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Introduction Highly effective oral antivirals (OAV) have been licensed for use in Chronic Hepatitis B (CHB). Efficacy of Tenofovir (TDF) and Entecavir (ETV) monotherapy has been demonstrated in randomised controlled trials. However, there may be a role for de novo combination therapy to reduce the development of resistance. For this reason, the authors offer patients combination therapy with TDF and Lamivudine (LAM) irrespective of whether they are OAV-naïve or experienced. In this study the authors test the hypothesis that combination therapy is superior to TDF monotherapy as assessed by viral suppression and ALT normalisation. Methods A retrospective prospective study of 185 patients (male=135), from a single centre, was performed. Viral suppression, was defined as <80 IU/ml and ALT normalisation <40 IU/l. Our real life data was compared with a published meta-analysis on the use of all treatments for HBV, but which reports TDF as the most potent OAV.1 Results Median age of patients was 45 (range 18–81). 74% were eAg negative prior to starting TDF and LAM. Median ALT at baseline was 46 (range 12–1141). 86 patients were treatment naïve prior to commencing combination therapy. Of 99 patients previously exposed to OAV's, 65 were partial responders and 34 virally suppressed when switching to TDF and LAM. 125/185 patients had completed 12 months and 84, 24 months of combination therapy. Overall viral suppression was recorded in 84% and 94% at 12 and 24 months respectively and ALT normalisation was seen in 67% and 74% at 12 and 24 months respectively. In the OAV-naïve group viral suppression was 81% compared with 84% in the OAV-experienced and ALT normalisation was 56% and 72% respectively in these groups at 12 months. In the published meta-analysis, viral suppression was 91% and ALT normalisation 67% at 12 months in a treatment naïve group. Comparing real life with published data showed no statistical significance for viral suppression and normalisation of ALT for combination versus monotherapy (p=0.12 and p=0.2 respectively). Conclusion These data highlight the efficacy of TDF in generating and sustaining viral suppression and ALT normalisation at 12 months and beyond. Combination OAV therapy versus TDF monotherapy does not show superiority. Furthermore, there is no reported resistance with TDF to date, but data are limited to 4-year follow-up. Given that OAV resistance may occur over many years, combination OAV may still have a role in the treatment of CHB, however larger randomised controlled trials are needed to determine this.

Introduction Bone Mineral Density (BMD) loss has been reported in chronic liver disease. In Chronic Hepatitis B (CHB) patients, Tenofovir Disoproxil Fumarate (TDF) is recommended as a first line therapy, in accordance with EASL guidelines. Concerns regarding the long-term safety of TDF have been raised, in particular changes in BMD in HIV patients, but limited data exist on similar changes in HBV treated patients. The aim of this study was to determine the impact of TDF on BMD in an ethnically diverse HBV infected population undergoing long-term treatment with this agent. Methods In a single centre, CHB patients treated with TDF for a minimum 12 months were prospectively offered a dual x-ray absorptiometry scan. BMD loss was defined by WHO criteria; T-score <−2.5 (osteoporosis) and between −1 and −2.5 (osteopenia). 83 consecutive patients were included (64 males), median age 45 (range 26–64). A control group, 27 patients with CHB (19 males), median age 32 (range 20–61), with no TDF exposure were also examined. Data on ethnicity, BMI, gender, fibrosis stage, comorbidities and drug history were recorded in all subjects. Results BMD loss was present in 45% of the treatment group (osteopenia 84%, osteoporosis 16%) and in 48% of the control group (osteopenia 85%, osteoporosis 15%). There was no difference in BMD loss when comparing both groups (p=0.45). In the ethnically diverse population studied, there was increased BMD loss in the non-White population (48%, treated group; 50%, controls) compared with the white population (33%, treated group; 40%, controls). By univariate analysis age, gender, fibrosis stage, comorbidities were all significant (p=<0.05, all variables), but particularly ethnicity (p=0.009). At multivariate analysis only ethnicity, BMI and male gender met statistical significance (p<0.015, <0.017 and <0.018 respectively), but not TDF. Conclusion This results demonstrate the prevalence of reduced BMD in CHB patients of diverse ethnicity, independent of TDF treatment. This cross-sectional study does not exclude the potential for BMD loss with TDF and further longitudinal studies are required to determine its effect on bone over time. Other factors also contribute to BMD loss, namely ethnicity and BMI, and should be given due consideration when selecting a treatment option.

Since 1990, Laboratory Services, First Nations and Inuit Health Branch (Health Canada) conducted an interlaboratory comparison program for mercury in human hair. Laboratory Services initiated this program to compare the performance of participating laboratories, analyzing mercury in human hair samples by a variety of analytical methods and instrumental detection techniques. The results of the quality assurance program, which included 31 participants on four continents, are described. Of the participating laboratories, 92% consistently meet QA/QC performance limits for the determination of Hg in human hair. A variety of analytical methods using different digestion and instrumental techniques gave similar results. The most frequently used instrumental techniques were: CV-AA, CV-AFS, and ICP-MS. A summary of results from 24 rounds is provided. The feedback from this program has assisted some laboratories in improving their results and solving some of their analytical problems.

Introduction Chronic hepatitis B (CHB) is a dynamic disease process with patients moving between disease phases over time. The majority of young adults infected with CHB are exposed to the virus perinatally or in the early years of life. Despite this, the extent of liver disease in this group remains ill-defined, as are the indications and timing of treatment. The aim of this study was to elucidate the extent of liver disease in a cohort of patients identified for a newly established young adult viral hepatitis clinic. Methods Only young adults who underwent liver biopsy for the assessment of CHB were included in the study. 70 patients (male=49), median age 26 (range 16–30), were examined. Data on ethnicity, BMI and eAg status were collated. Longitudinal data including viral load and ALT were recorded for 6–18 months prior to each patient undergoing liver biopsy. Normal ALT levels in the group were defined as;<30 IU/l males, <19 IU/l females in accordance with the Prati criteria. These clinical parameters were evaluated for their utility in predicting fibrosis stage (FS); fibrosis score 0–6, in accordance with the modified Ishak score. Disease severity in the young adult group, defined as FS, was compared with that reported in 51 consecutive CHB patients (>30 years), (male=45), median age 43 (range 32–71), undergoing liver biopsy for disease assessment. Results 38/70 of the young adults were eAg positive; median ALT over the course of follow-up was 61 (range 11–1050). 14 were Caucasian, 38 Asian and 18 Afro-Caribbean. Median BMI was 22.7 (range 17.9–35.6). By univariate analysis male gender and eAg positive disease were significant in predicting more marked disease with a higher FS (p≥0.05), but abnormal ALT and non-Caucasians in particular demonstrated marked significance (p=0.0002 and p=0.001 respectively). When evaluating the level of liver disease in young adults compared with that found in the 51 older CHB patients, there was no statistical difference between the FS reported in the two groups, presence of fibrosis (p=0.93); presence of moderate to severe fibrosis (p=0.6), demonstrating a trend towards higher FS with older age. However, normal ALT over the course of follow-up in the young adult group, was significantly associated with no fibrosis (p=.001). Conclusion These data highlight the importance of formal disease assessment in this age group, as comparable levels of liver fibrosis are present in young adults as in older patients. However, closer scrutiny with assessment of ALT according to Prati criteria may identify patients with milder disease. This study emphasises the advantages of a young adult clinic in providing greater focus on CHB in this age group, enabling the early and timely intervention with therapeutic options where indicated.

IntroductionTenofovir Disoproxil Fumarate (TDF) is now established as a very potent oral antiviral (OAV) agent in the treatment of chronic hepatitis B (CHB). However, as treatment with this OAV is often indefinite and potentially lifelong, concerns remain about its long-term safety. Bone Mineral Density (BMD) loss has been described in TDF treated HIV patients, but limited data exist for HBV treated patients. Furthermore, BMD loss has also been described in chronic liver disease in addition to being reported with certain patient characteristics.AimThe aim of this study was to determine the impact of TDF on BMD in an ethnically diverse HBV infected population undergoing long-term treatment with this agent.MethodCHB patients treated with TDF for a minimum of 12 months were recruited to this single centre study. Patients were prospectively offered a dual x-ray absorptiometry (DEXA) scan. Serum bone profile and Vitamin D levels were requested simultaneously. BMD loss was defined by WHO criteria; T-score < −2.5 (osteoporosis) and between −1 and −2.5 (osteopenia). 107 consecutive TDF treated patients were included (78 males), median age 45 (range 26–64). A control group, 27 CHB patients (19 males), median age 32 (range 20–61), with no TDF exposure were also studied. Data on gender, ethnicity, BMI, fibrosis stage, co-morbidities and drug history were recorded in all subjects. Analysis was performed with SPSS V.19.ResultsBMD loss was present in 44% of the treatment group (osteopenia 81%, osteoporosis 19%) and in 44% of the control group (osteopenia 83%, osteoporosis 17%) (p=0.21). In the ethnically diverse population studied, there was more marked BMD loss in the non-white population (47%, treated group; 45%, controls) compared with the white population (30%, treated group; 40%, controls). By univariate analysis age, gender, ethnicity, fibrosis stage, BMI, co-morbidities and low Vitamin D level were all significant for reduced BMD (p≤0.05, all variables). On multivariate analysis gender, ethnicity, BMI, fibrosis, co-morbidities and Vitamin D all met statistical significance for a reduction in BMD, but Vitamin D deficiency only was significant for the presence of osteoporosis (p=0.0001).ConclusionOur results demonstrate the prevalence of reduced BMD in CHB patients of diverse ethnicity and identify Vitamin D deficiency and not TDF as the likely cause. This cross-sectional study does not exclude the potential for BMD loss with TDF and further longitudinal studies are required to determine its effect on BMD over time. Vitamin D deficiency should be appropriately treated to avoid any potential for BMD loss associated with TDF when considering treatment with this OAV agent.

Introduction HBsAg is a surrogate marker of cccDNA, its loss is associated with sustained immune control and reduction in the development of HCC. HBsAg quantification (qHBsAg) has facilitated the on-treatment monitoring of response to pegylated interferon α (IFNα) with the potential to individualise therapy according to response. HBsAg decline with oral antivirals (OAV) is reported to be a slower process; however any reduction in HBsAg could potentially be used as a tool to determine duration of therapy, in lieu of recommended lifelong treatment. This study examined the utility of HBsAg quantification in developing individualised treatment strategies for both IFNα and OAV treated patients. Methods 86 CHB patients (male=72) were included for analysis. All patients underwent qHBsAg (ABBOTT Architect) in addition to longitudinal measurement of ALT and HBV DNA. 60 patients (male=54), median age 45 (range 21–70), were treated with combination Tenofovir and Lamivudine; qHBsAg was recorded at baseline, 12 and 24 months. 26 patients (male=18), median age 31 (range 18–55), were treated with IFNα. HBsAg was quantified at baseline, 12 and 24 weeks. HBsAg decline was compared in the OAV and IFNα groups at 12 and 24 months versus 12 and 24 weeks respectively. Results In the OAV group, baseline median ALT 42.5 (range 15–181) and median HBV DNA 3.43 log (range 1.5–7.9). At 12 months, ALT normalisation was achieved in 60% and undetectable DNA in 90%. Mean HBsAg decline in this group was 0.06 log at 12 months. ALT normalisation and viral suppression was sustained at 24 months. HBsAg decline, however, was not sustained and there was an overall mean increase of 0.1 log from baseline. In the IFNα group, baseline median ALT 113.6 (range 29–448) and median HBV DNA 7.21 log (range 3.58–9.25). HBsAg decline was measured 12 weekly. 8/26 (31%) patients had a >0.5 log decline at 12 weeks and this increased to 45% at 24 weeks. HBsAg decline was significantly greater in the IFNα group when compared with the OAV group at 12 weeks versus 12 months and more marked at 24 weeks versus 24 months (p=0.03 and p=0.006 respectively). Conclusion These data highlight the utility of qHBsAg in IFNα therapy and raises the possibility of an individualised, response guided approach allowing early changes in treatment regimen if indicated. Consistent with published data, the 24-week HBsAg is a better predictor of sustained immune control. Conversely, there was a limited HBsAg decline in OAV treated patients over prolonged follow-up and this reduction was not sustained. This suggests that HBsAg quantification alone cannot be used to individualise therapy and determine treatment duration with OAV's.

In this randomized, controlled trial conducted at Danish cardiac centers, intravenous antibiotic therapy was compared with partial oral antibiotic therapy for the treatment of bacterial endocarditis. The outcomes were similar in the two groups.

The 5-year outcomes from the Partial Oral Treatment of Endocarditis (POET) trial show continued effectiveness of oral antibiotic therapy as compared with intravenous antibiotic therapy for endocarditis.

Step-down oral antibiotic therapy is associated with a non-inferior long-term outcome compared with continued intravenous antibiotic therapy in the treatment of left-sided infective endocarditis. We aimed to analyze whether step-down oral therapy compared with continued intravenous antibiotic therapy is also associated with a non-inferior outcome in patients with large vegetations (vegetation length ≥ 10 mm) or among patients who underwent surgery before step-down oral therapy. We included patients without presence of aortic root abscess at diagnosis from the POET (Partial Oral Antibiotic Endocarditis Treatment) study. Multivariable Cox regression analyses were used to find associations between large vegetation, cardiac surgery, step-down oral therapy, and the primary end point (composite of all-cause mortality, unplanned cardiac surgery, embolic event, or relapse of positive blood cultures during follow-up). A total of 368 patients (age 68 ± 12, 77% men) were included. Patients with large vegetations (n = 124) were more likely to undergo surgery compared with patients with small vegetations (n = 244) (65% vs 20%, p <0.001). During a median 1,406 days of follow-up, 146 patients reached the primary end point. Large vegetations were not associated with the primary end point (hazard ratio 0.74, 95% confidence interval 0.47 to 1.18, p = 0.21). Step-down oral therapy was non-inferior to continued intravenous antibiotic in all subgroups when stratified by the presence of a large vegetation at baseline and early cardiac surgery. Step-down oral therapy is safe in the presence of a large vegetation at diagnosis and among patients who underwent early cardiac surgery.

Purpose Self-assessed poor health status is associated with increased risk of mortality in several cardiovascular conditions, but has not been investigated in patients with endocarditis. We examined health status and mortality in patients with endocarditis. Methods This is a re-specified substudy of the randomized POET endocarditis trial, which included 400 patients. Patients completed the single-question self-assessed health status from the Short-Form 36 questionnaire at time of randomization and were categorized as having poor or non-poor (excellent/very good, good, or fair) health status. Self-assessed health status and all-cause mortality were examined by a Cox regression model. Results Self-assessed health status was completed by 266 (67%) patients with a mean age of 68.0 years (± 11.8), 54 (20%) were females, and 86 (32%) had one or more major concurrent medical conditions besides endocarditis. The self-assessed health status distribution was poor ( n  = 21, 8%) and non-poor ( n  = 245, 92%). The median follow-up was 3.3 years and death occurred in 9 (43%) and 48 (20%) patients reporting poor and non-poor health status, respectively, and mortality rates [mortality/100 person-years, 95% confidence interval (CI)] were 18.1 (95% CI 9.4–34.8) and 5.4 (95% CI 4.1–7.2), i.e., the crude hazard ratio for death was 3.4 (95% CI: 1.7–7.0, p  < 0.01). Conclusion Self-assessed poor health status compared with non-poor health status as assessed by a single question was associated with a threefold increased long-term mortality in patients with endocarditis. POET ClinicalTrials.gov number, NCT01375257. Trial registry POET ClinicalTrials.gov number, NCT01375257.