Gilles Wandeler, Patrick A Coffie, Mark H Kuniholm, Ponsiano Ocama, Matthias Egger

We read with interest the Correspondence from Noemi García-Tardón and colleagues (Sept 23, 2017, p 1485) 1 describing the prevalence of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections among blood donors in Sierra Leone. Considering there are few data on viral hepatitis from the region, the authors should be congratulated for their efforts. However, we fear that some of their results and messages might be misleading.

Sanaka S, Kasarala G, Tillmann H.

AbstractCure of hepatitis C virus has become feasible in almost all patients. However, vigilance is needed in 3 scenarios: previous exposure to hepatitis B virus (HBV), history of organ transplantation, and history of cured hepatocellular carcinoma (HCC). The current data suggest that HBV reactivation occurs in about 10% of hepatitis B surface antigen (HBsAg)–positive patients and approximately 1% of hepatitis B core antibody–positive but HBsAg-negative patients. The risk of organ rejection is also around 1%, but can be fatal if not acted on immediately. Finally, the risk of early HCC recurrence may be increased but should not delay initiation of antiviral therapy in the setting of cured HCC; however, increased surveillance may be warranted.

The morbidity and mortality that are associated with hepatitis B virus (HBV) infection have been overshadowed by the public health prominence of other infectious diseases, including human immunodeficiency virus (HIV) infection, tuberculosis, and malaria. There is a dawning realization that the……

This Medical Letter review compares a newly approved 2-dose hepatitis B virus vaccine that uses a synthetic oligonucleotide immunostimulatory adjuvant, and is licensed for use in adults, with other commercially available 3-dose vaccines.

Journal of Medical Virology, EarlyView.

A. Mazzola, M. Tran Minh, S. Jauréguiberry, D. Bernard, P. Lebray, Y. Chrétien, C. Goumard, Y. Calmus, F. Conti

Infections are common in individuals with cirrhosis, especially in patients awaiting liver transplantation (LT) [1]. The occurrence of bacterial infection is associated with the severity of the liver disease [2]. Bacterial infection increases the probability of death among patients with decompensated cirrhosis by 3.75-fold, the rate reaching 30% at 1 month and 63% at 1 year after infection [1]. Hepatitis A virus (HAV) infection may cause fulminant hepatitis, especially in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) cirrhosis [3].

Wilson P, Parr J, Jhaveri R, et al.

AbstractHepatitis B virus (HBV) is a significant public health issue that has not been adequately addressed, especially in the high-prevalence region of Africa. Despite the incorporation of HBV vaccines into the Expanded Program on Immunization (EPI), children continue to be infected with HBV through maternal-to-child transmission (MTCT). The addition of a birth dose of HBV vaccine would be a cost-effective method to reduce MTCT. Birth-dose HBV vaccine policies have been adopted in the Western Pacific region but have yet to be implemented in the African region. Even better protection against HBV MTCT can be achieved by the treatment of pregnant women with high HBV viral loads with tenofovir. Tenofovir is already widely used in prevention of HIV maternal-to-child transmission (PMTCT) programs. We suggest that existing HIV PMTCT programs could be expanded to deliver care for HBV-infected pregnant women. With appropriate adoption of birth dose vaccination policies and expansion of PMTCT programs, elimination of HBV MTCT in Africa is achievable.

Li Liu, Di Xiao, Jin-Hong Yu, Rui Shen, Meng Wang, Qiang Li

In China, the epidemic pattern of acute hepatitis E virus (HEV) infection has changed from waterborne outbreaks to foodborne sporadic cases. However, the clinical course of sporadic acute hepatitis E has not been well defined.

Wu J, Song S, Lee C, et al.

AbstractBackgroundThis study aimed to elucidate predictors of liver fibrosis in chronic hepatitis B virus (HBV)-infected subjects.MethodsTransient elastography was performed to define liver fibrosis in 533 chronic HBV-infected patients at 30.72 ± 0.57 years of age. Protein array was performed on serum samples and lysates of Huh7 cells transfected with HBV mutants; the results were confirmed by ELISA. Single nucleotide polymorphisms in the interleukin-1β gene were examined chronic HBV-infected patients with and without liver fibrosis.ResultsMale gender, > 18 years old, and serum alpha-fetoprotein level > 3.6 ng/mL were independent predictors of a liver stiffness measurement of ≥ 7 kPa (P = 0.005, 0.019, and < 0.001, respectively). HBeAg-negative hepatitis is associated with increased liver stiffness (P…

Malhotra I, LaBeaud A, Morris N, et al.

AbstractBackgroundAntenatal exposure to parasites can affect infants’ subsequent responses to vaccination. The present study investigated how maternal prenatal infections and newborns’ anti-parasite cytokine profiles relate to IgG responses to standard vaccination during infancy.Methods450 Kenyan women were tested for parasitic infections during pregnancy. Their newborns’ responses to malaria, schistosome, and filaria antigens were assessed in cord blood (CB) lymphocytes. Following standard neonatal vaccination, this infant cohort was followed biannually to age 30 months for circulating IgG levels against Haemophilus influenzae b (Hib), diphtheria toxoid (DT), hepatitis B, and tetanus.ResultsTrajectories of post-vaccination IgG levels were classified by functional principal component (PC) analysis to assess each child’s response profile. Two main components, PC1, reflecting height of response over time, and PC2, reflecting crossover from high to low or low to high, were identified. CB cytokine responses to schistosome and filarial antigens showed a significant association between augmented anti-helminth IL-10 and reduced antibody levels, particularly to DT and hepatitis B, and a more rapid post-vaccination decline in circulating IgG against Hib.ConclusionAntenatal sensitization to schistosomiasis or filariasis, and related production of anti-parasite IL-10 at birth, are associated with reduced anti-vaccine IgG levels in infancy, with possibly impaired protection.

Liu H, Li F, Zhang X, et al.

AbstractBackgroundThe natural history of chronic HBV infection was divided into four phases. Patients in the inactive carrier status (IC) and immune tolerant (IT) phase had normal ALT levels but huge different viral loads. The mechanism underlying low viral replication status in IC phase is unknown.MethodsWe determined the intrahepatic transcriptomes of 83 chronic hepatitis B patients by microarray analysis of liver biopsies, and screened the effect of differentially regulated genes on HBV replication using specific siRNAs in vitro.ResultsThe gene profile distinguishing active chronic hepatitis from IT and IC was predominantly composed of immune-related genes. The liver transcriptomes between the IT and IC phase were largely similar, and 109 expressed genes were significantly different. By performing systematic screening, 5 candidate genes including EVA1A, which were expressed at relative higher level in IC phase than IT, were identified to regulate HBV replication and gene expression in cellular models.ConclusionsThe immune-related pathways were up-regulated in the active chronic hepatitis phase but not in the IT and IC phase. A number of intrahepatic genes highly expressed in the IC phase may participate in the control of HBV replication and determine the inactive status of HBV infection.

Su T, Yang H, Tseng T, et al.

AbstractBackgroundWe investigated the patterns; predictors for virological relapse (VR), clinical relapse (CR), sustained clinical response (SCR); and retreatment outcomes after nucleos(t)ide analogue (NUC) therapy discontinuation.MethodsChronic hepatitis B patients discontinuing NUC were prospectively enrolled. Viral and host predictors, including HBsAg, anti-HBc, the single nucleotide polymorphisms of NTCP (rs2296651), CTLA4 (rs231775), rs3077 (HLA-DPA1), and rs9277535 (HLA-DPB1), and post-therapy predictors were investigated. Patients’ retreatments and outcomes were recorded.ResultsOverall, 100 patients discontinuing 3-year entecavir (ETV) or tenofovir (TDF) therapy were enrolled. Patients discontinuing TDF exhibited significantly higher 3-month VR (52.9% vs. 6.1%, P…

Peiffer K, Kuhnhenn L, Jiang B, et al.

AbstractBackgroundThe hepatitis B virus (HBV) surface proteins (HBsAg) coat the viral particle and form subviral particles (SVPs). Loss of HBsAg represents a functional cure and is an important treatment goal.MethodsWe analyzed the impact of the HBV genotypes A-E and pre-S mutations on SVP expression in HBeAg negative chronic HBV infected patients. A HBV genome harboring a preS1-deletion was analyzed in hepatoma cells.ResultsWe observed a genotype-specific ratio of the three surface proteins (SHBs/MHBs/LHBs), which reflects differences in the morphology and composition of SVPs. Deletions/mutations in the preS1/preS2 domain, detected in released viral genomes, did not affect the molecular weight of MHBs and LHBs in these patients. In contrast, LHBs molecular weight was altered in vitro using a HBV genome harboring a preS1-deletion derived from one of these patients.ConclusionDifferences in composition of SVPs may result in a genotype-specific immunogenicity and pathogenesis. In the analyzed patients with preS-mutations secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from cccDNA, HBsAg is presumably derived from the integrated DNA. This important HBsAg source has to be considered for novel antiviral strategies in HBeAg negative chronic HBV infected patients.

Qi Zhu, Xiaoping Shao, Shaoli Chen, Dingliang Li, Xiaohong Chen, Wenjin Liu, Xianghua Wu, Zengyong Jian, Rutherford Shannon, Huizhen Zheng

Lucio Boglione, Giuseppe Cariti, Valeria Ghisetti, Elisa Burdino, Giovanni Di Perri

An alternative approach in the treatment of chronic hepatitis B (CHB) with pegylated (PEG)‐interferon (IFN) is the prolonged course to 96 weeks of therapy, with higher sustained response (SR) than patients treated for 48 weeks. This result was confirmed in patients with CHB and D genotype, while no data are currently available about the prolonged course of PEG‐IFN in E genotype. This retrospective analysis reported the role of different treatment duration of PEG‐IFN on the SR in patients affected by CHB and E genotype. 86 subjects with CHB and E genotype were considered in this analysis; different treatment durations were: 48 weeks (control group, 41 patients), 72 weeks (25 patients) and 96 weeks (19 patients). Treatment effectiveness was evaluated with sustained response (SR) and serological response. SR was significantly higher in patients who underwent PEG‐IFN for 96 weeks in comparison to 48 weeks: 14.6% vs 26.3% (p = 0.016). HBsAg loss rate was 5.3% in patients treated for 96 weeks and 2.4% in the control group. In the multivariate analysis only the 72 and 96 weeks of therapy (OR 2.335, 95% CI 1.550‐4.578; p = 0.020 and (OR 3.890, 95% CI 1.991‐10.961; p = 0003) were predictive of SR. The extended duration of PEG‐IFN course in patients with CHB and genotype E is a promising approach to increase the SR and HBsAg clearance. This article is protected by copyright. All rights reserved …

Journal of Medical Virology, EarlyView.

Piero Colombatto, Cristiana Barbera, Flavia Bortolotti, Anna M Maina, Francesco Moriconi, Daniela Cavallone, Pierluigi Calvo, Filippo Oliveri, Ferruccio Bonino, Maurizia R Brunetto

Background. Selection of HBeAg defective HBV mutants (mt) during childhood might influence infection outcome in adults. Aim of this study was to correlate the dynamics of Pre‐Core HBV mutant (Pre‐C mt) selection with virological/clinical outcomes in children followed‐up until adulthood. Methods. Eighty subjects (50‐M/30‐F), 70 HBeAg‐positive (87.5%) and 10 (12.5%) HBeAg‐negative/anti‐HBe‐positive at the admission, mostly genotype D infected (91.2%), with median age of 6.5 (range: 0.2‐17) years, were followed‐up for 14.3 years (range: 1.1‐24.5); 46 (57.5%) received IFN treatment. HBV‐DNA and q‐HBsAg were tested by commercial assays, Pre‐Core 1896 mt by direct‐sequence, oligo‐hybridization‐assay and allele‐specific‐PCR (sensitivity: 30%, 10% and 0.1% of total viremia). Results. HBeAg/anti‐HBe seroconversion (SC) occurred in 55/70 (78.6%) children. After SC, 8 (14.6%) developed HBeAg‐negative chronic hepatitis (CHB), 41 (74.5%) remain with HBeAg‐negative chronic infection, and 6 (10.9%) lost HBsAg. Baseline HBV‐DNA and HBsAg were lower in SC than in no‐SC children (median: 7.35 vs 8.95 Log IU/mL, P = 0.005 and 4.72 vs 5.04 Log IU/ml, P = 0.015). The prevalence of Pre‐C mt increased rapidly (10% to 40%) around SC. Eventually, Pre‐C mt was detected in 100% of CHB, in 33% of chronic infections without disease, and in 16% of subjects who cleared HBsAg (P …

Kuehn BM.

Healthy infants should be vaccinated with the hepatitis B within 24 hours of birth and physicians should not delay vaccination until after discharge, according to new recommendations from the US Advisory Committee on Immunization Practices (ACIP) and the US Centers for Disease Control and Prevention (CDC). Previously, the recommendations allowed for newborn vaccination after discharge.

Chiaho Shih, Ching-Chun Yang, Gansukh Choijilsuren, Chih-Hsu Chang, An-Ting Liou

This infographic about hepatitis B virus explores its replication cycle, natural history of infection and pathogenesis, and how this can be controlled and treated.Hepatitis B virus (HBV) is a common worldwide blood-borne pathogen. Chronic hepatitis B can progress to an inactive carrier state, and then, in some patients, give rise to cirrhosis and cancer of the liver, leading to death. An HBV surface-antigen vaccine is effective, but treatments are currently not curative. HBV replicates via reverse transcription.

Mahale P, Aka P, Chen X, et al.

AbstractPeople who inject drugs (PWID) are commonly exposed to hepatitis B virus (HBV) and hepatitis D virus (HDV). We evaluated the prevalence of HDV viremia among hepatitis B surface antigen (HBsAg)-positive PWID (n=73) by using a new quantitative microarray antibody capture (Q-MAC) assay, HDV Western blot and HDV RNA. HDV Q-MAC performed well in this cohort: anti-HDV, 100% sensitivity and specificity; HDV viremia, 61.5% sensitivity and 100% specificity. Hepatitis D viremia was present in 35.6% of HBsAg-positive participants and was more common in those with resolved compared to chronic hepatitis C (5.1% vs. 0.6%; adjusted odds ratio, 9.80; p…

Ngongondo, McNeil; Miyahara, Sachiko; Hughes, Michael D.; Sun, Xin; Bisson, Gregory P.; Gupta, Amita; Kumwenda, Johnstone; Lavenberg, Jeffrey A.; Torres, Thiago Silva; Nyirenda, Mulinda; Kidonge, Katende Kenneth; Hosseinpour, Mina C.; for the AIDS Clinical Trials Group A5274 (REMEMBER) Study Team

AbstractBackground:Hepatotoxicity associated with isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) has not been well studied in severely immunosuppressed people with HIV. Our objective was to determine risk factors for hepatotoxicity in severely immunosuppressed individuals taking IPT and ART.Setting:Multi-center study in resource limited settings with high burden of tuberculosis.Methods:We conducted a secondary analysis of data from one randomized arm of the REMEMBER trial. The analysis includes participants with pre-ART CD4 cell counts of 5 x upper limit of normal or symptomatic hepatitis during IPT and ART.Logistic regression was used to identify baseline risk factors for hepatotoxicity. Time to occurrence of hepatotoxicity was estimated by the Kaplan Meier method.Results:Among 426 participants (53% male, median age 35 years, median CD4 count 19 cells/µL), 31 developed hepatotoxicity (7.3%). Raised pretreatment AST/ALT (OR 3.6, 95% CI 1.7-7.7) and hepatitis B surface antigen (HBsAg) sero-positivity at baseline (OR 4.7, 95% CI 1.7-12.9) were significantly associated with an increased risk of developing hepatotoxicity. Participants with both raised AST/ALT and positive HBsAg had a higher risk (OR 19.9, 95% CI 5.3-74.3) and earlier onset of hepatotoxicity than participants who did not have these conditions at baseline.Conclusions:The incidence of hepatotoxicity during IPT and ART was high. Severely immunosuppressed individuals with raised pretreatment AST/ALT or HBsAg sero-positivity need closer monitoring for hepatotoxicity. Background: Hepatotoxicity associated with isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) has not been well studied in severely immunosuppressed people with HIV. Our objective was to determine risk factors for hepatotoxicity in severely immunosuppressed individuals taking IPT and ART. Setting: Multi-center study in resource limited settings with high burden of tuberculosis. Methods: We conducted a secondary analysis of data from one randomized arm of the REMEMBER trial. The analysis includes participants with pre-ART CD4 cell counts of 5 x upper limit of normal or symptomatic hepatitis during IPT and ART. Logistic regression was used to identify baseline risk factors for hepatotoxicity. Time to occurrence of hepatotoxicity was estimated by the Kaplan Meier method. Results: Among 426 participants (53% male, median age 35 years, median CD4 count 19 cells/µL), 31 developed hepatotoxicity (7.3%). Raised pretreatment AST/ALT (OR 3.6, 95% CI 1.7-7.7) and hepatitis B surface antigen (HBsAg) sero-positivity at baseline (OR 4.7, 95% CI 1.7-12.9) were significantly associated with an increased risk of developing hepatotoxicity. Participants with both raised AST/ALT and positive HBsAg had a higher risk (OR 19.9, 95% CI 5.3-74.3) and earlier onset of hepatotoxicity than participants who did not have these conditions at baseline. Conclusions: The incidence of hepatotoxicity during IPT and ART was high. Severely immunosuppressed individuals with raised pretreatment AST/ALT or HBsAg sero-positivity need closer monitoring for hepatotoxicity. Correspondence to: McNeil Ngongondo, UNC Project, Tidziwe Centre, Lilongwe, Malawi, Phone: +265 999 782 183, Fax: +265 1 755 954, mngongondo@unclilongwe.org Conflict of Interest and Source of Funding: A5274 was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701 and also supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). The primary author was supported by the ACTG-SDAC Internship program at the Center for Biostatistics AIDS Research under award number UM1 AI068634. The authors have no conflict of interest to declare. Presented at the Conference of Retroviruses and Opportunistic Infections (CROI) 2017, Seattle, 14 February 2017. Contribultors: MN did the literature search. MN, SM, XS, JAL analyzed the data and generated the figures. MN, SM, MDH, XS, JAL, TST, interpreted the data. MN, SM, MDH, MCH drafted the manuscript. MN, SM, XS, TST, JAL, MN, KK, JK, AG, GBP, MDH, MCH revised the manuscript and contributed intellectually. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Ngongondo, McNeil; Miyahara, Sachiko; Hughes, Michael D.; Sun, Xin; Bisson, Gregory P.; Gupta, Amita; Kumwenda, Johnstone; Lavenberg, Jeffrey A.; Torres, Thiago Silva; Nyirenda, Mulinda; Kidonge, Katende Kenneth; Hosseinpour, Mina C.; for the AIDS Clinical Trials Group A5274 (REMEMBER) Study Team

AbstractBackground:Hepatotoxicity associated with isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) has not been well studied in severely immunosuppressed people with HIV. Our objective was to determine risk factors for hepatotoxicity in severely immunosuppressed individuals taking IPT and ART.Setting:Multi-center study in resource limited settings with high burden of tuberculosis.Methods:We conducted a secondary analysis of data from one randomized arm of the REMEMBER trial. The analysis includes participants with pre-ART CD4 cell counts of 5 x upper limit of normal or symptomatic hepatitis during IPT and ART.Logistic regression was used to identify baseline risk factors for hepatotoxicity. Time to occurrence of hepatotoxicity was estimated by the Kaplan Meier method.Results:Among 426 participants (53% male, median age 35 years, median CD4 count 19 cells/µL), 31 developed hepatotoxicity (7.3%). Raised pretreatment AST/ALT (OR 3.6, 95% CI 1.7-7.7) and hepatitis B surface antigen (HBsAg) sero-positivity at baseline (OR 4.7, 95% CI 1.7-12.9) were significantly associated with an increased risk of developing hepatotoxicity. Participants with both raised AST/ALT and positive HBsAg had a higher risk (OR 19.9, 95% CI 5.3-74.3) and earlier onset of hepatotoxicity than participants who did not have these conditions at baseline.Conclusions:The incidence of hepatotoxicity during IPT and ART was high. Severely immunosuppressed individuals with raised pretreatment AST/ALT or HBsAg sero-positivity need closer monitoring for hepatotoxicity. Background: Hepatotoxicity associated with isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) has not been well studied in severely immunosuppressed people with HIV. Our objective was to determine risk factors for hepatotoxicity in severely immunosuppressed individuals taking IPT and ART. Setting: Multi-center study in resource limited settings with high burden of tuberculosis. Methods: We conducted a secondary analysis of data from one randomized arm of the REMEMBER trial. The analysis includes participants with pre-ART CD4 cell counts of 5 x upper limit of normal or symptomatic hepatitis during IPT and ART. Logistic regression was used to identify baseline risk factors for hepatotoxicity. Time to occurrence of hepatotoxicity was estimated by the Kaplan Meier method. Results: Among 426 participants (53% male, median age 35 years, median CD4 count 19 cells/µL), 31 developed hepatotoxicity (7.3%). Raised pretreatment AST/ALT (OR 3.6, 95% CI 1.7-7.7) and hepatitis B surface antigen (HBsAg) sero-positivity at baseline (OR 4.7, 95% CI 1.7-12.9) were significantly associated with an increased risk of developing hepatotoxicity. Participants with both raised AST/ALT and positive HBsAg had a higher risk (OR 19.9, 95% CI 5.3-74.3) and earlier onset of hepatotoxicity than participants who did not have these conditions at baseline. Conclusions: The incidence of hepatotoxicity during IPT and ART was high. Severely immunosuppressed individuals with raised pretreatment AST/ALT or HBsAg sero-positivity need closer monitoring for hepatotoxicity. Correspondence to: McNeil Ngongondo, UNC Project, Tidziwe Centre, Lilongwe, Malawi, Phone: +265 999 782 183, Fax: +265 1 755 954, mngongondo@unclilongwe.org Conflict of Interest and Source of Funding: A5274 was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701 and also supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). The primary author was supported by the ACTG-SDAC Internship program at the Center for Biostatistics AIDS Research under award number UM1 AI068634. The authors have no conflict of interest to declare. Presented at the Conference of Retroviruses and Opportunistic Infections (CROI) 2017, Seattle, 14 February 2017. Contribultors: MN did the literature search. MN, SM, XS, JAL analyzed the data and generated the figures. MN, SM, MDH, XS, JAL, TST, interpreted the data. MN, SM, MDH, MCH drafted the manuscript. MN, SM, XS, TST, JAL, MN, KK, JK, AG, GBP, MDH, MCH revised the manuscript and contributed intellectually. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Zimmer C, Rinker F, Höner zu Siederdissen C, et al.

AbstractBackgroundTreatment with nucleos(t)ide analogues (NA) efficiently suppress HBV DNA but rarely leads to functional cure of chronic hepatitis B (CHB). Following NA cessation, a fraction of HBeAg-negative CHB-patients experience HBsAg loss. Cellular immune responses, including those by natural killer cells, innate lymphocytes known to respond in CHB, explaining the virological events transpiring following NA treatment cessation remain elusive.MethodsIn a single-center prospective trial, 15 HBeAg-negative CHB-patients on long-term NA treatment underwent structured NA cessation and were studied longitudinally. The NK cell compartment was assessed using high-dimensional flow cytometry and correlated with the clinical course.ResultsUnsupervised stochastic neighbor embedding analysis revealed NA treated CHB-patients to have a significantly affected NK cell compartment as compared to controls. Cessation of NA treatment resulted in only minor phenotypic alterations, but it significantly augmented NK cell natural cytotoxicity responses in the CHB-patients. This increased NK cell functionality correlated with ALT flares experienced by the patients and was particularly enhanced in patients experiencing HBsAg seroclearance at long-term follow-up.ConclusionsIncreased NK cell function associates with active hepatitis and HBsAg seroclearance following structured NA cessation. This adds to our knowledge of the immunological events that develop following cessation of NA treatment in CHB.

Yurdaydin C, Keskin O, Kalkan Ç, et al.

AbstractBackgroundInterferon is the only treatment option in chronic delta hepatitis (CDH). A CDH database (333 patients, 161 with interferon treatment history) was analyzed for effects of treatment duration on virologic response and clinical outcomes.MethodsNinety-nine CDH patients who received at least 6 months of interferon were selected. Maintained virologic response (MVR) was defined as hepatitis D virus RNA negative for 2 years after treatment discontinuation. Cumulative median interferon treatment duration was 24 months (range 6–126 months), with a median of 2 courses (range 1–8). Post-treatment median follow-up was 55 months (24–225 months).ResultsThirty-five patients achieved MVR. Cumulative probability of MVR increased with treatment duration and reached 50% at 5 years. Patients with MVR were less likely to die from liver disease or develop complications compared to patients without MVR (P = .032, P = .006, respectively). Cirrhosis at baseline and no response to therapy (odds ratio 16.1 and 5.23, respectively) predicted an adverse endpoint. Hepatitis B surface antigen clearance occurred in 37% of patients with MVR.ConclusionViral response to interferon increases with treatment duration and favorably affects the natural course of disease. Interferon treatment duration has to be individualized with careful post-treatment assessment.

C.-H. Chen, C.-H. Hung, J.-H. Wang, S.-N. Lu, T.-H. Hu, C.-M. Lee

To investigate the long-term incidence and predictors for hepatitis B surface antigen (HBsAg) loss after nucleoside analogue therapy.

Abstract Purpose In 2016, the number of refugees worldwide reached 65.6 million. So far, only limited data are available on the health status of refugees and asylum seekers (RAs). Especially, notifiable infectious diseases (NIDs) carry the risk of outbreaks in communal accommodations hosting RAs. Methods We conducted a monocentric retrolective cross-sectional study including 15,137 RAs treated in a special health care unit for RAs located in the major reception center in Munich from November 2014 to October 2016. Altogether 811 RAs with NIDs according to sections 6 and 7 of the German Infection Protection Act or with other infections relevant in the setting of a communal accommodation (RIDs) could be identified. Results The gender and age distribution was generally comparable to that of refugees in Germany. However, patients from East Africa and Nigeria were significantly overrepresented. NIDs/RIDs were dominated by cases of tuberculosis, hepatitis B, and vaccine-preventable and parasitic diseases. Significant risk factors included country of origin (COI) and age for hepatitis B, age for hepatitis C, gender and age for HIV, and COI, gender and age for tuberculosis and ectoparasitosis. Calculated prevalences of hepatitis B, hepatitis C, and HIV were mostly below those of the COI. Incidences of tuberculosis were mostly strongly elevated. Conclusions COI, gender, and age have an impact on the occurrence of NIDs/RIDs. Early vaccinations and improved hygiene could be effective in preventing NIDs/RIDs in communal accommodations. Screening, prompt therapy, and infection protection measures are necessary to prevent the transmission of diseases.

Ngo Tat Trung, Dang Chieu Duong, Hoang Van Tong, Tran Thi Thu Hien, Phan Quoc Hoan, Mai Hong Bang, Mai Thanh Binh, Thai Doan Ky, Nguyen Lam Tung, Nguyen Tien Thinh, Vu Viet Sang, Le Thi Phuong Thao, C-Thomas Bock, Thirumalaisamy P. Velavan, Christian G. Meyer, Le Huu Song, Nguyen Linh Toan

by Ngo Tat Trung, Dang Chieu Duong, Hoang Van Tong, Tran Thi Thu Hien, Phan Quoc Hoan, Mai Hong Bang, Mai Thanh Binh, Thai Doan Ky, Nguyen Lam Tung, Nguyen Tien Thinh, Vu Viet Sang, Le Thi Phuong Thao, C-Thomas Bock, Thirumalaisamy P. Velavan, Christian G. Meyer, Le Huu Song, Nguyen Linh Toan Background Circulating microRNAs (miRNA) are biomarkers for several neoplastic diseases, including hepatocellular carcinoma (HCC). We performed a literature search, followed by experimental screening and validation in order to establish a miRNA panel in combination with the assessment of alpha-fetoprotein (AFP) levels and to evaluate its performance in HCC diagnostics. Methods Expression of miRNAs was quantified by quantitative PCR (qPCR) in 406 serum samples from 118 Vietnamese patients with hepatitis B (HBV)-related HCC, 69 patients with HBV-related liver cirrhosis (LC), 100 chronic hepatitis B (CHB) patients and 119 healthy controls (HC). Results Three miRNAs (mir-21, mir-122, mir-192) were expressed differentially among the studied subgroups and positively correlated with AFP levels. The individual miRNAs mir-21, mir-122, mir192 or the triplex miRNA panel showed high diagnostic accuracy for HCC (HCC vs. CHB, AUC = 0.906; HCC vs. CHB+LC, AUC = 0.81; HCC vs. CHB+LC+HC, AUC = 0.854). When AFP levels were ≤20ng/ml, the triplex miRNA panel still was accurate in distinguishing HCC from the other conditions (CHB, AUC = 0.922; CHB+LC, AUC = 0.836; CHB+LC+HC, AUC = 0.862). When AFP levels were used in combination with the triplex miRNA panel, the diagnostic performance was significantly improved in discriminating HCC from the other groups (LC, AUC = 0.887; CHB, AUC = 0.948; CHB+LC, AUC = 0.887). Conclusions The three miRNAs mir-21, mir-122, mir-192, together with AFP, are biomarkers that may be applied to improve diagnostics of HCC in HBV patients, especially in HBV-related LC patients with normal AFP levels or HCC patients with small tumor sizes.

Mani, N., Cole, A. G., Phelps, J. R., Ardzinski, A., Cobarrubias, K. D., Cuconati, A., Dorsey, B. D., Evangelista, E., Fan, K., Guo, F., Guo, H., Guo, J.-T., Harasym, T. O., Kadhim, S., Kultgen, S. G., Lee, A. C. H., Li, A. H. L., Long, Q., Majeski, S. A., Mao, R., McClintock, K. D., Reid, S. P., Rijnbrand, R., Snead, N. M., Micolochick Steuer, H. M., Stever, K., Tang, S., Wang, X., Zhao, Q., Sofia, M. J.

AB-423 is a sulfamoylbenzamide (SBA) class of HBV capsid inhibitor in Phase 1 clinical trials. In cell culture models AB-423 showed potent inhibition of HBV replication (EC50/EC90 = 0.08-0.27 μM/0.33-1.32 μM) with no significant cytotoxicity (CC50 >10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC50 values. AB-423 inhibited HBV genotypes A through D and nucleos/tide-resistant variants in vitro. Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pgRNA and rcDNA indicating it is a class II capsid inhibitor. In a de novo infection model AB-423 prevented the conversion of encapsidated rcDNA to cccDNA presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer:dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents such as nucleos/tide analogs, RNAi agents, or interferon-α resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher liver accumulation. A 7-day BID administration of AB-423 in a hydrodynamic injection mouse model of HBV model resulted in a dose-dependent reduction in serum HBV DNA levels and combination with ETV or ARB-1467 resulted in a trend towards greater antiviral activity than either agent alone consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports further evaluation for safety, pharmacokinetics and antiviral activity in CHB patients.

Zhengju Xu, Jiankun Shen, Xingnan Pan, Meijuan Wei, Liguan Liu, Kaipeng Wei, Lifei Liu, Huanwen Yang, Jinfa Huang

As a noninvasive marker, serum alanine aminotransferase (ALT) has limitations, because a large proportion of patients chronically infected with hepatitis B virus (HBV) suffer from severe hepatic necroinflammation, but have normal or mildly elevated ALT. In the present study, we aimed to investigate the potential value of serum Golgi protein 73 (GP73) in predicting significant hepatic necroinflamation among chronic HBV infected patients. A cohort of 497 chronic HBV infected patients was retrospectively recruited. Liver biopsy was performed in all patients and serum GP73 levels were measured by enzyme‐linked immunosorbent assay. Serum GP73 increased in parallel with the increase in hepatic necroinflammatory activity grade (r = 0.682) and the stage of liver fibrosis (r = 0.539). The positive correlation of serum GP73 with the degree of hepatic necroinflammatory activity was statistically significant, while serum GP73 with the stage of liver fibrosis was weaker than that with hepatic necroinflammation. Furthermore, serum GP73 levels were significantly greater in patients with normal or mildly elevated ALT and significant hepatic necroinflammation (≥G2) than in patients with minimal to mild hepatic necroinflammation. The sensitivity and specificity of GP73 for the diagnosis of G2 hepatic necroinflammation was 42.35% and 95.0%, respectively, at a cut‐off value of 88.38 ng/mL. When the cut‐off value was set at 124.76 ng/mL, the sensitivity and specificity of GP73 for the diagnosis of G3 hepatic necroinflammation was 55.56% and 97.29%, respectively. These findings indicate that GP73 holds promise as an important candidate for diagnosing significant hepatic necroinflammation. This article is protected by copyright. All rights reserved …

Armel M. Sanou, Kenza Benkirane, Bachirou Tinto, Assana Cissé, Tani Sagna, Abdoul Kader Ilboudo, Claire Dording, Zekiba Tarnagda, Claude P. Muller, Judith M. Hübschen

Abstract Background Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Treponema pallidum (TP) infections are considered classic transfusion-transmissible infections (TTIs). Few data are available about the prevalence of TTIs in patients before blood transfusion in China. This study aimed to investigate the seroprevalence of four TTIs among patients before blood transfusion in Xiangya Hospital Central South University, China. Methods From 2011 to 2016, 442,121 hospitalized patients before possible blood transfusion were tested for hepatitis B surface antigen (HBsAg), anti-HCV, syphilis antibody (anti-TP) and anti-HIV. Results Of the 442,121 patients, the overall positivity of the four TTI serum markers was 15.35%. The positive rates of HBsAg, anti-HCV, anti-HIV and anti-TP were 10.98, 1.43, 0.16 and 2.78%, respectively. TTI serum markers showed a significant difference by gender, with positive rates of 17.98% for males and 12.79% for females. The prevalence of TTI serum markers varied significantly by age. The overall co-infection rate was 0.63%, and the top three multiple infections were HBV-TP, HBV-HCV, and HCV-TP. The co-infection rates of HBV-TP and HBV-HCV showed a significant decrease from 2011 to 2016, while the rates of other co-infections remained stable. Conclusions The prevalence of TTIs in patients before blood transfusion is much higher compared to that in blood donors in the region. The infection rates of HIV and TP increased, and the infection rate of HBsAg decreased in recent years.

Carla Anna, Marcella Kelly Costa de Almeida, Patrícia Ferreira, Roseane Gomes Oliveira, Anna Rafaella Ferreira Baraúna, Evonnildo Costa Gonçalvez, Andrea Marinho Silva, Carolina Pereira, Luisa Carício Martins

In the present study, we evaluated the prevalence of occult hepatitis B (OBI) in a population from the Brazilian Amazon region, identify circulating genotypes and mutations in the S gene. 181 patients with negative serology for HBsAg and anti‐HBs and positive serology for anti‐HBc participated in the study. Detection of viral DNA, genotyping by sequencing and analysis of nucleotide sequences to detect possible mutations were performed. HBV DNA was detected in 14.36% of the patients. Genotyping revealed genotype A in 88.46% of HBV DNA‐positive subjects, with subgenotype A1 being the most prevalent (78.26%) followed by subgenotype A2 (21.74%). Genotype F was detected in 11.54% (all of them subgenotype F2). Amino acid substitutions were observed in the amplified S gene in individuals with OBI compared to HBsAg‐positive individuals (evident infection). In conclusion, the results show a high prevalence of OBI in the population studied, with a pattern of genotypes A and F that circulate in the Brazilian Amazon region. Amino acid substitutions were detected in part of the S gene in patients with OBI. Further studies on the molecular epidemiology of HBV in this region are important to identify patients considered healthy but who are potential transmitters of the disease. This article is protected by copyright. All rights reserved …

Journal of Medical Virology, EarlyView.

Jiao Gong, Yan‐Lan Liang, Wenying Zhou, Yusheng Jie, Cuicui Xiao, Yutian Chong, Bo Hu

Chronic severe hepatitis B (CSHB) is a critical clinical syndrome with a high mortality rate in China. The prognostic value of neutrophil to lymphocyte ratio (NLR) which is simple, low‐cost, and useful inflammatory marker for hepatitis B virus (HBV)‐infected patients is largely overlooked and without further exploration. This study assesses the association of NLR with prognosis of chronic hepatitis B (CHB) and CSHB patients. Two hundred and eighty subjects, including 79 with chronic hepatitis B (CHB) and 67 with chronic severe hepatitis B (CSHB), and 134 healthy individuals were retrospectively recruited into this study. Blood samples were collected to conduct liver function, prothrombin time activity (PTA), international normalized ratio (INR), HBV DNA measurement and routine hematological testing. All patients were followed up for at least 3 months. NLR values in patients with CSHB (4.984 ± 3.608) and CHB (2.020 ± 1.182) were significantly higher than those in healthy control (1.638 ± 0.601) and patients with CSHB had the highest NLR values than CHB and healthy control. Increased NLR values were clinically associated with severe liver disease and higher mortality rate. NLR was found to be an independent predictor of mortality in multivariable Cox Regression models (HR= 3.912, 95%CI: 1.587‐9.640, P= 0.003). NLR values are significantly increased in CHB and CSHB patients with the severity of liver disease. Moreover, NLR value is an independent predicting factor for the mortality rate in HBV‐infected patients. This article is protected by copyright. All rights reserved …

Journal of Medical Virology, Volume 90, Issue 4, Page 721-729, April 2018.

Abstract Background Efficient control of acute hepatitis B requires identification of current transmission routes. Countries in Central-Eastern Europe including Poland attribute an important fraction of cases to nosocomial transmission, as opposed to Western European countries. However, due to possible multiple exposures during the incubation time such assignment may be debatable. This study aimed at assessing of most affected groups and current transmission pattern of acute hepatitis B. Methods We investigated exposures reported by acute hepatitis B cases notified to routine surveillance system in Poland in 2010–2014 in comparison to data on hospitalization rates in general population. Results Hospitalization during incubation time significantly increased the risk of HBV infection (RR 3.13, 95%CI 2.58–3.80). Overall hospitalization population attributable risk (PAR%) was 25.7% (95% CI 20.3%–31.1%) as compared to 35% of acute cases assigned to hospital transmission in surveillance database. PAR% increased from 9.5% (1.12%–17.8%) in the age group 25–34 to 41.1% (28.2% - 53.9%) among those 65 +. In addition, cases …

Mother-to-child transmission of hepatitis B virus (HBV) accounts for the majority of cases of chronic HBV infection, a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Without immunization, 30 to 42% of the infants born to HBV-infected mothers, depending on the maternal status for……

Quercia, Romina; Perno, Carlo-Federico; Koteff, Justin; Moore, Katy; McCoig, Cynthia; St. Clair, Marty; Kuritzkes, Daniel

Innovation in medicine is a dynamic, complex, and continuous process that cannot be isolated to a single moment in time. Anniversaries offer opportunities to commemorate crucial discoveries of modern medicine, such as penicillin (1928), polio vaccination (inactivated, 1955; oral, 1961), the surface antigen of the hepatitis B virus (1967), monoclonal antibodies (1975), and the first HIV antiretroviral drugs (zidovudine, 1987). The advent of antiretroviral drugs has had a profound effect on the progress of the epidemiology of HIV infection, transforming a terminal, irreversible disease that caused a global health crisis into a treatable but chronic disease. This result has been driven by the success of antiretroviral drug combinations that include nucleoside reverse transcriptase inhibitors such as lamivudine. Lamivudine, an L-enantiomeric analogue of cytosine, potently affects HIV replication by inhibiting viral reverse transcriptase enzymes at concentrations without toxicity against human polymerases. Although lamivudine was approved more than 2 decades ago, it remains a key component of first-line therapy for HIV because of its virological efficacy and ability to be partnered with other antiretroviral agents in traditional and novel combination therapies. The prominence of lamivudine in HIV therapy is highlighted by its incorporation in recent innovative treatment strategies, such as single-tablet regimens that address challenges associated with regimen complexity and treatment adherence and 2-drug regimens being developed to mitigate cumulative drug exposure and toxicities. This review summarizes how the pharmacologic and virologic properties of lamivudine have solidified its role in contemporary HIV therapy and continue to support its use in emerging therapies. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Correspondence and reprint requests to: Romina Quercia, ViiV Healthcare, CN12, 980 Great West Road, Brentford, Middlesex, UK TW8 9GS, Phone: +44 (0)20 8380 6695, Email: romina.p.quercia@viivhealthcare.com Conflicts of interest and source of funding: RQ, JK, KM, CM, MSC are employees of ViiV Healthcare and hold stock in GlaxoSmithKline. C-FP is a consultant to and has received honoraria and/or grant support from Gilead, InnoVirVax, Janssen, Merck, Bristol Myers Squibb, and ViiV Healthcare. DK is a consultant to and has received honoraria from Bionor, Gilead, GlaxoSmithKline, InnoVirVax, Janssen, Merck, and ViiV Healthcare; he has received grant support and speaking honoraria from Gilead, Merck, and ViiV Healthcare. Funding for this work was provided by ViiV Healthcare. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Quercia, Romina; Perno, Carlo-Federico; Koteff, Justin; Moore, Katy; McCoig, Cynthia; St. Clair, Marty; Kuritzkes, Daniel

Innovation in medicine is a dynamic, complex, and continuous process that cannot be isolated to a single moment in time. Anniversaries offer opportunities to commemorate crucial discoveries of modern medicine, such as penicillin (1928), polio vaccination (inactivated, 1955; oral, 1961), the surface antigen of the hepatitis B virus (1967), monoclonal antibodies (1975), and the first HIV antiretroviral drugs (zidovudine, 1987). The advent of antiretroviral drugs has had a profound effect on the progress of the epidemiology of HIV infection, transforming a terminal, irreversible disease that caused a global health crisis into a treatable but chronic disease. This result has been driven by the success of antiretroviral drug combinations that include nucleoside reverse transcriptase inhibitors such as lamivudine. Lamivudine, an L-enantiomeric analogue of cytosine, potently affects HIV replication by inhibiting viral reverse transcriptase enzymes at concentrations without toxicity against human polymerases. Although lamivudine was approved more than 2 decades ago, it remains a key component of first-line therapy for HIV because of its virological efficacy and ability to be partnered with other antiretroviral agents in traditional and novel combination therapies. The prominence of lamivudine in HIV therapy is highlighted by its incorporation in recent innovative treatment strategies, such as single-tablet regimens that address challenges associated with regimen complexity and treatment adherence and 2-drug regimens being developed to mitigate cumulative drug exposure and toxicities. This review summarizes how the pharmacologic and virologic properties of lamivudine have solidified its role in contemporary HIV therapy and continue to support its use in emerging therapies. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Correspondence and reprint requests to: Romina Quercia, ViiV Healthcare, CN12, 980 Great West Road, Brentford, Middlesex, UK TW8 9GS, Phone: +44 (0)20 8380 6695, Email: romina.p.quercia@viivhealthcare.com Conflicts of interest and source of funding: RQ, JK, KM, CM, MSC are employees of ViiV Healthcare and hold stock in GlaxoSmithKline. C-FP is a consultant to and has received honoraria and/or grant support from Gilead, InnoVirVax, Janssen, Merck, Bristol Myers Squibb, and ViiV Healthcare. DK is a consultant to and has received honoraria from Bionor, Gilead, GlaxoSmithKline, InnoVirVax, Janssen, Merck, and ViiV Healthcare; he has received grant support and speaking honoraria from Gilead, Merck, and ViiV Healthcare. Funding for this work was provided by ViiV Healthcare. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

EK Alidjinou, C Michel, V Canva, F Ajana, D Hober, L Bocket

We investigated the decline of hepatitis B virus surface antigen (HBsAg) and core related antigen (HBcrAg) in chronic hepatitis B patients sussessfully treated with nucleos(t)ide analogues. In patients with plasma viral suppression, the baseline median levels of HBsAg and HBcrAg were 3.1 log IU/mL and 3.0 log U/mL, respectively. The levels in naïve patients were 4.2 log IU/mL and 3.6 log U/mL for HBsAg and HBcrAg respectively. No significant decline was observed in patients with viral suppression within a year period. A low reduction was observed during the first months after treatment initiation, especially regarding HBcrAg. The dynamics of these antigens after viral suppression should be further investigated. This article is protected by copyright. All rights reserved …

Journal of Medical Virology, EarlyView.

Alessia Lai, Caterina Sagnelli, Alessandra Lo Presti, Eleonora Cella, Silvia Angeletti, Silvia Spoto, Sebastiano Costantino, Evangelista Sagnelli, Massimo Ciccozzi

Hepatitis B virus (HBV) infection represents the most common cause of chronic liver diseases worldwide. Consequently, to the introduction of the universal HBV vaccination program, the prevalence of hepatitis B surface antigen was markedly reduced and less than 1% of the population of Western Europe and North America is chronically infected. To date, despite great advances in therapeutics, HBV chronic infection is considered an incurable disease. Ten hepatitis B virus genotypes (A–J) and several subgenotypes have been identified so far, based on intergroup divergences of 8% and 4%, respectively, in the complete viral genome. HBV‐D genotype has been found throughout the world, with highest prevalence in the Mediterranean area. In the present review, several articles concerning HBV epidemiology and phylogeny in Italy have been analyzed, mainly focusing on the changes occurred in the last decade. This article is protected by copyright. All rights reserved …

McArdle, Andrew J.; Turkova, Anna; Cunnington, Aubrey J.

Purpose of review Advances in diagnostic methods mean that coinfections are increasingly being detected in clinical practice, yet their significance is not always obvious. In parallel, basic science studies are increasingly investigating interactions between pathogens to try to explain real-life observations and elucidate biological mechanisms. Recent findings Coinfections may be insignificant, detrimental, or even beneficial, and these outcomes can occur through multiple levels of interactions which include modulation of the host response, altering the performance of diagnostic tests, and drug–drug interactions during treatment. The harmful effects of chronic coinfections such as tuberculosis or Hepatitis B and C in association with HIV are well established, and recent studies have focussed on strategies to mitigate these effects. However, consequences of many acute coinfections are much less certain, and recent conflicting findings simply highlight many of the challenges of studying naturally acquired infections in humans. Summary Tackling these challenges, using animal models, or careful prospective studies in humans may prove to be worthwhile. There are already tantalizing examples where identification and treatment of relevant coinfections seems to hold promise for improved health outcomes. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0 Correspondence to Dr Aubrey J. Cunnington, PhD, Section of Paediatrics, Imperial College, Norfolk Place, London W2 1PG, UK. Tel: +44 2075943915; e-mail: a.cunnington@imperial.ac.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.