is difficult to predict in one particular patient. Liver biopsy remains the best test to evaluate the severity of fibrosis, determine its prognosis and discuss the therapeutic options. At present, in a patient with hepatitis C, combined therapy associating pegylated alpha interferon and ribavirin results in a sustained response in approximately 55% of cases. Based on existing results, the sustained virological response with this treatment option appears to be long lasting, to be associated with a histological benefit and is also probably associated with a reduction in the risk of cirrhosis and hepatocellular carcinoma. The management of hepatitis C virus infections must include better knowledge of the natural history of the disease and existing available antiviral treatments (pegylated interferon and ribavirin) as well as in depth knowledge of the aims of treatment, the results obtained, the predictive factors of response and side effects. With close follow-up, doses can be rapidly modified and erythropoietin more frequently administered; new molecules may also be developed in this context. This paper will discuss the natural history, the factors associated with the progression of fibrosis, the predictive factors of response to treatment, and existing and future treatments for hepatitis C.

Quantitative measurement of hepatitis C virus core antigen is affected by the presence of cryoglobulins.

Mixed cryoglobulinaemia is associated strikingly with HCV infection. The aim of this study was to assess whether the adherence to proper methods of collecting samples for cryoglobulin detection was critical or not on virological parameters in hepatitis C virus (HCV) patients. We studied 56 consecutive patients. Blood samples were collected using a conventional method and a blood collection method at 37 degrees C adapted to cryoglobulin detection. HCV core antigen and HCV RNA were measured in sera and cryoglobulins issued from both blood collection methods. In cryoglobulin-positive patients, serum concentrations of HCV core antigen, but not that of HCV RNA, were significantly higher when a conventional method was used, compared to a blood collection method at 37 degrees C (P = 0.001). In the cryoprecipitates, concentration of HCV core antigen was optimum when the blood collection method at 37 degrees C, rather than the conventional method, was applied for cryoglobulin detection (P < 10(-4)). The recovery of HCV core antigen in the cryoprecipitate was improved when cryoglobulins were isolated using the blood collection method at 37 degrees C rather than the conventional method (P < 0.001). HCV parameter measurements and cryoglobulin study should not be performed on the same serum samples due to the potential impact of blood collection methods on results.

Accurate model predicting sustained response at week 4 of therapy with pegylated interferon with ribavirin in patients with chronic hepatitis C.

Current models used to predict response to peginterferon plus ribavirin treatment, based on viral decline during the first 12 weeks of therapy, have focused on creating an early stopping rule to avoid unnecessary prolongation of therapy. We developed a multivariate model that predicted sustained virological response and nonresponse at baseline and during the first 12 weeks of therapy using collected data from 186 unselected patients with chronic hepatitis C treated with peginterferon plus ribavirin. This model employed ordinal regression with similarity least squares technology to assign the probability of a given outcome. Model variables include sex, age, prior treatment status, genotype, baseline serum alanine aminotransferase levels, histologic necroinflammation and fibrosis scores and serum hepatitis C virus RNA concentration at baseline and weeks, 4, 8, and 12. A multivariate model demonstrated high performance values at all time points. At baseline, the model demonstrated a negative predictive value (NPV) and a positive predictive value (PPV) of 91% and 95%, respectively. At week 4, these values improved to 97% and 100%, respectively, with 95% sensitivity, 89% specificity and 93% accuracy. At week 4, the model was equally efficient for naïve or previously treated patients. Internal validation demonstrated 90% PPV, 94% NPV, 95% sensitivity, 88% specificity and 92% accuracy. A week 4 stopping rule for patients with chronic hepatitis C treated with peginterferon with ribavirin might be proposed by using the model developed in our study.

Safety and efficacy of peginterferon plus ribavirin in patients with chronic hepatitis C and bridging fibrosis or cirrhosis.

The combination of pegylated interferon and ribavirin is the most effective therapy in patients with chronic hepatitis C. We evaluated this combination in unselected patients with bridging fibrosis or cirrhosis. Eighty patients were treated with peginterferon alpha-2b plus ribavirin. Hepatitis C virus serum RNA was monitored. Tolerance and safety were evaluated by the rate of treatment's discontinuation for any reason, and occurrence of serious clinical adverse events, respectively. Sustained virologic response (SVR) rate was 36.3% overall, and was observed in every group of patients except those who had previously failed to respond to the combination of interferon and ribavirin. No serious clinical adverse event occurred. Treatment was withdrawn in 18.7% of patients. Variables associated with discontinuation of treatment were low prothrombin index [OR: 1.16 (1.05;1.27)] and low body mass index [OR: 1.47 (1.12;1.92)]. Initial blood count abnormalities were not associated with cessation of treatment. Furthermore, early virologic response at week 8 and week 12 of treatment had similar predictive value for SVR. Combination therapy with peginterferon plus ribavirin seems effective in this group of patients, except in those who had previously failed to respond to the combination of interferon and ribavirin. This therapy is safe with appropriate monitoring, but tolerance seems worse in patients with the most advanced liver disease.

Treatment of chronic hepatitis c.

Since the discovering of the hepatitis C virus in 1989, the treatment of hepatitis C has considerably improved. Initially, with interferon alpha used as a single drug, the sustained virological response rate was below 20%. Then, with the use of combination therapy of interferon a with ribavirin, the response rate increased to 41%. More recently, combination of pegylated interferons with ribavirin give a response rate of about 54-63%. The long-term follow-up studies showed that sustained virological response is generally associated with clinical and histological improvement. The indication of therapy is mainly based on the results of the liver biopsy which is the best way to assess the prognosis of the liver disease. Therefore, treatment is indicated in patients with moderate or severe necroinflammation or fibrosis. The tolerability of combination therapy is relatively poor with a frequent flu-like syndrome and an impaired quality of life. Factors associated with a poor response to treatment are essentially genotype 1 and high viral load. To further improve the efficacy of therapy, different new drugs are under investigation (amantadine, cytokines). These drugs may be candidates for new combinations. In addition, intensive research is currently done for the development of inhibitors of viral enzymes (helicase, protease or polymerase) and anti-sense oligonucleotides, ribozymes and therapeutic vaccine.

[Pancreatic necrosis infection by Candida parapsilosis associated with fungemia]. / Infection de nécrose pancréatique à Candida parapsilosis associée à une fungémie.

Pancreatic necrosis infection is the most common complication affecting mortality of severe acute pancreatitis (death rate 80%). Bacterial infections particularly with coliforms or anaerobes account for the majority of cases of infected necrosis. Fungal pancreatic infections with Candida species are rare and often nosocomial. We report herein the first case of pancreatic necrosis infection with Candida parapsilosis associated with fungemia confirmed by molecular typing.

[Acute intermittent porphyria associated with hyperaldosteronism and inappropriate antidiuretic hormone secretion syndrome]. / Porphyrie aiguë intermittente associée à un hyperaldostéronisme et à un syndrome de sécrétion inappropriée d'hormone anti-diurétique.

Acute intermittent porphyria, the most commun acute porphyria in France, is an autosomal dominant disorder of heme biosynthesis. The basic biochemical defect is reduced activity of the enzyme porphobilinogen deaminase. Clinical evolution is characterized by acute attacks, with a severe prognosis due to acute abdominal pain and risk of neurological complications, induced by drug intake, infection, alcohol intake or unknown factors. We report the case of a patient with an inappropriate antidiuretic secretion syndrome and secondary hyperaldosteronism associated with acute intermittent porphyria and polyradiculoneuritis syndrome. This syndrome was found to be induced a delayed reaction to thiopental. A favorable response was achieved with heme-arginate treatment.

[When should patients with bleeding peptic ulcer resume oral intake? A randomized controlled study]. / Quand faut-il reprendre l'alimentation orale après hémorragie ulcéreuse gastro-duodénale? Etude contrôlée randomisée.

OBJECTIVES: Patients presenting with bleeding peptic ulcers are often kept fasted. The contribution of feeding in bleeding recurrence rate is unknown. The aim of this prospective controlled study was to evaluate the effect of early feeding in (a) the bleeding peptic ulcer recurrence rate and (b) the outcome of patients with severe bleeding peptic ulcer. PATIENTS-METHODS: From January through December 1995, all consecutive patients admitted for active bleeding from peptic ulcer were included. All patients underwent emergency endoscopic injection with adrenaline around and into the base of the ulcer and were randomized in two groups. Group A patients (n = 12) received milk on day 1, mixed warm feeding on day 2 and normal diet from day 3, Group B patients (n = 14) were nil by mouth until day 3, then received milk on day 4, mixed warm feeding on day 5, and normal diet from day 6. Twenty-six patients (17 men, 9 women, mean age 71 years) were included. RESULTS: On day 0, both groups (group A vs group B) were comparable (mean +/- SD): hemoglobin (8.8 +/- 2.7 vs 8.1 +/- 2.0 g/dL), transfusion requirements in the first 24 h after admission (2.2 +/- 2.0 vs 2.1 +/- 1.4 units), localization of ulcers (duodenal ulcer: 8 vs 9, gastric ulcer : 4 vs 5). There were no significant differences in group A and group B for bleeding ulcer recurrence rate (0 vs 1 patient) and transfusion requirements (2.6 +/- 2.1 vs 3.3 +/- 2.1 units). Hospital stay was significantly shorter in group A (6.8 +/- 2.1 days) than in group B (9.9 +/- 3.7 days), P = 0.01. CONCLUSION: These results did not provide any evidence of advantages of fasting in patients with active bleeding peptic ulcer treated by endoscopic sclerotherapy. Early feeding did not worsen outcome in patients with active bleeding peptic ulcer and reduced hospital stay.

[Peripheral neuropathies and chronic hepatitis C: a frequent association?]. / Neuropathies périphériques et hépatite chronique virale C: une association fréquente?

OBJECTIVE: The aim of this prospective study was to evaluate the prevalence of the peripheral neuropathies associated with chronic hepatitis C and their clinical, electrophysiological and histological characteristics. PATIENTS AND METHODS: Thirty six patients admitted from December 1994 to January 1996 for chronic hepatitis C were prospectively investigated. Laboratory data included liver blood tests, serum cryoprecipitate immunoelectrophoresis, assays for anti-nuclear antibody, rheumatoid factor, circulating immune complexes, anti-SSA and anti-SSB antibodies. For each patient, a clinical neurological evaluation as well as an electrophysiological evaluation were performed by the same operator. In presence of peripheral neuropathy, a neuromuscular biopsy was performed. RESULTS: In seven patients (19%), a peripheral neuropathy was diagnosed related to hepatitis C virus in 3 patients. In these 3 patients presenting with leg paresthesia, an axonal sensitive neuropathy was evidenced by electromyography. A neuromuscular biopsy performed in two of these patients showed a severe diminution of the myelinated fibers associated with vasculitis lesions in one patient. A skin biopsy was performed in the third patient with leg purpura revealing a leukocytoclasic vasculitis. A positive cryoglobulinemia was found in two of these patients. CONCLUSION: In chronic hepatitis C, the prevalence of peripheral neuropathy is 8% and usually associated with cryoglobulinemia. It is an axonal neuropathy with diminution of the myelinated fibers and vasculitis lesions in the absence of cryoglobulinemia.

Early feeding or enteral nutrition in patients with cirrhosis after bleeding from esophageal varices? A randomized controlled study.

The aim of this randomized controlled study was to assess the nutritional and clinical effects of early enteral nutrition (EN) in cirrhotic patients with bleeding from esophageal varices. From August 1994 through August 1995, all patients admitted for acute variceal bleeding underwent emergency sclerotherapy or banding ligation and continuous infusion of octreotide and were randomized in two groups. In group A, patients received from day 1 discontinuous polymeric EN (1665 kcal/day, through nasogastric tube) and in group B, patients were nil by mouth. On day 4, all patients received oral diet. Nutritional status, liver function, and rebleeding were evaluated on days 4, 7, and 35. Twenty-two patients (17 men, 5 women, mean age 56 years) were included. On day 0, patients in group A (N = 12) and group B (N = 10) were comparable. On day 4, nitrogen balance was 0.7 +/- 2.5 g/day in group A and -11.2 +/- 6.7 g/day in group B (P = 0.01, Mann-Whitney test). On days 4, 7, and 35, no significant differences between the two groups were observed for nutritional status and liver function. Four (33%) group A patients rebled compared with one (10%) group B patient (NS). Hospital stay (14.5 +/- 4.1 days vs 12.9 +/- 5.3 days) and mortality (3 vs 2 patients), were comparable between the two groups. In conclusion, our study failed to demonstrate any favorable effect of short-term EN on nutritional status and liver function in cirrhotic patients hospitalized for variceal bleeding.