Efficacy of immunotherapy with TG4040, peg-interferon, and ribavirin in a Phase 2 study of patients with chronic HCV infection.

BACKGROUND & AIMS: TG4040 is a modified vaccinia Ankara (MVA) virus that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase II open-label study to determine the efficacy, safety, and immunotherapeutic properties of TG4040 in combination with pegylated interferon α-2a and ribavirin (PEG-IFNα/RBV) in patients with chronic HCV infection. METHODS: Treatment-naive patients with HCV genotype 1 infection were assigned randomly to 1 of the following groups: PEG-IFNα/RBV for 48 weeks (group A, n = 31), PEG-IFNα/RBV for 4 weeks followed by PEG-IFNα/RBV for 44 weeks with 6 injections of TG4040 (group B, n = 63), or TG4040 for 12 weeks (7 injections) followed by PEG-IFNα/RBV for 48 weeks with 6 injections of TG4040 (group C, n = 59). The primary end point was complete early virologic response (cEVR), defined as HCV-RNA level less than 10 IU/mL after 12 weeks of PEG-IFNα/RBV treatment. RESULTS: In group C, 64.2% of evaluable patients achieved cEVR, compared with 30.0% in group A and 45.9% in group B (P = .0003 for group C vs A). A higher percentage of patients achieved a sustained virologic response 24 weeks after therapy ended in group C (58.2%) than in groups A (48.4%) or B (50.8%). HCV- and MVA-specific T-cell responses were observed predominantly in group C. As expected, most patients given injections of TG4040 developed anti-MVA antibodies. The combination of TG4040 and PEG-IFNα/RBV was reasonably well tolerated. However, PEG-IFNα-associated thrombocytopenia developed in 3 patients who carried the class II HLA allele DRB01*04. CONCLUSIONS: A higher percentage of patients with chronic HCV infection who received immunotherapy with TG4040 followed by TG4040 and PEG-IFNα/RBV achieved a cEVR compared with patients who received only PEG-IFNα/RBV therapy. These findings show that immunotherapies that activate T cells are effective in patients with chronic HCV infection. ClinicalTrials.gov number, NCT01055821.

Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus. METHODS: Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0·3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476. FINDINGS: 867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1·55 [95% CI 1·10-2·19]; p=0·0129) and 10 mg/kg (167 [58%], 1·83 [1·30-2·59]; p=0·0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1·51 [1·07-2·14]; p=0·0189) and 10 mg/kg (169 [58%], 1·71 [1·21-2·41]; p=0·0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1·38 [0·93-2·04]; p=0·1064) and 10 mg/kg (236 [81%], 1·62 [1·09-2·42]; p=0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1·68 [1·15-2·47]; p=0·0078) and 10 mg/kg (231 [80%], 1·74 [1·18-2·55]; p=0·0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported. INTERPRETATION: Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease. FUNDING: Human Genome Sciences and GlaxoSmithKline.

Helicobacter pylori cultivation from gastric biopsies and susceptibility to antibiotics used in empirical therapy.

UNLABELLED: Helicobacter pylori is one of the most common among the numerous bacterial species of the stomach. It is classified as a class 1 carcinogen because of its causal relationship to gastric adenocarcinoma. The epidemiology of H. pylori infection is characterized by a marked difference between developing and developed countries. Treatment of H. pylori still remains a challenge due to the high rate of antibiotic resistance. The aim of this study was to investigate the susceptibility of H. pylori strains isolated from gastric biopsies to different antibiotics currently used in the H. pylori infection treatment schemes. MATERIALS AND METHODS: Upper gastrointestinal GI endoscopy was performed, followed by the rapid urease test on gastric biopsies. The positive samples were cultivated on specific media under microaerophilic conditions and the antibiotic susceptibility assay was performed on the isolated strains. RESULTS: A positivity rate of 70% was obtained for cultures performed from the biopsy samples positive for the urease test. The resistance rates for the antibiotics used in the classic triple therapy proved to be high, i.e. 92.8% for metronidazole, 50% for amoxicillin and 32% for clarithromycin. The isolated strains proved to be sensitive to ciprofloxacin and levofloxacin. CONCLUSIONS: The role of gastric microbiota and its contribution to the H. pylori associated pathology need to be established. The problem of antibiotic treatment failure in case of resistant H. pylori strains can be surpassed by routine culture and antibiotic susceptibility testings.

Correlation of anti-Helicobacter pylori cagA IgG antibodies with resistance to first line treatment, bleeding gastroduodenal ulcers and gastric cancer.

UNLABELLED: Helicobacter pylori was recognized in 1994 as a class I carcinogen by the International Agency for Research on Cancer (IARC). The prevalence of H. pylori infection varies from 20 to 50% in industrialized countries to over 80% in developing countries. The cagA strains are more virulent than others, being able to induce morphological changes, vacuolization and degeneration of in vitro cultured cells. AIM: During this study we investigated the possible correlations between the presence of H. pylori cagA (cytotoxin associated gene antigen)-IgG antibodies and the severity of clinical and endoscopical findings. METHODS: Anti-cagA IgG was screened by ELISA in 104 selected patients exhibiting resistance to first line therapy for H. pylori, bleeding gastroduodenal ulcers, non cardia gastric cancer and gastric polyps. RESULTS: A statistically significant association between resistant cases to first line therapy for H. pylori, bleeding gastroduodenal ulcers, non cardia gastric cancer, gastric polyps and cag A Ig G antibodies (p value 0.02 calculated by T-Test) was observed. As Cag A antibodies titer persist up to four months, their level could be an useful marker in detecting previous long-term H pylori infection especially in gastric cancer patients. CONCLUSIONS: CagA positive H. pylori are virulent strains and the cagA IgG antibodies titer is associated with persistence of infection after treatment, upper gastroduodenal ulcers or gastric cancer. The presence of these antibodies, associated with positive biopsy for H. pylori, indicates the need of H. pylori treatment.

Does this patient have cancer? The assessment of age, anemia, and erythrocyte sedimentation rate in cancer as a cause of weight loss. A retrospective study based on a secondary care university hospital in Romania.

BACKGROUND: "Does this patient have cancer?" is a question frequently asked when confronted by patients with involuntary weight loss. The aim of this study was to assess the value of age, erythrocyte sedimentation rate (ESR), and anemia in the diagnosis of cancer as a cause of involuntary weight loss. METHODS: A retrospective study of 7850 patients admitted to the Department of Internal Medicine from January to September 2003 was performed. Especially selected were 431 patients with weight loss. Age, ESR, hemoglobin, and the discharge diagnosis were recorded. RESULTS: Twenty-four percent of the patients with involuntary weight loss had cancer. Age, ESR, and anemia were found not to be of value in the diagnosis of cancer (areas under the curve were 0.684, 0.690, and 0.766, respectively). When diagnostic tests for age, a high ESR, and anemia were used serially, the positive predictive value for a malignancy was 64% (CI: 27-90%); when the tests were utilized in parallel, the negative predictive value was 91% (CI: 85-100%). CONCLUSIONS: Any patient admitted to our Department of Internal Medicine for involuntary weight loss had a 24% probability of having a malignancy. Neither age, nor ESR, nor anemia, used separately as a multilevel, diagnostic test or combined serially or in parallel, could exclude or rule in the diagnosis of cancer. However, they could increase (from 24% to 64%) or decrease (from 24% to 9%) the probability of cancer.

Correlation between cholestasis and infection.

This is an overview of cytokine-induced cholestasis, justified by the insufficient knowledge of this frequent type of cholestasis. In the presence of an infectious agent a systemic and intrahepatic production of proinflammatory cytokines results (TNF-alpha, IL-1beta, IL-6 etc.), stimulated by microbial lipopolysaccharides. In patients having systemic infections, the liver has several major functions: source of the inflammatory cytokines produced as a response to infection and a target of these inflammation mediators. The inflammatory cytokines interfere with the activity of both the sinusoidal and canalicular transporting systems. One of the potential consequences of this process is the appearance of cholestasis. An infection can lead to cholestasis despite the absence of direct invasion of the liver by the infectious agent. Particularly the cholestasis produced when the infection generating agent is not located in the liver (sepsis or extrahepatic infections) has been emphasized. The clinical aspect of the diseases associated with this type of cholestasis and the effects of anti-infectious therapy on cholestasis are presented. Cytokine-induced cholestasis represents a common pathogenic path for several diseases: hepatitides that present with an intrahepatic cholestatic pattern (viral, ethanol-induced, NSAID-induced), but also many other infections, which are sometimes overlooked because of the lack of clinical signs. When a preexistent liver disease is present, the cholestasis incidence is higher. In this latter condition, ignorance of this possible mechanism of cholestasis will lead to misdiagnosis and unnecessary tests, sometimes expensive and useless.

Vascular disease in rheumatoid arthritis: from subclinical lesions to cardiovascular risk.

Rheumatoid arthritis (RA) is one of the most prevalent and complex inflammatory diseases affecting primarily the joints, but also associating several extra-articular features. The vascular disease in RA encompasses a large spectrum of lesions, from rheumatoid vasculitis to atherosclerotic lesions. During the last years the importance of the vascular disease related to atherosclerosis in terms of cardiovascular morbidity and global mortality became evident in RA. The inflammatory hypothesis of atherosclerosis in RA implies that mediators originating from the inflamed synovial tissue or from the liver may have systemic vascular consequences, leading to endothelial dysfunction and structural abnormalities of the vessels. Hence, the global management of patients with RA must include the improvement of cardiovascular risk in parallel with the management of joint disease.

Cardiovascular risk and rheumatoid arthritis: from mechanisms of atherosclerosis to therapeutic approach.

Large epidemiological studies showed that one of the most important causes of death in patients with rheumatoid arthritis (RA) is represented by cardiovascular disease. Thus, the presence of RA is associated with an increased risk of the occurrence of stable angina, myocardial infarction, heart failure and stroke. However, studies performed during the last years failed to bring us clear evidence regarding the role of traditional cardiovascular risk factors (hyperlipidemia, diabetes mellitus, hypertension, smoking and obesity) in the pathogenesis of cardiovascular disease in these patients. Recently, the role of inflammation and its mediators not only in the atherosclerosis plaque development but also in the mechanisms of vulnerable plaque was clearly demonstrated. From this point of view, recent studies showed that inflammatory cells and mediators of inflammation are both markers of an increased cardiovascular risk and unfavorable cardiovascular outcome, and also cardiovascular risk factors that act in an active manner in the processes that promote atherosclerosis. Taking into account the fact that RA is a systemic inflammatory status, recent reports demonstrated the involvement of inflammation mediators in connection with prothrombotic factors and endothelial dysfunction in the development of cardiovascular disease in RA patients. There are only scarce data in the literature regarding the benefice of cardiovascular risk reduction therapies in this group. Further studies are required for the refinement of the cardiovascular risk stratification algorithms and for the improvement of the cardiovascular risk management in rheumatoid arthritis.

Fever of unknown origin-predictors of outcome. A prospective multicenter study on 164 patients.

BACKGROUND: To date, the studies that have been done on fever of unknown origin have mostly been descriptive. Therefore, we know the etiogical spectrum and how it has changed since 1966 for many regions of the world. However, we do not know if there are clinical or laboratory predictors of severe outcome. Being able to estimate the severity of the disease early on would allow one to determine how intensive the diagnostic work-up should be. METHODS: A multicenter cohort study was carried out on 164 consecutive patients who met the classic, modified criteria of fever of unknown origin. The study lasted 2 years (1997-1998) and included a follow-up period of another 2 years. The main outcome measured was the final diagnosis established at the end of follow-up. RESULTS: When the white cell count was abnormal, the relative risk for a serious disease was 1.49 (CI: 1.15-1.94; p=0.004), when anemia was present, the relative risk was 1.55 (CI: 1.21-1.98; p=0.003), and for high alanine aminotransferase (ALAT), bilirubin, or lactate dehydrogenase (LDH), the relative risks were 1.57 (CI: 1.21-2.02; p=0.010), 1.57 (CI: 1.18-2.08; p=0.007), and 3.43 (CI: 1.81-6.48; p=0.0002), respectively. In multivariate analysis, the odds ratios for serious diseases were 2.7 (CI: 1.17-6.4; p=0.02) for abnormal white cell count, 2.8 (CI: 1.14-7.16; p=0.02) for anemia, 4.3 (CI: 1.6-11.5; p=0.003) for high serum bilirubin, and 5.3 (1.5-18.6; p=0.009) for high serum ALAT. CONCLUSIONS: In patients having a fever of unknown origin, anemia, abnormal white cell count, and high ALAT and bilirubin are independent predictors of severe outcome.

Estudo de bioequivalencia comparada de duas preparacaoes de zopiclone / Comparative bioavailability of two preparations of zopiclone

O estudo avalia a bioequivalencia de duas formulacoes diferentes de zopiclone(comprimidos de 7,5mg) a saber:Neurolil (Novaquimica-Sigma Pharma,Brasil)e Imovane(Rhone-Poulenc Rorer,Italia)O estudo de bioequivalencia foi conduzido em 18 voluntarios sadios,com idade entre 22 e 40 anos.Uma dose oral unica de dois comprimidos(15mg) de Neurolil ou Imovane foi administrada a cada um dos voluntarios,em um desenho controlado,aleatorio,cruzado.As concentracoes plasmaticas obtidas com ambas as formulacoes foram medidas atraves do metodo HPLC(cromatografia liquida de alta performance)O procedimento experimental consistiu na extracao da droga com diclorometano de amostras alcalinizadas de plasma.A fase organica foi separada,evaporada e seca e o residuo dissolvido em fase movel para analise atraves do metodo HPLC.Os resultados mostraram que as concentracoes plasmaticas obtidas com as duas formulacoes sao semelhantes,concluindo-se que ambos os produtos sao bioequivalentes