High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma.

BACKGROUND: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.

Statins are not a risk factor for liver damage associated with intravenous glucocorticoid pulse therapy for Graves' orbitopathy.

OBJECTIVE: Acute liver damage (ALD) is associated with high-dose intravenous (iv) glucocorticoid (GC) (ivGC) pulse therapy in ~1 % of patients for Graves' orbitopathy (GO). It has been proposed that statins may increase the risk of ALD. Here we investigated the frequency of ALD according to the assumption of statins in a large retrospective cohort study. METHODS: We studied 1076 consecutive patients with GO given ivGC. ALD was defined as an increase in alanine aminotransferase ≥300 U/l. RESULTS: At the time of ivGC, 62 patients were taking statins and 1014 were not. The frequency of ALD has been reported to be 1.2 cases/100,000 statins users and 1300/100,000 in GO patients given ivGC. Thus, the expected frequency of ALD in patients given both statins and ivGC is 1560/100,000. Transferring these data to our series, one would have expected at least 0.96 cases of ALD (~one case), in the 62 patients given both ivGC and statins. However, no cases of ALD were observed in patients given statins, and the previously reported 14 cases of ALD in this series were seen in patients who were not taking statins. CONCLUSIONS: The lack of observation of cases of ALD in patients given ivGC and statins is quite reassuring. Although caution should be applied to any patient candidate to ivGC treatment and this should be particularly accurate in patients given statins, our findings somehow justify the use of ivGC in patients under statins, although further studies in larger cohorts are needed to confirm our conclusions.

Mixed Candida albicans and Candida glabrata populations associated with the pathogenesis of denture stomatitis.

INTRODUCTION: Oral yeasts are an important component of the resident microbial ecology of the oral cavity, but they are also associated with various forms of oral candidosis, such as denture stomatitis. Although Candida albicans is the predominant oral fungal pathogen, other species may also play an integral role in pathogenesis. The aim of this study was to examine the mycological ecology in patients with denture stomatitis, using an improved sampling technique, to determine whether species diversity and species quantity were related to oral pathology. METHODS: Thirty-seven patients attending the Glasgow Dental Hospital were enrolled in this study following informed consent. A full clinical history was obtained, including details of their oral hygiene practices and the levels of erythema based on Newton's classification scale. Oral rinse, denture sonicate, and swab samples were taken, which were processed for quantitative and qualitative analysis of oral yeasts. RESULTS: The proportion of patients with no inflammation or Newton's Types I, II, and III were 31, 33, 25, and 14%, respectively. Denture sonication was a superior sampling procedure, with statistically greater quantities of yeasts isolated using this methodology (P < 0.01). The predominant oral yeasts isolated were C. albicans (75%) and Candida glabrata (30%), which were isolated in higher proportions in patients with the highest grades of inflammation (100 and 80%), and in combination from 80% of these patients. CONCLUSIONS: This study has demonstrated that mixed C. albicans and C. glabrata biofilms may play an important role in the pathogenesis associated with severe inflammation in denture wearers.

Early and accurate prediction of Peg-IFNs/ribavirin therapy outcome in the individual patient with chronic hepatitis C by modeling the dynamics of the infected cells.

A novel biomathematical model that analyzes the combined alanine transaminase (ALT) and viral-load kinetics during the first month of pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy was successfully applied in 90 of 97 (93%) chronic hepatitis C patients in order to compute the number of infected cells at the end of therapy (I(eot)). The I(eot) indices were lower in sustained virological responders than in relapsers (RELs) and nonresponders (NRs) (median values: 31 vs. 2,190 vs. 1,090,000; P < 0.001), and were independently associated with treatment outcomes (P = 0.003). A threshold of 250 I(eot) was shown to identify sustained virological response (SVR) with high positive predictive value (93%) and good diagnostic accuracy (81%). The time taken to attain 250 I(eot) ranged from 3 to 11 months in patients with hepatitis C virus (HCV) genotypes 2 or 3 and from 3 to 18 months in those with HCV genotypes 1 or 4. Overall, the duration of therapy would have been 49 months less than that suggested by the most recent algorithms based on a rapid virological response (RVR) at week 4.

Emergence of hepatitis B virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment.

OBJECTIVES: We studied the impact of hepatitis B virus (HBV) polymerase/reverse transcriptase (Pol/Rt) heterogeneity on adefovir rescue therapy in 34 consecutive chronic hepatitis B patients with viral breakthrough during lamivudine monotherapy. METHODS: The Pol/Rt A-F domains were directly sequenced in all patients at baseline, and 12 and 24 months. Response to therapy was evaluated at 3, 6, 12 and 24 months by quantitative HBV-DNA. RESULTS: Primary treatment failures did not occur. At 6 months 24/34 (70.6%) patients had viraemia<10(4) copies/mL [initial viral response (IVR)]; at 12 and 24 months 23 (71.9%) and 26 (81.3%) of 32 had HBV-DNA<200 copies/mL [complete viral response (CVR)]. IVR or CVR patients did not show viral breakthroughs, which occurred in one of the six remaining patients. All but three patients had baseline rtM204I/V substitutions associated with rtL180M in 23, rtL80I/V in 14, rtV173L in 4, rtT184S in 3, rtQ215S in 2 and rtA181S in 2 cases. rtA181S without rtM204I/V was found in one patient. Four of the six patients (67%) without 24 month CVR showed rtA181S or rtT184S substitutions either alone or with typical lamivudine resistance profiles. Baseline HBV-DNA levels were negatively associated with IVR (univariate analysis, P=0.023). At least one of rtA181S and rtT184S substitutions correlated negatively with IVR and CVR (univariate analysis, P=0.001) and was independently associated with absence of CVR (P = 0.016). CONCLUSIONS: Lamivudine monotherapy favours the emergence of viral quasispecies that influence the response rate to adefovir rescue therapy independently from baseline viraemia and lower the susceptibility to other nucleos(t)ide analogues.

Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.

Liver stiffness was measured by transient elastography (FibroScan) in 228 consecutive patients with chronic viral hepatitis, with (115) or without cirrhosis (113), to study its correlations with serum transaminases [alanine aminotransferase (ALT)], fibrosis stage and surrogate noninvasive markers of fibrosis (APRI, FORNS, FibroTest and hyaluronic acid). The dynamic profiles of serum transaminases and liver stiffness were compared by multiple testing in 31 patients during a 6-month follow-up. We identified 8.3 and 14 kPa as the fibrosis >/=F2 and cirrhosis cut-offs, respectively: their sensitivities were 85.2%/78.3%; specificities 90.7%/98.2%; positive predictive values 93.9%/97.8%; negative predictive values 78.8%/81.6%; diagnostic accuracies 87.3%/88.2%. FibroScan performed better than the other surrogate markers of fibrosis (P < 0.001). Other than fibrosis, other factors independently associated with liver stiffness were ALT for all patients and chronic hepatitis patients (P < 0.001), and 12-month persistently normal ALT (biochemical remission, P < 0.001) in cirrhotics. In patients with biochemical remission either spontaneous or after antiviral therapy (48 of 228, 21%), liver stiffness was lower than in patients with identical fibrosis stage, but elevated ALT (P < 0.001). The liver stiffness dynamic profiles paralleled those of ALT, increasing 1.3- to 3-fold during ALT flares in 10 patients with hepatitis exacerbations. Liver stiffness remained unchanged in 21 with stable biochemical activity (P = 0.001). In conclusion, transient elastography is a new liver parameter that behaves as a reliable surrogate marker of fibrosis in chronic viral hepatitis patients, provided that its relationship with major changes of biochemical activity is taken into account.

In vitro interaction of posaconazole and caspofungin against clinical isolates of Candida glabrata.

Combinations of caspofungin and posaconazole were evaluated by fractional inhibitory concentration index against 119 Candida glabrata isolates. Synergy was seen in 18% of all isolates and in 4% of fluconazole-resistant isolates at 48 h without evidence of antagonism. This antifungal combination may have utility against this organism.

Comparison of antifungal susceptibilities to fluconazole and voriconazole of oral Candida glabrata isolates from head and neck radiation patients.

The antifungal susceptibilities of 79 oral Candida glabrata isolates to fluconazole and voriconazole were compared. The MICs at which 90% of the isolates tested were inhibited were 1 microg of voriconazole/ml and 32 microg of fluconazole/ml. Oral C. glabrata isolates for which the fluconazole MICs are elevated are commonly those for which the voriconazole MICs are elevated, but these increases may be transient for voriconazole, as they are for fluconazole.

Candida glabrata sepsis secondary to oral colonization in bone marrow transplantation.

Candida glabrata has emerged as a common cause of fungal sepsis in bone marrow transplant patients, particularly those receiving fluconazole prophylaxis. Colonization of the lower GI tract and indwelling catheters have been thought to be the primary sources of systemic infection with Candida. We report on a bone marrow transplant patient who developed Candida glabrata sepsis from pre-existing oral colonization.

Connection between a long-standing traumatic arteriovenous fistula and development of aneurysmal disease.

Long-standing peripheral arteriovenous fistulas (AVFs) are always accompanied by ectasia of the proximal arteries. In the literature, traumatic fistulas of the lower limbs are frequently reported to be associated with iliac and even infrarenal aortic aneurysms; however, no study dealing with associated visceral aneurysms has been published. We report a case in which a traumatic AVF was accompanied by the late development of not only an infrarenal aortic aneurysm but also both superior mesenteric and right renal artery aneurysm. No causal relationship may be inferred between the tibial fistula and the other aneurysms, but this previously unreported finding does raise the question of a possible connection.

[Multicenter study in southern South America of the in vitro activity of telithromycin in strains with defined resistance phenotypes isolated from community-acquired respiratory infections]. / Estudio multicéntrico en el Cono Sur Americano de la actividad comparativa in vitro de telitromicina en cepas con fenotipos definidos de resistencia asociadas a infecciones respiratorias adquiridas en la comunidad.

Telithromycin was the first ketolide to be approved in Europe and is in the approval process in the United States. It is structurally related to the macrolides; it has a keto group in the C3 position rather than cladinose. A carbamate group is also present at C11-C12. As a result, it has a reduced induction of the MLSB resistance mechanism (erm gene), it is not affected by the flux mechanism (mef gene), it has higher stability at low pH and has increased intrinsic activity compared with clarithromycin and azithromycin. Phase III studies have shown telithromycin to be effective in the treatment of community-acquired upper and lower respiratory tract infections. Its long half-life allows for oral once-daily dosing. From a pharmacokinetic point of view, its activity has been shown to be AUC(24h)/MIC dependent. It is active against bacteria involved in atypical pneumonia. The aim of our study was to determine the activity of telithromycin in isolates with defined resistance phenotypes obtained from community-acquired respiratory tract infections. Twelve centers in Argentina, Chile, Paraguay and Uruguay participated in the study. Each center collected three strains of the following species and resistance patterns: S. pyogenes, S. pneumoniae with resistance or intermediate resistance to oxacillin, erythromycin-resistant S. pneumoniae, clindamycin-resistant S. pneumoniae, oxacillin-susceptible S. aureus, erythromycin-resistant S. aureus, ampicillin-susceptible and -resistant M. catarrhalis and H. influenzae. Agar diffusion susceptibility tests with NeoSensitabs tablets (Rosco, Denmark) were carried out at each center. Isolates were sent to the coordinating center, where MICs were determined using agar microdilution and the Seppala test was used to determine the resistance mechanism to macrolides. The 327 isolates received were susceptible to telithromycin. Eighty percent of the erythromycin-resistant S. pneumoniae isolates were likely resistant due to a flux mechanism, and all those resistant to clindamycin were resistant due to the erm inducible mechanism. Only 20 out of 36 strains of clindamycin-resistant S. pneumoniae and 25 of the 36 ampicillin-resistant H. influenzae strains could be collected, thereby showing that these resistance patterns are less common in the participating South American countries than in other areas. The in vitro activity of telithromycin suggests that it is a promising antibacterial drug for the treatment of community-acquired respiratory tract infections.

Estudio multicéntrico en el Cono Sur Americano de la actividad comparativa in vitro de telitromicina en cepas con fenotipos definidos de resistencia asociadas a infecciones respiratorias adquiridas en la comunidad / Multicenter study in southern South America of the in vitro activity of telithromycin in strains with defined resistance phenotypes isolated from community-acquired respiratory infections

La telitromicina es el primer cetólido aprobado en Europa y en vías de aprobación en Estados Unidos. Su estructura deriva de los macrólidos. Presenta en C3 un grupo ceto en lugar de cladinosa y un sustituyente unido a carbamato en C11-C12. Como consecuencia, tiene menor capacidad de inducción del mecanismo de resistencia MLSB (gen erm), no resulta afectado por el mecanismo de flujo (gen mef), tiene mayor estabilidad en el medio ácido gástrico y presenta una acción intrínseca aumentada en relación a claritromicina y azitromicina. La telitromicina ha demostrado su eficacia en estudios de fase III en infecciones respiratorias de vías altas y bajas adquiridas en la comunidad. Su larga vida media le permite ser administrada por vía oral en una sola dosis diaria. Bajo el punto de vista farmacodinámico se ha demostrado que su actividad es dependiente del cociente AUC24h/CMI. Tiene actividad frente a bacterias productoras de neumonías atípicas. Nuestro interés fue determinar su actividad en cepas seleccionadas según su fenotipo de resistencia, aisladas de infecciones respiratorias. El estudio incluyó 12 centros del Cono Sur Americano. Cada uno de ellos recolectó tres cepas de cada una de las siguientes especies y resistotipos: S. pyogenes, S. pneumoniae resistente o con resistencia intermedia a oxacilina, S. pneumoniae resistente a eritromicina, S. pneumoniae resistente a clindamicina, S. aureus sensible a oxacilina, S. aureus resistente a eritromicina, M. catarrhalis y H. influenzae sensible y resistente a ampicilina. En cada centro se determinó la sensibilidad a diversos antibacterianos por el método de difusión con tabletas NeoSensitabs (Rosco, Dinamarca), y en el Centro Coordinador se determinó la CMI por macrodilución en agar, así como el mecanismo de resistencia a macrólidos por el test de Seppala. Las 327 cepas recibidas fueron sensibles a telitromicina. El 80 por ciento de las cepas de S. pneumoniae resistentes a eritromicina fue resistente, probablemente debido al mecanismo de flujo, y todas las resistentes a la clindamicina lo fueron por erm inducible. Sólo 20 de 36 cepas de S. pneumoniae resistentes a clindamicina pudieron ser recuperadas, así como 25 de 36 H. influenzae resistentes a ampicilina, demostrando que estos resistotipos son menos frecuentes en el Cono Sur Americano que en otras áreas. La telitromicina se presenta como un antibacteriano prometedor para el tratamiento de las infecciones respiratorias adquiridas en la comunidad (AU)

Hepatitis C virus infection: early diagnosis and identification of response to antiviral therapy.

Early diagnosis of hepatitis C infection and early identification of virologic response to antiviral therapy represent major hallmarks of the quality of a case. They contribute to reducing the risk of hepatitis C infection from blood product and improve disease management in patients treated with antivirals. Some of the current issues and perspectives involved in detection and quantification of viral load during the incubation phase of infection and monitoring the early phase of antiviral therapy are discussed.

Treatment of patients with chronic hepatitis C and cirrhosis.

The most cost effective strategy for antiviral therapy of chronic hepatitis C is the earliest identification and treatment of patients at risk of developing life-threatening complications such as hepatocellular carcinoma. Liver fibrosis represents the best predictor of unfavourable outcome. However, some patients with liver fibrosis already have a histological diagnosis of cirrhosis and there is a debate about whether alpha interferon is still effective in lowering the risk of disease progression in such patients. We identified some of the reasons that may explain seemingly contradictory results of studies addressing this issue. A major cause appears the beginning of follow-up at different starting points during the course of clinically compensated cirrhosis. Some investigators recruited patients because of anti-HCV positivity and elevated transaminases and found cirrhosis only at histology, whereas others recruited patients because cirrhosis had been diagnosed. Ultrasonographic signs of portal hypertension appear to be a useful tool to distinguish the two phases of the disease. Another important cause of reduced response rate to antiviral therapy is the presence of cofactors of liver disease and hepatocellular carcinoma such as present or past HBV infection. Early phase cirrhotics without cofactors appear to benefit most from therapy with a significant lower risk for hepatocellular carcinoma than untreated controls. The therapeutic decision in these patients could be the same as in patients with chronic hepatitis C without cirrhosis. In contrast, the efficacy of interferon remains questionable in HCV patients who already have ultrasonographic signs of portal hypertension and/or past or present HBV coinfection. Prospective, randomized clinical trials should be performed after stratification of these patients for stage and cofactors of liver disease.