Evaluation of portal hypertension in the cirrhotic patient: hepatic vein pressure gradient and beyond.

Portal hypertension (PH) is a major complication of liver cirrhosis, as it predisposes to the development of serious clinical manifestations such as ascites, hepatic encephalopathy and variceal bleeding. Till now, the measurement of hepatic vein pressure gradient (HVPG) is the gold standard method to ascertain the presence and significance of PH, as many studies have shown its correlation with the appearance of varices and the possibility of variceal bleeding. However, the invasiveness of this procedure makes it difficult to be used in daily clinical practice. Several noninvasive methods with adequate capability of evaluating liver fibrosis, including elastographic techniques, are currently used as alternatives to HVPG in order to assess the presence and the severity of PH. The aim of this paper is to express an overview of the literature about the actual role of HVPG and all available noninvasive tests on the prediction of development of PH complications, to highlight their advantages and their potential limitations, and to provide the latest trends on clinical practice.

A baseline tool for predicting response to peginterferon alfa-2a in HBeAg-positive patients with chronic hepatitis B.

BACKGROUND: Peginterferon induces off-treatment responses in approximately one-third of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. AIM: To develop an easy-to-use baseline prediction score to identify hepatitis B virus (HBV) genotype B-/C-infected HBeAg-positive Asian patients likely to respond to peginterferon alfa-2a. METHODS: Generalised additive models, multiple logistic regression (MLR) analysis and internal validation methods were applied to data from 647 HBeAg-positive patients from China, Hong Kong and Taiwan to develop a scoring system to predict response 24 weeks after completing a 48-week course of peginterferon alfa-2a. RESULTS: Five baseline factors (age, sex, alanine aminotransferase ratio, hepatitis B surface antigen (HBsAg) level and HBV DNA level) were retained in the final MLR for HBeAg seroconversion and used to develop a scoring system from 0 to 7. Among patients with scores of 0-1, 2-3, 4 or ≥5, HBeAg seroconversion was achieved in 6.4% (6/94), 23.0% (61/265), 36.4% (67/184) and 54.8% (57/104), respectively, and a combined response (HBeAg seroconversion plus HBV DNA <2000 IU/mL) in 5.3% (5/94), 12.8% (34/265), 25.0% (46/184) and 36.5% (38/104), respectively. Among patients with scores of 0-1, 2-3, 4 or ≥5, 57.0% (53/93), 12.3% (31/253), 3.4% (6/178) and 1.0% (1/100) had HBsAg ≥20 000 IU/mL at treatment Week 12; only 3/91 (3.3%) with HBsAg ≥20 000 IU/mL experienced a combined response at 24 weeks post-treatment (negative predictive value = 97% [88/91]). CONCLUSION: A pre-treatment scoring system using readily available baseline characteristics identifies HBeAg-positive Asian patients likely to experience sustained HBeAg seroconversion after treatment with peginterferon alfa-2a.

Hepatitis C: The beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe.

Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely "silent pandemic," its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week.

Real-life cost of managing chronic HCV infection in Greece prior to Direct-Acting Antivirals (DAAs): an undeniable truth of spending more for less.

PURPOSE: Chronic hepatitis C virus (HCV) infection is a major public health challenge across the world. Before the introduction of Direct-Acting Antivirals (DAAs), managing and treating the disease and its possible complications (cirrhosis, hepatocellular carcinoma) placed a considerable financial burden on public health resources. This study estimates the financial burden of managing HCV in Greece before the introduction of DAAs. PATIENTS AND METHODS: We reviewed the clinical records of 146 consecutive patients with chronic HCV that were regularly followed-up at two tertiary hospitals in Athens. Public health resources utilization was recorded by category for consultations, hospitalizations, medications [for the pre-DAAs: pegylated interferon (PEG-IFN) and ribavirin (RBV) regimens), and laboratory and imaging tests. Overall disease burden was stratified according to fibrosis stage in four categories [F1-F2, F3-F4, decompensated cirrhosis, and hepatocellular carcinoma (HCC) - liver transplantation (LT)]. All cost calculations were based on current prices in the Greek Public Health System. RESULTS: The average cost per patient on treatment was €8,629 for F1-F2 patients, €13,302 for F3-F4 patients, €14,678 for patients with decompensated cirrhosis, and €48,152 for patients with HCC or LT.  Main cost drivers were medications (75.6 % of total cost), laboratory and imaging tests (12.4 %) and hospitalizations (11.4 %). Hospitalization cost grew significantly as the disease progressed. CONCLUSIONS: Chronic hepatitis C places a substantial economic burden on the Greek Public Health System. This burden is expected to increase exponentially as patients move to more advanced disease stages. Robust interventions to deter chronic HCV infection progression should be considered beneficial from a long-term economic perspective. HIPPOKRATIA 2018, 22(3): 127-131.

Hippocratic views in the treatment of rectal prolapse.

Known since antiquity, rectal prolapse was first studied systematically by Hippocrates (460-377 BC) who recognized the predisposing factors and proposed several therapeutic approaches such as defecation positions, manual retraction and specific herbal or mineral based anti-haemorrhagic and pain-killing poultices. Hippocratic medicine avoided invasive surgical procedures probably due to a lack of knowledge in human anatomy. However, Hippocrates' views astonishingly lasted in time, presenting similarities to current medical theories on rectal prolapse.

Predictors of response to tenofovir disoproxil fumarate plus peginterferon alfa-2a combination therapy for chronic hepatitis B.

BACKGROUND: In patients with chronic hepatitis B, tenofovir disoproxil fumarate (TDF) plus pegylated interferon (PEG-IFN) for 48-weeks results in higher rates of hepatitis B surface antigen (HBsAg) loss than either monotherapy. AIM: To identify baseline and on-treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks. METHODS: A secondary analysis of data from an open-label study where patients were randomised to TDF (300 mg/day, oral) plus PEG-IFN (PI, 180 µg/week, subcutaneous) for 48 weeks (TDF/PI-48w); TDF plus PEG-IFN for 16 weeks, TDF for 32 weeks (TDF/PI-16w+TDF-32w); TDF for 120 weeks (TDF-120w) or PEG-IFN for 48 weeks (PI-48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72. RESULTS: Rates of HBsAg loss at Week 72 were significantly higher in the TDF/PI-48w group (6.5%) than in the TDF/PI-16w+TDF-32w (0.5%), TDF-120w (0%) and PI-48w (2.2%) groups (P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 (P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/PI-48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72. CONCLUSIONS: HBsAg decline at Week 24 of TDF plus PEG-IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72.

Addressing barriers to the prevention, diagnosis and treatment of hepatitis B and C in the face of persisting fiscal constraints in Europe: report from a high level conference.

In the WHO-EURO region, around 28 million people are currently living with chronic viral hepatitis, and 120,000 people die every year because of it. Lack of awareness and understanding combined with the social stigma and discrimination exacerbate barriers related to access to prevention, diagnosis and treatment services for those most in need. In addition, the persisting economic crisis has impacted on public health spending, thus posing challenges on the sustainable investment in promotion, primary and secondary prevention, diagnosis and treatment of viral hepatitis across European countries. The Hepatitis B and C Public Policy Association in cooperation with the Hellenic Center for Disease Prevention and Control together with 10 partner organizations discussed at the Athens High Level Meeting held in June 2014 recent policy developments, persisting and emerging challenges related to the prevention and management of viral hepatitis and the need for a de minimis framework of urgent priorities for action, reflected in a Call to Action (Appendix S1). The discussion confirmed that persisting barriers do not allow the full realisation of the public health potential of diagnosing and preventing hepatitis B and C, treating hepatitis B and curing hepatitis C. Such barriers are related to (a) lack of evidence-based knowledge of hepatitis B and C, (b) limited access to prevention, diagnosis and treatment services with poor patient pathways, (c) declining resources and (d) the presence of social stigma and discrimination. The discussion also confirmed the emerging importance of fiscal constraints on the ability of policymakers to adequately address viral hepatitis challenges, particularly through increasing coverage of newer therapies. In Europe, it is critical that public policy bodies urgently agree on a conceptual framework for addressing the existing and emerging barriers to managing viral hepatitis. Such a framework would ensure all health systems share a common understanding of definitions and indicators and look to integrate their responses to manage policy spillovers in the most cost-effective manner, while forging wide partnerships to sustainably and successfully address viral hepatitis.

Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis B in the UK: systematic review and economic evaluation.

We compared the cost-effectiveness of various noninvasive tests (NITs) in patients with chronic hepatitis B and elevated transaminases and/or viral load who would normally undergo liver biopsy to inform treatment decisions. We searched various databases until April 2012. We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes quality-adjusted-life-years (QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four decision-making strategies: testing with NITs and treating patients with fibrosis stage ≥F2, testing with liver biopsy and treating patients with ≥F2, treat none (watchful waiting) and treat all irrespective of fibrosis. Treating all patients without prior fibrosis assessment had an incremental cost-effectiveness ratio (ICER) of £28,137 per additional QALY gained for HBeAg-negative patients. For HBeAg-positive patients, using Fibroscan was the most cost-effective option with an ICER of £23,345. The base case results remained robust in the majority of sensitivity analyses, but were sensitive to changes in the ≥ F2 prevalence and the benefit of treatment in patients with F0-F1. For HBeAg-negative patients, strategies excluding NITs were the most cost-effective: treating all patients regardless of fibrosis level if the high cost-effectiveness threshold of £30,000 is accepted; watchful waiting if not. For HBeAg-positive patients, using Fibroscan to identify and treat those with ≥F2 was the most cost-effective option.

Association of antiviral therapy with reduced disease progression in chronic Hepatitis B patients: Results from a nation-wide cohort study.

BACKGROUND AND AIMS: Although effective treatment in terms of inducing virological and biochemical response for chronic hepatitis B (CHB) is available, its effect on the clinical course of the disease has not yet been accurately estimated. Objective of this study was to evaluate the effect of antiviral therapy and its type [interferon +/- nucleos(t)ide analogs (NAs) vs. NAs] on the occurrence of a clinical event (liver decompensation, liver transplant, hepatocellular carcinoma and death from a liver-related cause) in CHB patients. METHODS: The study population was derived from the HEPNET-Greece, a nationwide cohort study aimed to evaluate the current epidemiological course of viral hepatitis. To account for time-dependent confounding, Cox marginal structural models were used to analyze data. RESULTS: Thirty out of 2,125 eligible patients experienced a clinical event during their follow-up. When comparing treated to untreated individuals, the hazard ratio (HR) for a clinical event was 0.39 (95% CI: 0.16-0.98; p =0.044) in the whole sample, whereas there were indications of a more intense effect in the subgroup of patients with cirrhosis at presentation (HR =0.16, 95% CI: 0.02-1.21; p =0.075). The effect of Interferon initiated treatment was not significantly different of that of NAs. There was some evidence, albeit not statistically significant, of a protective treatment effect on hepatocellular carcinoma development (HCC). CONCLUSIONS: Data from observational studies can provide useful inference, provided they are analyzed appropriately. The current study has shown that the available treatment options for CHB offer a significant clinical benefit to CHB infected individuals. Hippokratia 2016, 20(3): 214-221.

Serum HBsAg kinetics and usefulness of interferon-inducible protein 10 serum in HBeAg-negative chronic hepatitis B patients treated with tenofovir disoproxil fumarate.

The kinetics of serum HBsAg and interferon-inducible protein 10 (IP10) levels in patients with chronic hepatitis B infection treated with tenofovir are unclear. We evaluated the changes of HBsAg levels and the predictability of IP10 for HBsAg decline in 160 HBeAg-negative patients receiving tenofovir for ≥12 months. Serum samples taken before and at 6, 12, 24, 36 and 48 months after tenofovir were tested for HBsAg levels. In 104 patients, serum samples before tenofovir were tested for IP10 levels. Compared to before tenofovir, HBsAg levels decreased by a median of 0.08, 0.11, 0.24, 0.33 and 0.38 log10 IU/mL at 6, 12, 24, 36 and 48 months, respectively (P < 0.001). HBsAg kinetics did not differ between nucleos(t)ide analogue(s) naive and experienced patients. The 12-, 24-, 36- and 48-month cumulative rates of ≥0.5 log10 HBsAg decline were 8%, 16%, 24% and 41% and of HBsAg ≤100 IU/mL were 9%, 12%, 14% and 18%, respectively. The only factor associated with HBsAg ≤100 IU/mL was lower HBsAg levels before tenofovir (P < 0.001), while HBsAg decline ≥0.5 log10 was associated with higher IP10 levels (P = 0.002) and particularly with IP10 > 350 pg/mL (P < 0.001). In conclusion, tenofovir decreases serum HBsAg levels in both nucleos(t)ide analogue(s) naive and experienced patients with HBeAg-negative chronic hepatitis B infection. After 4 years of therapy, HBsAg ≤100 IU/mL can be achieved in approximately 20% of patients, particularly in those with low baseline HBsAg levels. HBsAg decline is slow (≥0.5 log10 in 40% of patients after 4 years) and is associated only with higher baseline serum IP10 levels.

Associations between dietary intake and the presence of the metabolic syndrome in patients with non-alcoholic fatty liver disease.

BACKGROUND: Although dietary habits have been associated with the likelihood of the metabolic syndrome (MetS) in the general population, similar associations in non-alcoholic fatty liver disease (NAFLD) patients have not been explored. The aim of this cross-sectional study was to assess the presence of the MetS and to explore its potential association with dietary habits in a sample of NAFLD patients. METHODS: Seventy-three adult patients with recent NAFLD diagnosis based on elevated liver enzyme levels and evidence of hepatic steatosis on ultrasound were enrolled. Participants' habitual food consumption was retrospectively assessed through a food frequency questionnaire and adherence to the Mediterranean diet (MD) was assessed via the Mediterranean Diet Score (MedDietScore). The presence of the MetS was defined as the concomitant presence of at least three of its individual components, according to the criteria proposed by a recent joint statement of several major organisations. RESULTS: The MetS was present in 46.5% of the sample, with increased waist circumference values and decreased high-density lipoprotein cholesterol levels being the most prevalent disorders (63% and 88.7%, respectively). Consumption of refined grains [odds ratio (OR) = 1.02, 95% confidence interval (CI) = 1.00-1.05] and red meat and products (OR = 1.10, 95% CI = 1.01-1.21) were positively associated with the presence of the MetS, whereas the consumption of whole grains (OR = 0.92, 95% CI = 0.84-0.99) and MedDietScore (OR = 0.87, 95% CI = 0.76-0.99) were negatively associated, after adjusting for participants' age, sex, daily energy intake and time spent in sedentary activities. CONCLUSIONS: Low refined grain and red meat intake, high whole grain intake and high adherence to the MD were associated with lower odds of the MetS in NAFLD patients.

Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort.

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first-line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg-negative CHB patients treated with entecavir. HBeAg-negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0-4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir-treated HBeAg-negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.

Estimating the treatment cascade of chronic hepatitis B and C in Greece using a telephone survey.

Accurate diagnosis and treatment rates for chronic hepatitis B (HBV) and C virus (HCV) infections are usually missing. Aim of this study was to estimate the HBV and HCV treatment cascade (proportion and absolute numbers of tested, aware/unaware, infected and treated) in Greek adults. A telephone survey was conducted in a sample representative of the Greek adult general population. Prevalence rates were age-standardized for the Greek adult population and corrected for high-risk individuals not included in the survey. Of the 9974 participants, 5255 (52.7%) had been tested for HBV and 2062 (20.7%) for HCV with the proportion varying according to age and being higher in middle-age groups (P < 0.001). HBsAg was reported positive in 111/5255 (2.11%) and anti-HCV in 26/2062 (1.26%) tested cases. The age-adjusted prevalence was estimated to be 2.39% for HBV and 1.79% for HCV. Taking into account individuals at high risk for viral hepatitis not included in the survey, the 'true' prevalence was estimated to be 2.58% for HBV and 1.87% for HCV. Anti-HBV and anti-HCV treatment had been taken by 36/111 (32.4%) chronic HBV and 15/26 (57.7%) chronic HCV patients. In conclusion, almost 50% of chronic HBV and 80% of chronic HCV patients in Greece may be unaware of their infection, while only 32% or 58% of diagnosed chronic HBV or HCV patients, respectively, have been ever treated. Therefore, intensive efforts are required to improve the efficacy of screening for HBV and particularly for HCV as well as to reduce the barriers to treatment among diagnosed patients.

Genotype 4 HCV infection is difficult to cure with pegylated interferon and ribavirin. Results from a Greek Nationwide Cohort Study.

BACKGROUND AND AIM: Patients with genotype 4 (G4) chronic hepatitis C (CHC) are considered a difficult to treat population, although current data on G4 treatment responsiveness and duration are controversial. Greece represents a country with an intermediate prevalence of G4 infections, offering an opportunity to compare treatment outcomes by genotype and to identify potential prognostic factors for sustained virologic response (SVR). METHODS: All CHC patients from the HepNet.Greece, an ongoing nationwide cohort study on viral hepatitis, with known hepatitis C virus (HCV) genotype who received treatment with Peg-IFNa and ribavirin were analyzed. RESULTS: From 4443 patients, 951 (61.7% males, 78.4% Greeks, median age 40.6 years, 10% cirrhosis) fulfilled the inclusion criteria. G4 was found in 125 (13.1%) patients. Genotype distribution was not significantly different between Greeks and immigrants. Patients with G4 had similar odds of SVR compared to G1 but significantly lower compared to G2/G3. Age, treatment discontinuation, presence of cirrhosis and previous history of HCV-treatment were associated with lower probabilities of SVR. Ethnicity did not affect SVR for all genotypes while response to treatment was similar between Greek and Egyptian patients groups (35.7% vs 40.9%, p=0.660%) with G4 infection. The relation between SVR and genotype did not substantially change after adjustment for age, gender, cirrhosis, treatment interruption and history of HCV-treatment. CONCLUSIONS: The findings of this large cohort of CHC patients with a well balanced genotype distribution further supports the idea of considering G4 as a difficult to treat genotype. Further investigation is needed to identify genotype specific prognostic factors.

The usefulness of transient elastography in the assessment of patients with HBeAg-negative chronic hepatitis B virus infection.

Histological severity is often mandatory for the management of HBeAg-negative chronic HBV patients. We evaluated the performance of transient elastography (TE) in this setting. We included 357 untreated HBeAg-negative patients with ≥ 1 reliable liver stiffness measurement (LSM-kPa) by TE: 182 inactive carriers with HBV-DNA < 2000 (n = 139) or 2000-19 999 IU/mL (n = 43) and 175 patients with chronic hepatitis B (CHB). In carriers, HBV-DNA > 2000 and/or LSM > 6.5 were considered as biopsy indications. LSMs did not differ between carriers with low and high viremia, but were lower in carriers than in patients with CHB (5.8 ± 1.7 vs 9.0 ± 5.6, P < 0.001) offering moderate differentiation between these two groups (AUROC: 0.705). LSMs did not change significantly in carriers after 16 (12-24) months. In carriers with a liver biopsy, Ishak's staging scores were similar between cased with low and high viremia but higher in cases with LSM > 6.5 than ≤ 6.5 kPa. Moderate fibrosis (stages: 2-3) was detected in 0/10 carriers with only HBV-DNA > 2000 IU/mL, 2/10 (20%) carriers with only LSM > 6.5 and 5/10 (50%) carriers with both HBV-DNA > 2000 and LSM > 6.5 (P = 0.009). In patients with CHB, LSMs correlated significantly with grading and staging scores and offered excellent accuracy for ≥ moderate, ≥ severe fibrosis or cirrhosis (AUROC ≥ 0.919-0.950). TE can be helpful for the noninvasive assessment of HBeAg-negative chronic HBV patients. In conclusion, LSMs offer excellent accuracy for fibrosis severity in HBeAg-negative patients with CHB and can identify carriers with high risk of moderate fibrosis, which may be present in up to 35% of carriers with LSM > 6.5 kPa and 50% of carriers with LSM > 6.5 kPa and HBV-DNA > 2000 IU/mL.

Cirrhosis but not neutropenia is associated with the development of infection in patients with chronic hepatitis C undergoing treatment with pegylated interferon-alpha and ribavirin.

Peginterferon-alpha (PegIFNa) frequently causes neutropenia, mainly due to bone marrow suppression. The aim of this study was to explore factors that are associated with infections during antiviral treatment. We analysed data from 275 chronic hepatitis C (CHC) patients with compensated liver disease who underwent 318 courses of PegIFNa and ribavirin. Neutropenia was defined as neutrophils <1000 cells/µL. Mean leucocytes count significantly decreased from baseline to treatment nadir (7081 ± 2182 vs 3293 ± 1331 cells/µL, P < 0.001), while neutropenia was observed in 32% during treatment. Thirty-one infections were observed. The incidence rate for infection was assessed at 1.46 infections per 100 person-months of therapy. The hazard rate for infection did not correlate with the neutrophils' nadir or the decrease in white blood cells. In multivariate Cox's regression analysis, cirrhosis was the only factor that was significantly associated with the occurrence of infection. Our data show that the development of bacterial infections during treatment with PegIFNa and ribavirin in patients with compensated CHC is not associated with reduction or the nadir of white cells or neutrophil counts. Baseline cirrhosis is the only factor related with infection during treatment. The common practice of dose adjustment or discontinuation of interferon should be revised; careful assessment of liver damage before therapy and close monitoring during therapy are essential in all patients receiving interferon-based regimes, to minimize the detrimental consequences of infections.

Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease.

BACKGROUND: The treatment of chronic hepatitis B (CHB) in patients with chronic kidney disease (CKD) is based on nucleoside (lamivudine, telbivudine, entecavir) or nucleotide (adefovir, tenofovir) analogues (NAs), but it may be complex and the information is scarce. Entecavir and tenofovir represent the currently recommended first-line NAs for NA-naive CHB patients, while tenofovir is the NA of choice for CHB patients with resistance to nucleosides. AIM: To review the efficacy and safety of NAs in adult CHB patients with CKD and to provide reasonable recommendations for their optimal management. METHODS: Literature search in PubMed/Medline and manual search of relevant articles, reviews and book chapters. RESULTS: NAs are cleared by kidneys and their dosage should be adjusted in patients with creatinine clearance <50 mL/min. There are concerns about nephrotoxic potential of the nucleotides, particularly adefovir, while improvements of creatinine clearance have been reported under telbivudine. Most existing data in CHB patients with CKD are for lamivudine and, less frequently, for other NAs, mostly entecavir. Besides CHB, NA should be used in case of immunosuppressive therapy in any HBsAg-positive patient with CKD including renal transplant (RT) recipients and in anti-HBs-positive recipients of kidney grafts from HBsAg-positive donors. CONCLUSIONS: Chronic hepatitis B patients with chronic kidney disease receiving nucleoside analogues should be followed carefully for treatment efficacy and renal safety. Despite the absence of strong data, entecavir and telbivudine seem to be the preferred options for nucleoside analogue-naive CHB patients with chronic kidney disease, depending on viraemia and severity of renal dysfunction. More studies are certainly needed in this setting.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Efficacy and safety of continuous 4-year telbivudine treatment in patients with chronic hepatitis B.

In the phase-III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2-year treatment in HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine-treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2-year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per-protocol population. Amongst 293 HBeAg-positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg-negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off-treatment follow-up). The cumulative 4-year resistance rate was 10.6% for HBeAg-positive and 10.0% for HBeAg-negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m(2) (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg-positive and HBeAg-negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg-positive patients.

High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review.

The combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues [NA(s)] is considered as the standard of care for prophylaxis against HBV recurrence after liver transplantation (LT), but the optimal protocol is controversial. We evaluated the efficacy of the newer NAs with high genetic barrier (hgbNA) [i.e. entecavir (ETV) or tenofovir (TDF)] with or without HBIG as prophylaxis against HBV recurrence after LT. In total, 519 HBV liver transplant recipients from 17 studies met the inclusion criteria and they were compared to those under lamivudine (LAM) and HBIG who had been selected in our previous review. Patients under HBIG and LAM developed HBV recurrence (115/1889 or 6.1%): (a) significantly more frequently compared to patients under HBIG and a hgbNA [1.0% (3/303), p < 0.001], and (b) numerically but not significantly more frequently compared to the patients who received a newer NA after discontinuation of HBIG [3.9% (4/102), p = 0.52]. The use of a hgbNA without any HBIG offered similar antiviral prophylaxis compared to HBIG and LAM combination, if the definition of HBV recurrence was based on HBV DNA detectability [0.9% vs. 3.8%, p = 0.11]. Our findings favor the use of HBIG and a hgbNA instead of HBIG and LAM combined prophylaxis against HBV recurrence after LT.