Journal of Viral Hepatitis

Viêm gan B là một căn bệnh nghiêm trọng đang lưu hành ở nhiều vùng trên thế giới. Một tỷ lệ đáng kể bệnh nhân viêm gan B mãn tính (CHB) bị nhiễm một dạng biến thể của virus viêm gan B (HBV) làm giảm hoặc làm mất sự sản xuất kháng nguyên e viêm gan B (HBeAg). Mục đích của bài tổng quan tài liệu này là mô tả dịch tễ học của CHB âm tính với HBeAg (e-CHB) trên toàn cầu. Một cuộc tìm kiếm tài liệu đã được thực hiện để xác định các nghiên cứu liên quan đến e-CHB và các biến thể cơ bản (precore và core promoter). Năm mươi nghiên cứu đã được đưa vào phân tích của chúng tôi. Tỷ lệ e-CHB trung vị trong số bệnh nhân nhiễm HBV mãn tính là 33% ở khu vực Địa Trung Hải, 15% ở khu vực châu Á Thái Bình Dương, và 14% ở Hoa Kỳ và Bắc Âu. Biến thể codon dừng precore được phát hiện ở mức trung vị là 60% (khoảng 0–100%) ở tất cả bệnh nhân âm tính với HBeAg, 92% ở khu vực Địa Trung Hải, 50% ở khu vực châu Á Thái Bình Dương và 24% ở Hoa Kỳ và Bắc Âu. Rất ít dữ liệu về tỷ lệ xuất hiện của các biến thể core promoter ngoài châu Á, nơi tỷ lệ trung vị ở bệnh nhân âm tính với HBeAg là 77%. Tổng quan tài liệu này đã tiết lộ rằng e-CHB phổ biến hơn so với những gì đã được nghi ngờ trước đó và rằng nó hiện diện trên toàn thế giới với những khác biệt đáng kể về tỷ lệ xuất hiện của các biến thể HBV liên quan ở các vùng địa lý khác nhau. Cần có thêm nghiên cứu sử dụng các mẫu dân số với kích thước đủ lớn dựa trên định nghĩa đồng thuận về e-CHB và sử dụng các xét nghiệm DNA HBV chuẩn hóa để ước lượng tốt hơn tỷ lệ thực sự của e-CHB và các biến thể HBV liên quan.

Recent evidence has shown that anti‐HCV‐positive serologic status is significantly linked to lower patient and graft survival after renal transplant, but conflicting results have been given on this point. The aim of this study was to conduct a systematic review of the published medical literature concerning the impact of HCV infection on all‐cause mortality and graft loss after RT. The relative risk of all‐cause mortality and graft loss was regarded as the most reliable outcome end‐point. Study‐specific relative risks were weighted by the inverse of their variance to obtain fixed‐ and random‐effect pooled estimates for mortality and graft loss with HCV across the published studies. We identified eighteen observational studies involving 133 530 unique renal transplant recipients. The summary estimate for adjusted relative risk (aRR) of all‐cause mortality was 1.85 with a 95% confidence interval (CI) of 1.49; 2.31 (P < 0.0001); heterogeneity statistics, Ri = 0.87 (P‐value by Q‐test = 0.001). The overall estimate for adjusted RR of all‐cause graft loss was 1.76 (95% CI, 1.46; 2.11) (P < 0.0001), heterogeneity statistics, Ri = 0.65 (P‐value by Q‐test = 0.001). Stratified analysis did not change meaningfully these results. Meta‐regression showed that living donor rate had a favourable influence on patient (P = 0.031) and graft survival (P = 0.01), whilst diabetes mellitus having a detrimental role on patient survival (P = 0.001). This meta‐analysis of observational studies supports the notion that HCV‐positive patients after RT have an increased risk of mortality and graft loss. Further studies are in progress to understand better the mechanisms underlying the relationship between HCV and mortality or graft dysfunction after renal transplant.

Adefovir dipivoxil (bis‐POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co‐infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double‐blind, placebo‐controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for ≥ 6 months, with elevated hepatic transaminases and serum HBV DNA ≥ 50 pg ml^–1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log₁₀ in all active drug recipients (median fall 1.8 log₁₀ pg ml^–1) but increased by 0.01 log₁₀ pg ml^–1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1–6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l^–1 were observed in three patients during therapy (leading to protocol‐specified treatment discontinuation or dose reduction) and in four patients during follow‐up. On‐treatment transaminase elevations were associated with HIV status, occurring in three of six HIV‐uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non‐HIV‐infected patients. Treatment for chronic hepatitis B as a once‐daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.

Summary.  T helper (Th) 17 cells have been demonstrated to participate in the pathogenesis of HBV‐associated liver damage. However, little is known regarding the immunopathogenic role of liver fibrosis in patients with HBV‐associated liver cirrhosis. The aims of this study were to evaluate whether Th17 cells are related to disease progression in patients and to explore the possible mechanisms. The frequencies of circulating Th17 cells were analysed in 78 patients with hepatitis B and cirrhosis (Child A: 34; Child B: 22; Child C 22) and matched controls. Liver samples were collected from 13 patients with HBV‐associated cirrhosis, 23 patients with chronic hepatitis B and 12 healthy controls for immunohistochemical analysis. IL‐17 receptor expression was studied on liver biopsies and in human hepatic stellate cells as well as their response to recombinant IL‐17 by flow cytometry. Patients with hepatitis B‐associated cirrhosis with more severe disease displayed significant increases in peripheral numbers of Th17 cells as well as in IL‐17 plasma levels. The increased intrahepatic IL‐17⁺ cells correlated positively with fibrotic staging scores and clinical progression from CHB to cirrhosis. Moreover, many IL‐17⁺ cells were located in fibrotic areas in the liver of patients with cirrhosis. In vitro, IL‐17 together with IL‐17‐activated monocytes, could promote the activation of stellate cells, which, in turn, aggravated liver fibrosis and the inflammatory response. In summary, increased peripheral and intrahepatic Th17 cells are enriched in patients with hepatitis B and cirrhosis and contribute further to the severity of disease progression through induction of stellate cell activation.

Summary.  In Argentina, the annual incidence rate of reported hepatitis A disease ranged from 70.5 to 173.8 per 100 000 during 1995–2004. A single dose universal hepatitis A immunization program aimed at children aged 12 months was started in June 2005. The aim was to observe the impact of universal vaccination against hepatitis A in Argentina. A longitudinal analysis of hepatitis A rates reported in Argentina since 1995 to the National Notifiable Diseases Surveillance System (SINAVE). Incidence rates in 2007 were compared with those for the prevaccination baseline period (1998–2002), overall and by age group and geographical regions. Overall vaccine coverage in Argentina was 95% in 2006 for the single dose. After initiating the program, a sharp decrease in disease rates was observed. The annual incidence of 10.2 per 100 000 during 2007 represents 88.0% reduction with respect to the average incidence rate for the period 1998–2002 (P < 0.001). For children aged 1 year, an 83.1% reduction in disease was observed in 2007, compared with the baseline period (P < 0.001). Furthermore, a sharp decline was also observed in all other age groups 87.1% [2–4 years], 88.7% [5–9 years], 83.6% [10–14 years], 78.8% [15–49 years], 20.7% [>50 years]. Also important reductions were observed in all Argentinian regions. Following the implementation of universal hepatitis vaccination with a single dose to children at 12 months of age, hepatitis A rates have declined substantially in Argentina. Monitoring is needed to verify that vaccination continues to proceed and that low rates are sustained.

Summary.  Hepatitis C virus (HCV) is an enveloped, positive‐strand RNA virus of the family Flaviviridae that primarily infects hepatocytes, causing acute and chronic liver disease. HCV is also associated with a variety of extrahepatic symptoms including central nervous system (CNS) abnormalities, cognitive dysfunction, fatigue and depression. These symptoms do not correlate with the severity of liver disease and are independent of hepatic encephalopathy. HCV RNA has been associated with CNS tissue, and reports of viral sequence diversity between brain and liver tissue suggest independent viral evolution in the CNS and liver. This review will explore the data supporting HCV infection of the CNS and how this fits into our current understanding of HCV pathogenesis.

Hepatitis C virus (HCV), the major causative agent of chronic and sporadic non‐A, non‐B hepatitis worldwide, is a distinct member of the Flaviviridae virus family. These viruses have in common a plus‐strand RNA genome that is replicated in the cytoplasm of the infected cell via minus‐strand RNA intermediates. Owing to the lack of reliable cell culture systems and convenient animal models for HCV, the mechanisms governing RNA replication are not known. As a first step towards the development of appropriate in vitro systems, we expressed the NS5B RNA‐dependent RNA polymerase (RdRp) in insect cells, purified the protein to near homogeneity and studied its biochemical properties. It is a primer‐ and RNA template‐dependent RNA polymerase able to copy long heteropolymeric templates without additional viral or cellular cofactors. We determined the optimal reaction parameters, the kinetic constants and the substrate specificity of the enzyme, which turned out to be similar to those described for the 3D polymerase of poliovirus. By analysing a series of nucleosidic and non‐nucleosidic compounds for their effect on RdRp activity, we found that ribavirin triphosphates have no inhibitory effect, providing direct experimental proof that the therapeutic effect observed in patients is not related to a direct inhibition of the viral polymerase. Finally, mutation analysis was performed to map the minimal NS5B sequence required for enzymatic activity and to identify the ‘classical’ polymerase motifs important for template and NTP binding and catalysis.

Recent studies found that hepatitis C virus (HCV) may invade the central nervous system, and both HCV and Parkinson's disease (PD) have in common the overexpression of inflammatory biomarkers. We analysed data from a community‐based integrated screening programme based on a total of 62 276 subjects. We used logistic regression models to investigate association between HCV infection and PD. The neurotoxicity of HCV was evaluated in the midbrain neuron–glia coculture system in rats. The cytokine/chemokine array was performed to measure the differences of amounts of cytokines released from midbrain in the presence and absence of HCV. The crude odds ratios (ORs) for having PD were 0.62 [95% confidence interval (CI), 0.48–0.81] and 1.91 (95% CI, 1.48–2.47) for hepatitis B virus (HBV) and HCV. After controlling for potential confounders, the association between HCV and PD remained statistically significant (adjusted OR = 1.39; 95% CI, 1.07–1.80), but not significantly different between HBV and PD. The HCV induced 60% dopaminergic neuron death in the midbrain neuron–glia coculture system in rats, similar to that of 1‐methyl‐4‐phenylpyridinium (MPP⁺) but not caused by HBV. This link was further supported by the finding that HCV infection may release the inflammatory cytokines, which may play a role in the pathogenesis of PD. In conclusion, our study demonstrated a significantly positive epidemiological association between HCV infection and PD and corroborated the dopaminergic toxicity of HCV similar to that of MPP⁺.

Summary.  The relationship between the balance of helper T‐cell type 1 (Th1) or type 2 (Th2) cytokines and the clinical course of hepatitis C virus (HCV) infection is unclear. We evaluated Th1 [interleukin (IL)‐2, interferon‐gamma (IFN‐γ)] and Th2 cytokine (IL‐4, IL‐10) and 2,5‐oligoadenylate synthetase (OAS, an IFN‐induced antiviral protein) production by peripheral blood mononuclear cells from 10 healthy anti‐HCV‐positive individuals (group A), 10 HCV‐RNA‐positive with persistently normal alanine aminotransferase (ALT) levels (group B), 10 HCV‐RNA‐positive with abnormal ALT (group C) and 10 uninfected healthy controls. IL‐2 production was significantly increased in group B when compared with all the other groups. No difference was found for IFN‐γ. IL‐4 was significantly higher in group C than in both group B (P = 0.0006) and controls (P = 0.004). Compared with controls, IL‐10 was significantly decreased in group A (P = 0.013) and B (P = 0.004). The production of 2,5‐OAS was significantly higher in group B than in A (P = 0.04) and in C (P = 0.004). Finally, in all HCV‐RNA‐positive patients, a significant correlation was found between ALT and both IL‐2 (r = −0.78; P = 0.0008) and IL‐4 (r = 0.75; P = 0.0008). In conclusion: (i) subjects who cleared HCV showed a cytokine profile similar to controls; (ii) a preferential shift towards a Th1 profile seems associated with a more favourable clinical outcome in chronic hepatitis C; and (iii) a prevalent Th2 profile seems implicated in HCV pathogenesis and severity of liver disease.