Journal of Viral Hepatitis

Community‐based real‐world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re‐emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti‐HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re‐emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg‐positive and HBeAg‐negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti‐HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on‐treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re‐emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community‐based real‐world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti‐HBs, nearly all patients achieved sustained undetectable virus.

Sofosbuvir/ledipasvir (SOF/LDV) is the first all‐oral ribavirin‐free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real‐world outcomes of this regimen are lacking. We aim to evaluate real‐world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community‐based real‐world cohort of Asian chronic HCV genotype 6 patients treated with all‐oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.

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.

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.

Patients with active hepatitis C virus (HCV) infection at transplantation experience rapid allograft infection, increased risk of graft failure and accelerated fibrosis. MBL‐HCV1, a neutralizing human monoclonal antibody (mAb) targeting the HCV envelope, was combined with a licensed oral direct‐acting antiviral (DAA) to prevent HCV recurrence post‐transplant in an open‐label exploratory efficacy trial. Eight subjects received MBL‐HCV1 beginning on the day of transplant with telaprevir initiated between days 3 and 7 post‐transplantation. Following FDA approval of sofosbuvir, two subjects received MBL‐HCV1 starting on the day of transplant with sofosbuvir initiated on day 3. Combination treatment was administered for 8‐12 weeks or until the stopping rule for viral rebound was met. The primary endpoint was undetectable HCV RNA at day 56 with exploratory endpoints of sustained virologic response (SVR) at 12 and 24 weeks post‐treatment. Both subjects receiving mAb and sofosbuvir achieved SVR24. Four of eight subjects in the mAb and telaprevir group met the primary endpoint; one subject achieved SVR24 and three subjects relapsed 2‐12 weeks post‐treatment. The other four subjects experienced viral breakthrough. There were no serious adverse events related to study treatment. This proof‐of‐concept study demonstrates that peri‐transplant immunoprophylaxis combined with a single oral direct‐acting antiviral in the immediate post‐transplant period can prevent HCV recurrence.

Summary.  Host genetic factors and environment factors including hepatitis B virus (HBV) genotypes are widely studied for the different outcomes of HBV infection. Recent studies suggest that tumour necrosis factor‐alpha (TNF‐alpha) plays a pivotal role in the viral clearance and host immune response to HBV, and the capacity for TNF‐alpha production in individuals is influenced by a major genetic component. In this study, we aimed to explore whether the single‐nucleotide polymorphisms (SNPs) of TNF‐alpha promoter are associated with the outcomes of HBV infection in the Chinese Han population. One hundred and forty‐three spontaneously recovered HBV subjects and 196 chronic hepatitis B patients were recruited in this case–control study in the Beijing area of China. Polymerase chain reaction–restriction fragment‐length polymorphism (PCR‐RFLP) and sequence‐specific primer‐PCR (SSP‐PCR) were used to detect the SNPs of five sites in the TNF‐alpha promoter (−238G/A, −308G/A, −857C/T, −863C/A, −1031T/C). The frequency distributions of genotypes and haplotypes in two groups were analysed by EPI and EH programs. The presence of the −238GG genotype was significantly correlated with persistence of HBV infection (OR = 4.08, P = 0.02), and −857TT genotype appeared in relation to the spontaneous clearance of HBV (OR = 0.47, P = 0.03). Frequency of haplotype GGCCT (−238/−308/−857/−863/−1031) in the chronic HB group was significantly lower than that in spontaneously recovered group (P = 0.03), and frequencies of haplotypes GGCAT and GGTAT in the chronic HB group were significantly higher than those in the spontaneously recovered group (P = 0.0001, P = 0.0004). In conclusion, TNF‐alpha promoter polymorphisms are independently associated with different outcomes of HBV infection.

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.

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.