Cryptogenic liver cirrhosis and hepatitis E virus (HEV): Are they related?

INTRODUCTION AND OBJECTIVES: Hepatitis E virus (HEV) is one of the most common causes of acute hepatitis. In recent years, its role in the development of chronic hepatitis and cirrhosis especially in immunosuppressed patients and its wide range of extrahepatic involvement have increased the amount of research on HEV. In this study we aimed to investigate the presence of HEV infection in individuals with cryptogenic cirrhosis. MATERIALS AND METHODS: HEV antibodies were analysed using the Anti HEV enzyme-linked immunosorbent assay (ELISA) kit (anti-HEV ELISA; Diapro Prodiagnostic Bioprobes, Milan, Italy). HEV RNA was isolated with using QIAMP Viral RNA mini kit (QIAGEN, Hilden, Germany). The HEV RNA titre was detected with the Rotor Gene 3000 real time polymerase chain reaction (PCR) system using GenoSen's HEV (Rotor Gene) Quantitative Real Time PCR Kit (Genome Diagnostics Private Limited, the Netherlands). RESULTS: Our study included 21 healthy volunteers (12 males) and 35 cryptogenic cirrhosis patients (19 males). The ages of the patients and the controls were similar (46±12.1 vs. 37.5±9.7years). The mean Child-Pugh score was 8±2.5. The anti HEV immunoglobulin G(IgG) positivity rate was 9.5% and 25.7% in the control and patient groups respectively (p>0.05). HEV RNA positivity was not detected in the control group, but 3 cases (8.6%) in the patient group were positive (p>0.05). The HEV RNA, aspartate aminotransferase (AST) and alanine aminotransferase(ALT) levels for these 3 cases were 326.461copies/mL, 91IU/L and 67IU/L; 480copies/mL, 68IU/L and 36IU/L and 72copies/mL, 42IU/L and 24IU/L respectively. There were positive correlations between HEV RNA levels and AST and ALT levels (p<0.05). CONCLUSIONS: Anti HEVIgG and HEV RNA positivity rates are high in cryptogenic cirrhosis although it is not statistically significant and there is a positive correlation between HEV RNA and aminotransferases.

Mutations in Core Gene Region of Hepatitis B Virus in Patients with Chronic Hepatitis B.

BACKGROUND: The HBV core protein plays a major role in host immune response. Mutations occurring in the HBV core gene may cause alterations in the major epitopes being effective in the host immune response. Until now, the persistent effects of core gene mutations on HBV infections have not been fully understood. The aim of this study is to analyze the core gene mutations for epitopes in the T lymphocytes [T helper (Th) and cytotoxic (CTL)] and B cell and C terminal region in patients with chronic hepatitis using ultra-deep pyrosequencing (UDPS) method. METHODS: Eleven patients with chronic hepatitis B infection were included in the study. Amplification of the core gene was performed by a conventional PCR method. Mutations in the epitopes for T lymphocytes (Th and CTL) and B cell and in the C terminal region of HBV core gene were screened by UDPS. These mutations were analyzed in HBeAg positive and negative patients. RESULTS: The minimum percentages of amino acid substitutions were found with 0.9% in HBeAg positive patients and 1.2% in negative patients. The number of missense mutation was higher in patients with HBeAg positive than negative patients (p < 0.005). The number of amino acid substitutions in the region of aa49 - 69 in the Th epitopes was found to be the highest in both HBeAg positive and negative patients. The mutation frequency was higher in the C-terminal region of the core protein compared to the Th, CTL, and B cell regions and these were more common in subjects with high-grade fibrosis. Some types of mutations (V27I, R47H, Y132I, R174STOP, S181P, Q182K) were only detected in subjects with liver cirrhosis. CONCLUSIONS: Unlike literature, our results show that there is no significant increase in number of mutations in the core gene of the virus during the anti-HBe positive period. The role of low abundance variants and mutations in the immune system can be understood using methods such as UDPS in the near future.

Production and characterization of a conserved M2e peptide-based specific IgY antibody: evaluation of the diagnostic potential via conjugation with latex nanoparticles.

Antibodies play an important role in combating and controlling viral diseases such as influenza. Immunoglobulin Y (IgY) antibodies have several advantages such as a less invasive manufacturing process, ease of isolation, higher affinity compared with IgG antibodies, and cost-effectiveness. To date, although specific IgY production has been performed for different strains of influenza A, to the best of our knowledge, an IgY against the M2e peptide has not been produced. In the current study, IgY antibodies are produced, purified, and characterized using the M2e peptide sequence for the first time with the intent to apply them for the diagnosis of influenza A virus. Anti-M2e IgY antibodies are obtained from eggs using a two-step purification method. The activity and characterization of the antibodies are determined using an enzyme-linked immunosorbent assay, a nano-spectrophotometer, an SDS-Page assay, and a Western Blot analysis. Finally, anti-M2e IgY antibodies are conjugated to the latex nanoparticles, and the reaction between the influenza A virus and the nanoparticles is demonstrated using light microscopy, transmission electron microscopy, and energy dispersive X-ray spectroscopy. In conclusion, this study shows that anti-M2e IgY antibodies can contribute to the diagnosis, treatment, and prevention of the influenza A virus.

[Prevalence of maternal measles, rubella, mumps and varicella antibodies in the first six months of life]. / Ilk alti ayda maternal kizamik, kizamikçik, kabakulak ve suçiçegi antikorlarinin durumu.

The protection of infants against infections during the first few months of life is provided mainly by maternal antibodies. The presence of maternal antibodies can decrease vaccine efficacy. The waning time of maternal antibodies shows variations therefore seroepidemiological studies are important for the development of vaccination schedules. Some recent studies showed that the maternal measles antibodies may disappear around 3 months of age especially in infants born from mothers who were vaccinated. There are few cross-sectional studies from Turkey evaluating the maternal antibody levels of infants against measles in recent years. The aim of this prospective, multicentre study is to evaluate the seropositivity of measles, rubella, mumps, and varicella in mothers and their infants at 1 and 6 months after birth. The study was carried out at the Social Pediatrics Units of two university hospitals, a private hospital and a state hospital. The exclusion criteria were known impaired immune system or immune deficiency disorder in mother or child, preterm delivery (< 37 gestational week), administration of immunoglobulins or any blood products before admission or during the follow-up period, and history of vaccination or exposure to one of these diseases during the study period. The final analysis encompassed 209 mother-infant pairs. Blood samples were collected 1 month after birth from mothers and 1 and 6 months after birth from their babies. Antibody levels were determined by ELISA (Enzyme-Linked ImmunoSorbent Assay) method. Information on the socio-economic and demographic characteristics of the families were collected by a face-to-face questionnaire. Seropositivity was found as 95.7%, 92.8%, 92.8% and 96.7% for measles, mumps, rubella and varicella (MMRV) respectively. Majority of infants lost maternal antibodies at 6 months of age. Of all 6 month-old infants 25% were seropositive for measles,14.6% for mumps, 23.2% for rubella and 17.1% for varicella. The proportion of seropositive infants born from seropositive mothers was higher than those born from seronegative mothers for all four diseases. This difference was statistically significant only at 1 month of age (p= 0.001). Our study showed that maternal antibodies against MMRV decreased rapidly by 6 months of age therefore necessary measures should be taken to close this gap between the loss of maternal protection and the vaccination of infants for MMRV. As the epidemiology of the diseases changes in time, it is important to carry out such studies with large series in different countries and settings. Important results were determined in our study within this respect.

[Mortality related factors in patients requiring hospitalization for influenza like illness]. / Influenza benzeri hastalik nedeniyle hastaneye yatis gerektiren hastalarda mortaliteyle iliskili faktörler.

The knowledge about the viral etiologies causing respiratory disease in adults is limited. Viral respiratory diseases may lead deterioration in certain patient populations. The aim of this study was to determine the viral etiologies of influenza-like illness among patients requiring hospitalization and to document the risk factors for mortality. This prospective study was performed in one of the 7 centers in Turkey in the context of influenza surveillance by the Global Influenza Hospital Surveillance Network. A 35-bed Adult Emergency Service and 10-bed Acute Care Unit were screened for consequent recruitment of eligible patients daily, on weekdays only. ICD-10 codes in the electronic health records and direct patient encounters were used to screen for the following eligibility diagnoses: acute respiratory tract infection, asthma, heart failure, pneumonia, influenza, chronic obstructive lung disease, dyspnea/respiratory abnormality, respiratory symptoms, cough and fever. A total of 334 patients who were admitted with the eligible ICD-10 codes within the 24th and 48th hours were screened during the study period and of those eligible ones, 106 consented and were swabbed. Nasal or nasopharyngeal swabs were collected using Virocult (Medical Wire & Equipment, UK) and sent to the central laboratory in 1-3 days. Swabs were collected and specimens were introduced to real-time polymerase chain reaction based multiplex kits, as well as, ABI 7500 platform with CDC primers and probes. A total of 106 patients were swabbed. Hospital mortality was 12.2%. More than one fourth of the patients needed a sort of mechanical ventilation support and at least one organ failure developed in one third of the patients. One or more viral pathogens were detected in 56 (52.8%) of the swabbed patients, with influenza H3N2 being the most prevalent one. Having a lower body mass index (OR, 0.845, p= 0.034) was associated with mortality. Chronic lung diseases were shown to confer a survival advantage (OR, 0.127, p= 0.009). Community acquired viral respiratory infections might lead to significant compromise in adult patients. Prevention of malnutrition might result in better outcomes in patients who need acute admission. The survival advantage of those with chronic lung diseases warrants further investigation.

Analytical performance of the BD veritor™ system for rapid detection of influenza virus A and B in a primary healthcare setting.

BACKGROUND: Infections with influenza A virus cannot be clinically differentiated from infections caused by influenza B virus or other respiratory viruses. Additionally, although antiviral treatment is available for influenza A virus, it is not effective for the other viruses and must be initiated early in the course of disease for it to be effective. For these reasons, there is a need for a rapid, accurate diagnostic test for use in physicians' offices at the time patients are seen. We report the first field performance of BD Veritor™ System for Rapid Detection of Flu A + B test compared to real time PCR. The performance of this test was compared to real time PCR performed in the Istanbul University Influenza Reference Laboratory. METHOD: A single-blinded cross sectional study was conducted in nine different family medicine centers in Istanbul, Turkey between 01 November 2014 and 01 May 2015. For every patient, two specimens were collected, one for real time PCR and one for the Veritor test. Specimens for the Veritor test were immediately tested at the participating clinic according to the manufacturer's instructions. The specimens for real time PCR were transferred to the reference laboratory. RESULTS: A total of 238 persons were included in the study: 72 (30 %) of the patients included in the study were below 19 years old and accepted as childhood group. Mean age of adults was 42.4 and children 10.2 years. A total of 122 patients out of 238 were positive for influenza. The clinical sensitivity and specificity of the Veritor test in all age groups was determined to be 80 and 94 %, respectively. Positive predictive value was 93 % and the negative one was 81 %. CONCLUSION: Field performance of the rapid influenza test was high and found to be useful with respect to rational antiviral use, avoiding unnecessary antibiotic usage and the management of cases by the family physicians.

Influenza epidemiology and influenza vaccine effectiveness during the 2014-2015 season: annual report from the Global Influenza Hospital Surveillance Network.

The Global Influenza Hospital Surveillance Network (GIHSN) has established a prospective, active surveillance, hospital-based epidemiological study to collect epidemiological and virological data for the Northern and Southern Hemispheres over several consecutive seasons. It focuses exclusively on severe cases of influenza requiring hospitalization. A standard protocol is shared between sites allowing comparison and pooling of results. During the 2014-2015 influenza season, the GIHSN included seven coordinating sites from six countries (St. Petersburg and Moscow, Russian Federation; Prague, Czech Republic; Istanbul, Turkey; Beijing, China; Valencia, Spain; and Rio de Janeiro, Brazil). Here, we present the detailed epidemiological and influenza vaccine effectiveness findings for the Northern Hemisphere 2014-2015 influenza season.

Influenza in the pediatric population in Istanbul: a one center experience 2009-2014.

INTRODUCTION: The aim of the study was to evaluate the clinical characteristics of pediatric patients with influenza infection. MATERIAL AND METHODS: The patients hospitalized with confirmed influenza between October 2009 and May 2014 were enrolled in this study. RESULTS: The mean age of the patients was 66 ± 53 months (1-204 months). Fifty-four percent of patients had a chronic underlying disease. Twenty-four patients needed mechanical ventilation support and a two-month-old patient with liver disease died. Except for the 2009-2010 season, all patients who received mechanical ventilation had underlying disease. The hospital admission months were December-February in 2010-2011 and January-March in 2011-2012 as well as in 2012-2013. Convulsion was observed frequently in influenza A cases, and influenza B tended to be detected in older patients (p = 0.024). The most common symptoms in pediatric patients were fever and cough. CONCLUSION: It is obvious that to protect against circulating influenza viruses, the risk-based strategy of annual influenza immunization should target school-aged children and children with underlying conditions, especially neurological and pulmonary diseases.

[Evaluation of sentinel influenza surveillance of the last two seasons: 2013-2014 and 2014-2015]. / Sentinel influenza sürveyansinda son iki sezonun degerlendirilmesi: 2013-2014 ve 2014-2015.

Flu caused by influenza viruses, is a serious public health problem all over the world with its high morbidity and mortality. Therefore World Health Organization (WHO) regularly collects the results of national influenza surveillance, evaluates the results and shares them on international portal. Thus, it provides the possibility of rapid prevention and preparation of countries that needs to be taken on the fight against the epidemic flu. Starting from 2004-2005 season until today the current flu activity in our country is also followed in accordance with sentinel surveillance. The aim of this study was to evaluate the results of sentinel surveillance data obtained by National Influenza Reference Laboratory in Istanbul University Faculty of Medicine, in 2013-2014 and 2014-2015 seasons. For this purpose, nasal/nasopharyngeal swab samples taken from the patients diagnosed as influenza-like illness by the volunteer family physicians in Izmir, Istanbul, Antalya, Edirne and Bursa were included in the study. A total of 1240 samples were delivered to our laboratory in three days, in Virocult® transport culture medium according to cold chain rules. All the samples were studied by real-time polymerase chain reaction (Rt-PCR) according to the protocols of Centers for Disease Control and Prevention (CDC). In our study, the positivity rates of influenza viruses in 2013-2014 and 2014-2015 seasons were detected as 31.4% (202/641) and 44.4% (289/650), respectively. In 2013-2014 season, influenza A(H3N2) virus was the predominant type with a rate of 93.1% (188/202), and the rest was influenza B virus (14/202; 6.9%). In 2014-2015 season, influenza B virus has been dominated with a rate of 60.2% (174/289), and the rates of influenza A(H1N1)pdm09 and influenza A(H3N2) were 30.4% (88/289) and 9.3% (27/289), respectively. The flu season in 2013-2014 has started at 48th week and peaked at 52nd week, while it was started later in the second week in 2014-2015 season and peaked at 10th-13th week. The lineage of the influenza B viruses isolated in both seasons were identified as B/Yamagata. Antigenic characterization of influenza A viruses isolated in our laboratory was found compatible with the vaccine strains. In conclusion, surveillance studies are highly important for the determination of the effects of flu on public health and identification of the approaches for fighting with flu. In this sense, influenza surveillance of the countries are required to implement more effectively in an expanded field of scale.

Tenofovir disoproxil fumarate has a substantial efficacy against multidrug-resistant strains of hepatitis B virus.

BACKGROUND & AIMS: To evaluate the efficacy of tenofovir in chronic hepatitis B (CHB) patients with adefovir resistance (ADF-R) and suboptimal response to adefovir (ADF-S). METHODS: Nucleos(t)ide analogue (NA)-naïve patients and patients with previous adefovir failure receiving tenofovir therapy for at least 6 months were included in the study. Biochemical and virological tests were obtained at baseline and 3-month intervals in the first year and every 6 months thereafter. The primary outcome measure was complete virological response (CVR) (HBVDNA < 20 IU/ml). CVR rates were calculated by Kaplan-Meier analysis, and a multivariate Cox proportional hazard model was generated to find out factors independently associated with CVR. RESULTS: A total of 165 patients (118 men, mean age 42 ± 12, 64 HBeAg(+) ) were included in the study. There were 105 patients in NA-naïve, 32 patients in ADF-S and 28 patients in ADF-R groups. All patients in the ADF-R group had multidrug resistance patterns. Mean duration of tenofovir treatment was 29 ± 14 months. CVR rates in NA-naïve, ADF-S and ADF-R groups were 65% vs. 75% vs. 58% at 12th month, 77% vs. 87% vs. 79% at 24th month and 83% vs. 94% vs. 79% at 36th month respectively. According to multivariate Cox regression model, HBeAg positivity (HR = 0.56, 95%CI 0.36-0.86, P = 0.008), high baseline HBVDNA level (HR = 0.64, 95%CI 0.55-0.74, P < 0.001) and ADF-R (HR = 0.47, 95%CI 0.28-0.81, P = 0.006) were independent predictors for CVR. Seven patients encountered mild renal dysfunction and were managed by dose adjustments. CONCLUSION: CVR rates during the follow-up show that tenofovir has a decreased, yet still potent in vivo efficacy against multidrug-resistant strains of HBV.

Anti-interferon alpha antibodies and autoantibodies in patients with Behçet's disease uveitis treated with recombinant human interferon alpha-2a.

BACKGROUND: Recombinant human (rh) interferon alpha2a (IFN-α2a) therapy is successfully used for the treatment of Behçet's disease (BD) uveitis refractory to conventional immunosuppressive treatment. PURPOSE: Our aim in this study was to investigate the frequency and clinical significance of anti-IFN-α antibodies and autoantibodies during recombinant human rhIFN-α2a therapy in patients with BD uveitis. METHODS: This comparative, cross-sectional, serological screening study included 30 BD patients treated with rhIFN-α2a (Group 1), 29 BD patients treated with conventional immunosuppressive agents (Group 2), 29 BD patients who received only colchicine (Group 3), and 30 healthy subjects (Group 4). Anti-IFN-α-binding antibodies and autoantibodies, including anti-nuclear antibody, anti-thyroid peroxidase antibody, and anti-cardiolipin antibody, were measured in serum samples. Antibody seropositivity was compared between study groups. Retrospective clinical data were compared between antibody-positive and antibody-negative patients. RESULTS: A significantly higher proportion of patients in Group 1 had anti-interferon-α (26.6 %) and autoantibody (30 %) seropositivity compared to the other groups. No correlation was found between seropositivity for anti-interferon-α and other autoantibodies. No significant difference was found in cumulative dose of IFN-α, duration of IFN-α therapy, time to first uveitis attack, or attack rate between anti-interferon-α antibody-positive and antibody-negative patients in Group 1. Uveitis attacks were observed in 22 % of autoantibody-positive and 71 % of autoantibody-negative patients in Group 1 (p = 0.018). CONCLUSIONS: Patients with BD uveitis develop anti-IFN-α-binding antibodies and autoantibodies during treatment with rhIFN-α2a. While the clinical relevance of anti-IFN-α-binding antibodies remains unclear in this study, induction of autoimmunity was found to be associated with a tendency for better therapeutic response.

Viral etiology of influenza-like illnesses during the influenza season between December 2011 and April 2012.

The aim of this study was to determine the frequency of respiratory viruses responsible for respiratory tract infections in Turkish children during the 2011-2012 influenza season. Nasal swabs were obtained from patients with symptoms suggestive of an influenza-like illness between December 2011 and April 2012. Samples were analyzed with multiplex real-time polymerase chain reaction (RT-PCR) to help identify the causative viral pathogen. A total of 200 patients were enrolled in the study. A respiratory virus was detected successfully in 102 (51%) children; influenza A (H3N2) in 39.2%, influenza B in 23.5%, RSV in 15.6%, rhinovirus in 13.7%, bocavirus in 2.9%, coronavirus in 2.9%, and metapneumovirus in 0.9% of patients. Only one patient was co-infected with bocavirus and influenza A virus. A statistically significant difference in the mean age of presentation was observed between the various viral pathogens (P < 0.001). Patients with RSV were significantly younger whereas children infected with the influenza viruses were significantly older. Comparison of symptoms revealed that fever and headache occurred more frequently with the influenza viruses than the other viruses combined (P < 0.001, <0.05). Durations of symptoms such as fever, cough, nasal congestion, and rhinorrhea were also significantly longer in the influenza group (P < 0.001, <0.005, <0.001, <0.005, respectively). Demographic analyses revealed that the school/daycare attendance was the only parameter associated with a significantly increased risk for influenza infection. With an overall viral pathogen detection rate of 51%, findings of the present study suggest other respiratory pathogens, whether viral or bacterial, may also lead to hospital visits due to influenza-like illnesses in children.

Predictors of fatality in pandemic influenza A (H1N1) virus infection among adults.

BACKGROUND: The fatality attributed to pandemic influenza A H1N1 was not clear in the literature. We described the predictors for fatality related to pandemic influenza A H1N1 infection among hospitalized adult patients. METHODS: This is a multicenter study performed during the pandemic influenza A H1N1 [A(H1N1)pdm09] outbreak which occurred in 2009 and 2010. Analysis was performed among laboratory confirmed patients. Multivariate analysis was performed for the predictors of fatality. RESULTS: In the second wave of the pandemic, 848 adult patients were hospitalized because of suspected influenza, 45 out of 848 (5.3%) died, with 75% of fatalities occurring within the first 2 weeks of hospitalization. Among the 241 laboratory confirmed A(H1N1)pdm09 patients, the case fatality rate was 9%. In a multivariate logistic regression model that was performed for the fatalities within 14 days after admission, early use of neuraminidase inhibitors was found to be protective (Odds ratio: 0.17, confidence interval: 0.03-0.77, p=0.022), nosocomial infections (OR: 5.7, CI: 1.84-18, p=0.013), presence of malignant disease (OR: 3.8, CI: 0.66-22.01, p=0.133) significantly increased the likelihood of fatality. CONCLUSIONS: Early detection of the infection, allowing opportunity for the early use of neuraminidase inhibitors, was found to be important for prevention of fatality. Nosocomial bacterial infections and underlying malignant diseases increased the rate of fatality.

BAb and MxA as functional biomarkers in routine clinical laboratories for the determination of anti-IFN-beta antibodies and their bioactivity levels in multiple sclerosis patients.

In MS patients under IFNß treatment to seek alternative treatments timely is important that anti-IFNß antibodies and/or in vivo biologic activity loss detection in these. The most common diagnostic markers used for this purpose are BAb, Nab, and MxA. In this article, we aimed to establish the availability and feasibility of the correlation between BAb and MxA gene expression (mRNA) levels using evaluation of responses to IFNß treatment for MS patients with a routine laboratory follow-up strategy in a major Turkish MS center. Bab seropositivity was determined in blood samples of 218 MS patients treated with different IFNß preparations and MxA mRNA levels were measured in 128 patients among the total population. BAb seropositivity ratios to im INF-ß 1a, scINF-ß 1a, and sc INF-ß 1b were 21.4%, 28.6%, and 70.4%, respectively (total 40%), and total loss of bioactivity (MxA mRNA) were 9.3%, 9.5%, and 11.6%, respectively (total 10.2%). The correlation between high BAb titers and low MxA mRNA levels was highly significant (P = 0.00003). Our data indicate that there is a good correlation between especially high BAbs levels and diminished MxA mRNA levels.

4CMenB Vaccination to Prevent Meningococcal B Disease in Vietnam: Expert Review and Opinion.

An advisory board meeting was held with experts in Vietnam (Hanoi, August 2022), to review the evidence on invasive meningococcal disease (IMD) epidemiology, clinical management, and meningococcal vaccines to reach a consensus on recommendations for meningococcal vaccination in Vietnam. IMD is a severe disease, with the highest burden in infants and children. IMD presents as meningitis and/or meningococcemia and can progress extremely rapidly. Almost 90% of deaths in children occur within the first 24 h, and disabling sequelae (e.g., limb amputations and neurological damage) occur in up to 20% of survivors. IMD patients are often hospitalized late, due to mild and nonspecific early symptoms and misdiagnosis. Difficulties related to diagnosis and antibiotic misuse mean that the number of reported IMD cases in Vietnam is likely to be underestimated. Serogroup B IMD is predominant in many regions of the world, including Vietnam, where 82% of IMD cases were due to serogroup B (surveillance data from 2012 to 2021). Four component meningococcal B vaccine (4CMenB) is used in many countries (and is part of the pediatric National Immunization Program in 13 countries), with infant vaccination starting from two months of age, and a 2 + 1 dosing schedule. Experts recommend 4CMenB vaccination as soon as possible in Vietnam, starting from two months of age, with a 2 + 1 dosing schedule, and at least completing one dose before 6 months of age.

Efficacy of tenofovir in patients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-naive patients with chronic hepatitis B.

We evaluated the efficacy of tenofovir disoproxil fumarate (TDF) in patients with lamivudine failure (LAM-F) in comparison with that in nucleoside/nucleotide analogue (NA)-naïve patients with chronic hepatitis B (CHB). The criteria for inclusion were being NA naïve or having previous LAM-F and receiving TDF therapy for at least 6 months. Biochemical and virological tests were performed at the baseline, at 3-month intervals in the first year, and every 6 months thereafter. The primary outcome measure for efficacy was a complete virological response (CVR), defined as an HBV DNA level of <20 IU/ml. CVR rates were calculated by Kaplan-Meier analysis, and a multivariate Cox proportional-hazard model was generated in order to find predictive factors independently associated with the time to a CVR. We included 197 patients in the study (136 males; mean age, 43 ± 12 years; 105 patients were NA naïve). Sixty-five patients had hepatitis B e antigen (HBeAg)-positive CHB. The median duration of TDF treatment was 29 (range, 6 to 52) months. Seventy-one patients (77%) in the LAM-F group were treated with TDF add-on therapy. The CVR rates of the NA-naïve and LAM-F groups were comparable in HBeAg-negative (94% versus 96% at month 36, P = 0.10) and HBeAg-positive patients (67% versus 83% at month 36, P = 0.48). According to the multivariate Cox regression model, only HBeAg positivity (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.26 to 0.59; P < 0.001) and a high baseline HBV DNA level (HR, 0.44; 95% CI, 0.29 to 0.67; P < 0.001) had a significant influence on the time to a CVR. The similar cumulative CVR rates during the follow-up show that TDF has comparable efficacy in lamivudine-experienced and NA-naïve patients, and the presence of resistance mutations did not alter the response rates.

Role of the line probe assay INNO-LiPA HBV DR and ultradeep pyrosequencing in detecting resistance mutations to nucleoside/nucleotide analogues in viral samples isolated from chronic hepatitis B patients.

Despite the effectiveness of nucleoside/nucleotide analogues in the treatment of chronic hepatitis B (CHB), their long-term administration is associated with the emergence of resistant hepatitis B virus (HBV) mutants. In this study, mutations resulting in antiviral resistance in HBV DNA samples isolated from 23 CHB patients (nine treatment naïve and 14 treated previously) were studied using a line probe assay (INNO-LiPA HBV DR; Innogenetics) and ultradeep pyrosequencing (UDPS) methods. Whilst the INNO-LiPA HBV DR showed no resistance mutations in HBV DNA samples from treatment-naive patients, mutations mediating lamivudine resistance were detected in three samples by UDPS. Among patients who were treated previously, 19 mutations were detected in eight samples using the INNO-LiPA HBV DR and 29 mutations were detected in 12 samples using UDPS. All mutations detected by the INNO-LiPA HBV DR were also detected by UDPS. There were no mutations that could be detected by INNO-LiPA HBV DR but not by UDPS. A total of ten mutations were detected by UDPS but not by INNO-LiPA HBV DR, and the mean frequency of these mutations was 14.7 %. It was concluded that, although INNO-LiPA HBV DR is a sensitive and practical method commonly used for the detection of resistance mutations in HBV infection, UDPS may significantly increase the detection rate of genotypic resistance in HBV at an early stage.

Molecular and serological investigations of the Influenza A(H1N1) 2009 pandemic virus in Turkey.

Intense research has been conducted on influenza A(H1N1)pdm09 virus to determine the virulence markers. Limited information on characteristics of pandemic virus has become available in Turkey since the pandemic. In this first report from Turkey, we investigated the molecular markers that have been associated with increased virulence and oseltamivir resistance. We also conducted serological studies in people after infection, vaccination, exposure, and no-exposure controls to determine the level of protection against the pandemic H1N1 influenza virus. Thirteen rRT-PCR positive samples were analyzed for presence of mutations that have been associated with host range, virulence, and antiviral resistance: substitution D222G in the HA, E627K in the PB2, and H275Y in the neuraminidase (NA). In addition, 135 serum samples from vaccinated, recovered, asymptomatic contacts, and control individuals were tested using hemagglutination inhibition (HI) assay. D222G was detected in nasal samples from two severe cases. No specified mutations in the PB2 and NA were identified. Additional substitutions, I216V, V321I, E374K, S203T in HA, V655I in PB2, and I163V in NA, were detected. HI testing from vaccinated individuals, recovered patients, asymptomatic contacts, and control individuals showed that 97.9, 99.7, 88.2, and 44.2 % had HI titers ≥40, respectively. Molecular markers promoting influenza A(H1N1)pdm09 to become a pandemic virus are still under investigation. Serological results confirm that younger, un-exposed individuals are at increased risk of pandemic virus infections. Influenza A(H1N1)pdm09 viruses are still in circulation around the globe. Therefore, these viruses need to be monitored closely for development of new markers including antiviral resistance mutations.

A role for immune modulation in achieving functional cure for chronic hepatitis B among current changes in the landscape of new treatments.

INTRODUCTION: Chronic hepatitis B (CHB) is rarely cured using available treatments. Barriers to cure are: 1) persistence of reservoirs of hepatitis B virus (HBV) replication and antigen production (HBV DNA); 2) high burden of viral antigens that promote T cell exhaustion with T cell dysfunction; 3) CHB-induced impairment of immune responses. AREAS COVERED: We discuss options for new therapies that could address one or more of the barriers to functional cure, with particular emphasis on the potential role of immunotherapy. EXPERT OPINION/COMMENTARY: Ideally, a sterilizing cure for CHB would translate into finite therapies that result in loss of HBV surface antigen and eradication of HBV DNA. Restoration of a functional adaptive immune response, a key facet of successful CHB treatment, remains elusive. Numerous strategies targeting the high viral DNA and antigen burden and aiming to restore the host immune responses will enter clinical development in coming years. Most patients are likely to require combinations of several drugs, personalized according to virologic and disease characteristics, patient preference, accessibility, and affordability. The management of CHB is a global health priority. Expedited drug development requires collaborations between regulatory agencies, scientists, clinicians, and within the industry to facilitate testing of the best drug combinations.

Chronic hepatitis B virus infection (CHB) is a major cause of liver cirrhosis and liver cancer worldwide. Persons with CHB have a dysfunctional immune response that is not capable of clearing the virus from the liver. Two types of treatment are currently available for individuals with CHB. These treatments can have some impact on reducing the risk of cirrhosis and cancer, but they rarely eliminate the virus, and relapse can occur. There are numerous new treatments, such as new antivirals and immunotherapies, being explored for their ability to restore an effective immune response, although to date, there has been little success in this area. Because of the many ways the hepatitis B virus uses to evade the immune system, it is unlikely that one drug or immunotherapy will be able to reliably silence the infection in significant proportions of patients with CHB. Combination regimens involving direct-acting drugs targeting different stages of the virus life cycle, along with stimulation of antiviral immune response are likely to be needed.

Meningococcal disease within the Gulf Cooperation Council Countries.

This review reports on the recent epidemiology of invasive meningococcal disease (IMD) within the Gulf Cooperation Council (GCC) Countries (focusing from 2012 onwards), the existing immunization strategies and the potential for IMD resurgence. MenACWY vaccination is now established in infant or adolescent immunization programs in Saudi Arabia, Bahrain, Kuwait, and the United Arab Emirates. At present, GCC Countries do not include MenB immunization. National health surveillance reports indicate a total of 156 IMD cases reported across the GCC Countries between 2012 and 2021; between 30% and 80% of cases were reported in individuals aged ≥15 years. Lack of serogroup data hinders the assessment of vaccine impact and decision-making on additional vaccine introductions (e.g. MenB immunization). Hajj/Umrah pilgrimage and the increasing number of large-scale commercial and social events held in the GCC Countries pose a potential risk for future IMD outbreaks. Immunization policies for such events could be strengthened.