Showing papers in "Journal of Viral Hepatitis in 2015"

The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm.

Abstract: The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing.

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 3.

Abstract: Detailed, country-specific epidemiological data are needed to characterize the burden of chronic hepatitis C virus (HCV) infection around the world. With new treatment options available, policy makers and public health officials must reconsider national strategies for infection control. In this study of 15 countries, published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates were gathered from the literature and validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Iran and Lebanon to 4.2% in Pakistan. The largest viraemic populations were in Pakistan (7 001 000 cases) and Indonesia (3 187 000 cases). Injection drug use (IDU) and a historically unsafe blood supply were major risk factors in most countries. Diagnosis, treatment and liver transplant rates varied widely between countries. However, comparison across countries was difficult as the number of cases changes over time. Access to reliable data on measures such as these is critical for the development of future strategies to manage the disease burden.

Estimates on HCV disease burden worldwide - filling the gaps.

Abstract: Hepatitis C is caused by infection with the hepatitis C virus (HCV) and represents a major global health burden. Persistent HCV infection can lead to progressive liver disease with the development of liver cirrhosis and hepatocellular carcinoma, possibly accounting for up to 0.5 million deaths every year. Treatment of HCV infection is undergoing a profound and radical change. As new treatments are extremely safe and effective, there are virtually no medical reasons to withhold therapy. Yet, the new therapies are expensive. As resources are limited, solid data to estimate the disease burden caused by HCV are urgently needed. Epidemiology data and disease burden analyses for 16 countries are presented. For almost all countries, the peak of HCV-related cirrhosis, hepatocellular carcinoma and liver-related death is a decade or more away. However, a surprising heterogeneity in country-specific HCV-associated disease burden exists. Also, HCV diagnosis and treatment uptake varied markedly between countries. A consistent finding was that a reduction of HCV liver-related mortality is dependent on access to therapy. Increasing efficacy of therapy alone with a constant numbers of treatments will not have a major impact on the HCV-related disease burden. The data presented here should inform public health policy and help drive advocacy for enhanced strategic investment and action. HCV kills patients, and the disease burden will continue to rise in most countries unless action is taken soon. Chronic HCV is a curable infection and a reversible liver disease. Fortunately, the tools to eliminate HCV are now available.

Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis.

Abstract: Summary Patients with chronic hepatitis B (HBsAg-positive) are at risk of viral reactivation if rituximab is administered without antiviral treatment, a potentially fatal complication of treatment. Patients with so-called ‘resolved hepatitis B virus infection’ (HBsAg-negative/cAb-positive) may also be at risk. We performed a systematic review of the English and Chinese language literature to estimate the risk of hepatitis B virus (HBV) reactivation in HBsAg-negative/cAb-positive patients receiving rituximab for lymphoma. A pooled risk estimate was calculated for HBV reactivation. The impact of HBsAb status and study design on reactivation rates was explored. Data from 578 patients in 15 studies were included. ‘Clinical HBV reactivation’, (ALT >3 × normal and either an increase in HBV DNA from baseline or HBsAg seroreversion), was estimated at 6.3% (I2 = 63%, P = 0.006). Significant heterogeneity was detected. Reactivation rates were higher in prospective vs retrospective studies (14.2% vs 3.8%; OR = 4.39, 95% CI 0.83–23.28). Exploratory analyses found no effect of HBsAb status on reactivation risk (OR = 0.083; P = 0.151). Our meta-analysis confirms a measurable and potentially substantial risk of HBV reactivation in HBsAg-negative/cAb-positive patients exposed to rituximab. However, heterogeneity in the existing literature limits the generalizability of our findings. Large, prospective studies, with uniform definitions of HBV reactivation, are needed to clarify the risk of HBV reactivation in HBsAg-negative/cAb-positive patients.

HCV treatment rates and sustained viral response among people who inject drugs in seven UK sites: real world results and modelling of treatment impact.

Abstract: Hepatitis C virus (HCV) antiviral treatment for people who inject drugs (PWID) could prevent onwards transmission and reduce chronic prevalence. We assessed current PWID treatment rates in seven UK settings and projected the potential impact of current and scaled-up treatment on HCV chronic prevalence. Data on number of PWID treated and sustained viral response rates (SVR) were collected from seven UK settings: Bristol (37-48% HCV chronic prevalence among PWID), East London (37-48%), Manchester (48-56%), Nottingham (37-44%), Plymouth (30-37%), Dundee (20-27%) and North Wales (27-33%). A model of HCV transmission among PWID projected the 10-year impact of (i) current treatment rates and SVR (ii) scale-up with interferon-free direct acting antivirals (IFN-free DAAs) with 90% SVR. Treatment rates varied from <5 to over 25 per 1000 PWID. Pooled intention-to-treat SVR for PWID were 45% genotypes 1/4 [95%CI 33-57%] and 61% genotypes 2/3 [95%CI 47-76%]. Projections of chronic HCV prevalence among PWID after 10 years of current levels of treatment overlapped substantially with current HCV prevalence estimates. Scaling-up treatment to 26/1000 PWID annually (achieved already in two sites) with IFN-free DAAs could achieve an observable absolute reduction in HCV chronic prevalence of at least 15% among PWID in all sites and greater than a halving in chronic HCV in Plymouth, Dundee and North Wales within a decade. Current treatment rates among PWID are unlikely to achieve observable reductions in HCV chronic prevalence over the next 10 years. Achievable scale-up, however, could lead to substantial reductions in HCV chronic prevalence.

Memory re-differentiation and reduced lymphocyte activation in chronic HCV-infected patients receiving direct-acting antivirals.

Abstract: Recently, the treatment of HCV has advanced significantly due to the introduction of direct-acting antivirals (DAAs). Studies using interferon (IFN)-containing regimens failed to consistently show restoration of immunologic responses. Therefore, IFN-free DAA formulations provide a unique opportunity to dissect the immunologic effect of HCV cure. This study investigates the restoration of the immune compartment as a consequence of rapid viral clearance in patients successfully treated with DAAs and in the absence of IFN and ribavirin. Here, we evaluate the immunologic changes that occurred following DAA-mediated HCV cure. Peripheral blood from nineteen previously treatment-naive patients with chronic HCV genotype 1a/1b who received an IFN and ribavirin-free regimen of daclatasvir, asunaprevir and BMS-791325 was evaluated. Immune reconstitution occurs in patients in whom HCV was successfully eradicated via DAA therapy. Restoration of the CD4(+) T-cell compartment in the peripheral blood and a re-differentiation of the T lymphocyte memory compartment resulted in a more effector memory cell population and a reduction in expression in the co-inhibitory molecule TIGIT in bulk T lymphocytes. Furthermore, we observed a partial reversal of the exhausted phenotype in HCV-specific CD8(+) T cells and a dampening of the activation state in peripheral NK cells. Collectively, our data provide the groundwork for dissecting the effect of DAA therapy on the immune system and identifying novel mechanisms by which chronic HCV infection exerts immunosuppressive effects on T cells through the recently described co-inhibitory molecule TIGIT.

Strategies to manage hepatitis C virus infection disease burden - Volume 3

Abstract: The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries in Europe, the Middle East and Asia, and the relative impact of two scenarios was considered: increased treatment efficacy while holding the annual number of treated patients constant and increased treatment efficacy and an increased annual number of treated patients. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. A 90% reduction in total HCV infections within 15 years is feasible in most countries studied, but it required a coordinated effort to introduce harm reduction programmes to reduce new infections, screening to identify those already infected and treatment with high cure rate therapies. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. Among European countries, the majority of patients were born between 1940 and 1985. A wider range of birth cohorts was seen in the Middle East and Asia (between 1925 and 1995).

Interferon‐free, direct‐acting antiviral therapy for chronic hepatitis C

Abstract: The treatment environment for chronic hepatitis C has undergone a revolution, particularly in genotype 1. Gone are interferon-based therapy and its associated tolerability challenges, inadequate response rates and numerous baseline factors that affect response to therapy. New and emerging treatment regimens employ all-oral combinations of direct-acting antiviral agents, and results of clinical trials suggest that these regimens routinely achieve cure rates >90%, even in patients who failed prior interferon-based triple therapy. In 2015, three all-oral FDA-approved regiments will be available for genotype 1 (sofosbuvir /ledipasvir, sofosbuvir/simeprevir, and paritaprevir/r/ombitasvir/dasabuvir). Furthermore, new treatment combinations appear to be more tolerable and require shorter duration of therapy. We provide an overview of the classes of direct-acting antiviral agents (DAAs), the clinical factors affecting their integration into combination therapies and recent findings from trials of such combination therapies in patients with genotype 1 HCV infection.

A meta-analytic assessment of the risk of chronic kidney disease in patients with chronic hepatitis C virus infection.

Abstract: Epidemiological studies have reported conflicting results regarding hepatitis C virus (HCV) infection and the risk of chronic kidney disease (CKD). We systematically reviewed the literature to determine the risk of developing CKD in HCV-infected individuals compared to uninfected individuals. MEDLINE and PUBMED were searched to identify observational studies that had reported an association between HCV and CKD or end-stage renal disease (ESRD) through January 2015. Quantitative estimates [hazard ratio (HR) or odds ratio (OR)] and their 95% confidence intervals (CI) were extracted from each study. A random-effects meta-analysis was performed. Fourteen studies evaluating the risk of developing CKD/ESRD in HCV-infected individuals (n = 336,227) compared to uninfected controls (n = 2,665,631) were identified- nine cohort studies and five cross-sectional studies. The summary estimate indicated that individuals with HCV had a 23% greater risk of presenting with CKD compared to uninfected individuals (risk ratio = 1.23; 95% CI: 1.12-1.34). Results were similar by study type, for cohorts (HR = 1.26; 95% CI: 1.12-1.40) and cross-sectional studies (OR = 1.21; 95% CI: 1.09-1.32). Country-stratified analysis demonstrated a significantly increased risk between HCV and CKD in the Taiwanese subgroup (risk ratio = 1.28; 95% CI: 1.12-1.34) and the US subgroup (risk ratio = 1.17; 95% CI: 1.01-1.32). Egger regression revealed no evidence of publication bias. HCV infection is associated with a greater risk of developing and progression of CKD compared to uninfected controls.

Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection

Abstract: Hepatocyte clone size was measured in liver samples of 21 patients in various stages of chronic hepatitis B virus (HBV) infection and from 21 to 76 years of age. Hepatocyte clones containing unique virus-cell DNA junctions formed by the integration of HBV DNA were detected using inverse nested PCR. The maximum hepatocyte clone size tended to increase with age, although there was considerable patient-to-patient variation in each age group. There was an upward trend in maximum clone size with increasing fibrosis, inflammatory activity and with seroconversion from HBV e-antigen (HBeAg)-positive to HBeAg-negative, but these differences did not reach statistical significance. Maximum hepatocyte clone size did not differ between patients with and without a coexisting hepatocellular carcinoma. Thus, large hepatocyte clones containing integrated HBV DNA were detected during all stages of chronic HBV infection. Using laser microdissection, no significant difference in clone size was observed between foci of HBV surface antigen (HBsAg)-positive and HBsAg-negative hepatocytes, suggesting that expression of HBsAg is not a significant factor in clonal expansion. Laser microdissection also revealed that hepatocytes with normal-appearing histology make up a major fraction of the cells undergoing clonal expansion. Thus, preneoplasia does not appear to be a factor in the clonal expansion detected in our assays. Computer simulations suggest that the large hepatocyte clones are not produced by random hepatocyte turnover but have an as-yet-unknown selective advantage that drives increased clonal expansion in the HBV-infected liver.

Hepatitis C virus infection: a risk factor for Parkinson's disease

Abstract: 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(+) .

Long‐term entecavir or tenofovir disoproxil fumarate therapy in treatment‐naïve chronic hepatitis B patients in the real‐world setting

Abstract: The aim of this study was to determine the long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment-naive CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End-Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long-term follow-up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients.

Experimental infection of pregnant rabbits with hepatitis E virus demonstrating high mortality and vertical transmission.

Abstract: A high mortality rate of approximately 20% in pregnant women with hepatitis E has been reported in previous studies. However, other studies showed no difference between pregnant and nonpregnant women in the severity of hepatitis E. To determine the effects of HEV infection on pregnancy, we successfully established HEV infection in six pregnant rabbits (PR) and six nonpregnant rabbits (NPR) with a rabbit HEV isolate, taking three PR and one NPR without HEV infection as controls. Tests for HEV RNA by RT-PCR, anti-HEV antibodies by ELISA and HEV antigen via immunohistochemistry and histopathology were carried out. Two of six infected PR miscarried and three of the remaining four PR died which may be attributed to severe liver necrosis caused by HEV infection. Moreover, vertical transmission was found to be associated with the replication of HEV in placenta, indicated by the presence of HEV RNA and antigen in placenta from the infected PR. Our findings strongly suggest that HEV infection could lead to adverse outcomes in pregnancy and vertical transmission, suggesting the necessity for pregnant women at risk of HEV infection to be vaccinated.

Genome-free hepatitis B virion levels in patient sera as a potential marker to monitor response to antiviral therapy.

Abstract: Complete virions of hepatitis B virus (HBV) contain a DNA genome that is enclosed in a capsid composed of the HBV core antigen (HBcAg), which is in turn surrounded by a lipid envelope studded with viral surface antigens (HBsAg). In addition, HBV-infected cells release subviral particles composed of HBsAg only (HBsAg 'spheres' and 'filaments') or HBsAg enveloping HBcAg but devoid of viral DNA ('empty virions'). The hepatitis B e antigen (HBeAg), a soluble antigen related to HBcAg, is also secreted in some HBV-infected patients. The goals of this study were to explore the levels of empty virions in HBV-infected patients before and during therapy with the nucleotide analog tenofovir disoproxil fumarate (TDF) that inhibits HBV DNA synthesis and the relationships of empty virions to complete virions, HBsAg and HBeAg. HBV DNA, HBcAg and HBsAg levels were determined in serum samples from 21 patients chronically infected with HBV and enrolled in clinical TDF studies. Serum levels of empty virions were found to exceed levels of DNA-containing virions, often by ≥ 100-fold. Levels of both empty and complete virions varied and were related to the HBeAg status. When HBV DNA replication was suppressed by TDF, empty virion levels remained unchanged in most but were decreased (to the limit of detection) in some patients who also experienced significant decrease or loss of serum HBsAg. In conclusion, empty virions are present in the serum of chronic hepatitis B patients at high levels and may be useful in monitoring response to antiviral therapy.

Acute hepatitis C infection in HIV-negative men who have sex with men

Abstract: Acute hepatitis C infection is recognized in HIV-infected men who have sex with men (MSM), but the risk in HIV-negative MSM remains unclear. We evaluated a population of MSM with acute hepatitis C. From January 2010 to May 2014, all cases of HCV antibody positive HIV-negative MSM were identified. European AIDS Network criteria were applied to determine acute infection, and 44 individuals fulfilled the criteria for acute hepatitis C. Ten were RNA negative at baseline and classed as prior spontaneous clearance. 15 (34.1%) had a previously negative HCV antibody within 1 year. 11 (25.0%) had significant elevation in ALT levels, and 18 (40.9%) were clinically diagnosed from risk exposure and history. Median age was 37 years (range 24-75). 41 (93.2%) individuals reported unprotected anal sex, 36 with (87.8%) both insertive and receptive intercourse, 4 (9.8%) with receptive intercourse, 1 (2.4%) with insertive intercourse, and no data were recorded for 3 (7.3%) patients. Individuals had an average of 7.3 reported (median 2, range 1-100) partners. 12 (27.3%) engaged in group sex, 11 (25.0%) practised fisting, 11 (25.0%) admitted using drugs during sexual activity, 16 (36.4%) reported nasal, and 9 (20.5%) reported injection drug use. 14 (31.8)% had unprotected sex whilst under the influence of recreational drugs. 29 individuals were aware of a partner's status. 2 (4.5%) individuals had sexual contact with a known HCV monoinfected partner, 13 (29.5%) with a HIV monoinfected partner and 6 (13.6%) with a HCV/HIV coinfected partner. 9 (20.5%) reported a partner/partners with no known infection. No data were available in 14 (31.8%) individuals. 13 (29.5%) individuals had a coexisting STI at the time of acute HCV diagnosis. 8 (18.2%) received HIV postexposure prophylaxis (PEP) within the 6 months prior to the HCV diagnosis (2 were participants in a HIV pre-exposure prophylaxis trial). 15 (34.1%) individuals achieved spontaneous clearance of HCV, and 11 patients received HCV treatment. Similar to the ongoing epidemic of acute HCV infection in HIV+ MSM, HIV-negative MSM remain at risk.

Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy

Abstract: Summary Clinical phase II/III studies of the nucleotide analogue HCV NS5B inhibitor sofosbuvir (SOF) have demonstrated high efficacy in HCV-infected patients in combination therapy. To date, resistance to SOF (S282T in NS5B) has rarely been detected in patients. In this study, we investigated the evolution of S282T viral variants detected in one HCV genotype 2b-infected patient who relapsed following 12 weeks of SOF monotherapy. Deep sequencing of the NS5B gene was performed on longitudinal plasma samples at baseline, days 2 and 3 on SOF, and longitudinal samples post-SOF treatment through week 48. Intrapatient HCV evolution was analysed by maximum-likelihood phylogenetic analysis. Deep sequencing analysis revealed a low level pre-existence of S282T at 0.05% of viral sequences (4/7755 reads) at baseline and 0.03% (6/23 415 reads) at day 2 on SOF. Viral relapse was detected at week 4 post-treatment where 99.8% of the viral population harboured S282T. Follow-up analysis determined that S282T levels diminished post-treatment reaching undetectable levels 24–48 weeks post-SOF. Phylogenetic analysis together with the persistence of unique post-treatment mutations in all post-SOF samples suggested that growth of wild type resulted from reversion of the S282T mutant to a wild type and not outgrowth of the baseline wild-type population. Our data suggest that a very low level of pre-existing S282T at baseline in this patient was enriched and transiently detected following SOF monotherapy. Despite relapse with drug resistance to SOF, this patient was successfully retreated with SOF plus ribavirin for 12 weeks and is now cured from HCV infection.

Impact of nucleos(t)ide analogues on the estimated glomerular filtration rate in patients with chronic hepatitis B: a prospective cohort study in China.

Abstract: Chronic hepatitis B therapy with nucleos(t)ide analogues, particularly tenofovir or adefovir, may affect renal function. To date, there has not been a head-to-head controlled study to assess estimated glomerular filtration rate (eGFR) fluctuations in nucleos(t)ide-treated CHB patients. We aimed to evaluate the long-term effects of nucleos(t)ide on eGFR in Chinese patients with chronic hepatitis B. This prospective cohort study included 275 patients. Patient subgroups included those treated with lamivudine (n = 50), adefovir (n = 60), telbivudine (n = 68) and entecavir (n = 61); untreated patients (n = 36) served as control. After an average follow-up duration of 23 months, eGFR calculated by Cockcroft-Gault and Modification of Diet in Renal Disease formulas increased by 18.35 mL/min and 19.34 mL/min (P < 0.0001) in the telbivudine group, respectively, and decreased by 10.95 mL/min and 12.17 mL/min (P = 0.0001) in the adefovir group, respectively. Even if renal function was normal or mildly impaired at baseline, eGFR increased significantly more in the telbivudine group than in the other groups (P < 0.001). More patients in the adefovir group (23%) had a ≥20% decrease in eGFR than the other groups (P < 0.0001). More patients in the telbivudine group (31%) had a ≥20% increase in eGFR than the other groups (P < 0.0001). In conclusion, prolonged telbivudine therapy resulted in improved eGFR, while adefovir therapy was associated with decreased eGFR. Lamivudine and entecavir therapy did not significantly influence eGFR.

Dried blood spot in the genotyping, quantification and storage of HCV RNA: a systematic literature review

Abstract: The entry of new all-oral direct acting antiviral therapy for hepatitis C provides an opportunity to scale up HCV care in low- and middle-income countries. In HIV, use of dried blood spots (DBS) has facilitated the diagnosis and management of HIV in resource-poor settings. DBS may be used in a similar way to facilitate diagnosis and management of HCV. Here, we present a systematic review of the literature of DBS for HCV RNA detection and genotyping. Using an a priori review protocol, three databases were searched for studies published up to August 2013 that reported the use of dried blood and serum spots in genotyping, detection and measurement of HCV RNA, as well as the rate of degradation of HCV RNA when stored in DBS at room temperature. Nine papers were eligible for inclusion; eight studied DBS and one dried serum. Two studies measured concordance between genotype and subtype determined by DBS and whole plasma and both found 100% concordance. Four studies measured endpoint detection limits of HCV RNA-positive samples by DBS and found positive predictive values of 100% down to 250, 334, 2500 and 24160 IU/mL. Two studies found deterioration of HCV RNA in DBS samples stored at room temperature, while two others failed to detect such deterioration. These results support the potential use of DBS for genotyping and HCV RNA detection. Studies of the use of DBS for HCV RNA viral load measurement and of the rate of degradation of HCV RNA when stored in DBS at ambient temperatures remain inconclusive.

A phase 1, randomized, dose‐ranging study of GS‐5816, a once‐daily NS5A inhibitor, in patients with genotype 1–4 hepatitis C virus

Abstract: Summary GS-5816 is an inhibitor of the hepatitis C virus (HCV) NS5A protein that has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. The aim of this study was to evaluate the safety, antiviral activity and pharmacokinetics of once-daily doses of GS-5816 in patients with genotype 1–4 HCV infection. Patients with genotype 1–4 HCV infection were randomized to 3 days of GS-5816 at doses ranging from 5 to 150 mg or placebo. Adverse events were recorded, and plasma samples obtained for analysis of pharmacokinetics, HCV RNA and NS5A sequencing studies. GS-5816 5–150 mg for 3 days was well tolerated and resulted in rapid declines in HCV RNA that were sustained over the dosing period. In patients treated with the 150 mg dose of GS-5816, the mean maximal HCV RNA declines were 4.0, 4.0, 4.4, 3.3 and 3.5 log10 IU/mL in patients with genotype 1a, 1b, 2, 3 and 4 HCV infection, respectively. Pretreatment NS5A resistance-associated polymorphisms were detected in 31% (22/70) of patients. Genotype 1 and 3 HCV-infected patients without pretreatment NS5A resistance-associated polymorphisms had greater declines in HCV RNA than patients with resistance-associated polymorphisms. Plasma pharmacokinetics were supportive of once-daily dosing. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.

Antiviral therapy in chronic hepatitis E: a systematic review

Abstract: Hepatitis E viral infection can lead to a chronic infection in immunocompromised patients, resulting in progressive liver disease and cirrhosis. Isolated cases have shown that treatment with ribavirin or pegylated interferon-alpha can result in viral eradication. This systematic review evaluated efficacy and safety of both treatments in chronic hepatitis E. A systematic literature search was performed on PubMed, Web of Science and clinicaltrials.gov for articles and abstracts. The keywords '"Hepatitis E" or HEV' AND 'ribavirin or Rebetol or Copegus' OR 'pegylated interferon OR peginterferon' were combined. The primary outcome was sustained viral response (SVR). Secondary endpoints include rapid viral response (RVR), relapse rates and side effects. Twenty-four studies matched our criteria, representing a total of 105 ribavirin-treated and 8 pegylated interferon-treated patients. The majority of patients had a solid organ transplant. Sixty-four per cent of ribavirin-treated patients achieved a SVR at 6 months after treatment cessation compared to 2/8 peginterferon-treated patients. Ribavirin was relatively well tolerated with the main side effect being anaemia, requiring dose reduction in 28% of patients. Peginterferon leads to acute transplant rejection in 2/8 patients. Ribavirin monotherapy appears to be an effective and safe treatment in all immunocompromised patients with chronic hepatitis E. The use of pegylated interferon in transplant patients may lead to transplant rejection and is not recommended. Therefore, ribavirin should be the antiviral treatment of choice in chronic hepatitis E.

Cost-effectiveness of sofosbuvir in the treatment of patients with hepatitis C.

Abstract: In France, 190 306 patients were suffering from chronic hepatitis C in 2012. These patients have a decreased life expectancy and are susceptible to complications associated with chronic hepatitis. Current treatments are poorly tolerated and their effectiveness varies depending on the genotype of the virus. Sofosbuvir, a new class of treatment, has demonstrated in five phase III trials sustained viral response (SVR) rates of over 90% across genotypes, higher than current treatments and has a tolerance profile similar to placebo. The objective was to determine the cost-effectiveness of using sofosbuvir in the treatment of chronic HCV infection. A Markov model was used to compare treatment strategies with and without sofosbuvir. The model simulated the natural history of HCV infection. SVR rates were based on data from clinical trials. Utilities associated with different stages of disease were based on data from the literature. French direct medical costs were used. Price for sofosbuvir was the price used in the early access program for severe fibrosis stages. The incremental cost–effectiveness ratio for sofosbuvir versus current reference treatments was € 16 278/QALY and varied from 40 000 €/QALY for F0 stages to 12 080 €/QALY for F4 stages. The sensitivity analyses carried out confirmed the robustness of this result. Sofosbuvir is a cost-effective treatment option for patients with hepatitis C.

Chronic hepatitis C virus infection is associated with increased risk of preterm birth: a meta-analysis of observational studies.

Abstract: Summary Although several epidemiological studies reported that maternal chronic hepatitis C virus (HCV) infection had significantly increased risk of undergoing adverse obstetrical and perinatal outcomes, studies on the relationship between HCV infection and risk of preterm birth (PTB) have yielded inconclusive and inconsistent results. Therefore, we conducted a meta-analysis to investigate the association between HCV infection and PTB. The electronic database was searched until 1 September 2014. Relevant studies reporting the association between HCV infection and the risk of PTB were included for further evaluation. Statistical analysis was performed using revmen 5.3 and stata 10.0. Nine studies involving 4186698 participants and 5218 HCV infection cases were included. A significant association between HCV infection and PTB was observed (odds ratio = 1.62, 95% CI 1.48–1.76, P < 0.001, fixed-effects model). Stratification according to maternal smoking/alcohol abuse, maternal drug abuse or coinfected with HBV and/or HIV matched groups still demonstrated that women with HCV infection had a high risk for PTB. Findings from our meta-analysis suggested that maternal HCV infection was significantly associated with an increased risk of PTB. In the future, pathophysiological studies are warranted to ascertain the causality and explore the possible biological mechanisms involved.

Hepatitis C virus infection in China: an emerging public health issue

Abstract: Hepatitis C virus now represents a global viral pandemic and is the fourth most commonly reported infectious disease in China. Information on China's national HCV epidemic was limited to cross -sectional seroprevalence studies of special populations, and a national surveillance effort had been launched to inform prevention and control. We analysed novel data from two national databases: (i) China's national medical HCV case report system and (ii) the national disease sentinel surveillance system. Between 1997 and 2012, reporting incidence of medical cases for HCV infection rose from 0.7 to 15.0 cases per 100 000 with the largest burden of disease concentrated among individuals over 35 years of age, rural residents and those tested as part of routine screening. Between 2010 and 2012, disease sentinel surveillance identified the highest HCV seropositive rates among persons who use drugs and haemodialysis patients, with far lower but not negligible rates among sexually active population. The concentration of cases among older age groups is consistent with past studies of age-specific prevalence rates in Asia. Differences across regions and testing modes suggest diverse biological and social forces driving the spread of HCV in China. Surveillance data show ongoing transmission, particularly among persons who use drugs and persons undergoing invasive medical treatments, particularly haemodialysis. Improvements in case detection and data reporting systems will be critical for understanding current drivers of transmission and identifying key areas for prevention.

Evaluation of an antigen-capture EIA for the diagnosis of hepatitis E virus infection.

Abstract: Summary An enzyme immunoassay (EIA) has been developed for hepatitis E virus (HEV) antigen (HEV-Ag) detection and marketed in China. This study aimed to evaluate the sensitivity of the assay and assess the value of HEV-Ag detection in the diagnosis of HEV infection in comparison with HEV RNA detection. Using serial dilutions of a genotype 4 HEV strain, significant correlation was found between the EIA (S/CO) and HEV RNA (IU/mL) concentration in the range 103.5 to 100.5 IU/mL HEV RNA, the Pearson correlation coefficient r approached 0.97. The EIA detection limit was 54.6 IU/mL, compared to 24 IU/mL for HEV RNA using real-time RT-PCR. In clinical samples from hepatitis E patients, the HEV-Ag and HEV RNA positivity rates were 55.6% (65/117) and 60.7% (71/117) in sera and 76.7% (56/73) and 84.9% (62/73) in stools, and the concordance of these two markers was 77.8% in sera and 80.8% in stools. In serum samples, the HEV-Ag positivity rate and the concordance between HEV-Ag and HEV RNA were inversely proportional to the presence of anti-HEV antibody. The presence of anti-HEV IgG could reduce the S/CO of the HEV-Ag EIA. These results reveal a significant correlation between the detection of HEV-Ag and HEV RNA. The sensitivity of the HEV-Ag EIA was lower than real-time RT-PCR but could be higher than conventional nested RT-PCR. Therefore, the detection of HEV-Ag in serum and faeces is valuable for the diagnosis and prognosis of HEV infection in developing regions where real-time RT-PCR is not available.

Efficacy and safety of telbivudine treatment: an open-label, prospective study in pregnant women for the prevention of perinatal transmission of hepatitis B virus infection.

Abstract: We evaluated the efficacy and safety of telbivudine (LdT, 600 mg/day) vs control patients (no treatment) in decreasing vertical transmission of HBV, in HBeAg-positive mothers (HBVDNA >6log(10) copies/mL). HBeAg-positive pregnant women either in the second or third trimester were recruited in a prospective, case-control, open-label study, at the Second Affiliated Hospital of the Southeast University, China (February 2008-December 2010). Efficacy (month 7: HBVDNA (+), HBsAg (+) infants) in either the overall group or the treated group and control group was analysed using student's t-test. Infants were followed for at least 1 year. 362 women received LdT (second trimester n = 257; third trimester n = 105) and 92 were untreated. Before delivery, the mean maternal HBVDNA was 2.73, 2.47, 3.34 and 7.94 log10 copies/mL in the overall, second and third trimester treated and control groups, respectively (P < 0.001). At birth, 11.8% of babies overall (43/365), 13.5% (35/259) of those treated in the second trimester, 7.5% of those treated in the third trimester (8/106) and 20.7% (19/92) of untreated infants were HBsAg positive. At month 7, none of the LdT-treated infant had detectable HBVDNA, while eight infants from control mothers were HBsAg positive. Vertical transmission was 0% in LdT treated and 9.3% (8/86) in the control groups (P < 0.001). No difference in the vertical transmission rate was found in mothers treated in the second or third trimester. LdT treatment was safe for mothers and infants, and no congenital deformities were reported.

Hepatitis B reactivation during cancer chemotherapy: an international survey of the membership of the American Association for the Study of Liver Diseases.

Abstract: Hepatitis B virus reactivation (HBVr) can be a serious complication of cancer chemotherapy. However, underutilization of HBV screening and secondary underutilization of antiviral prophylaxis have been frequently reported. The authors electronically distributed a 30-point questionnaire to members of the American Association for the Study of Liver Diseases to capture experiences with HBVr during cancer chemotherapy. The questionnaire specified diagnostic criteria and collected information on HBV screening, antiviral prophylaxis and clinical outcomes. Ninety-nine respondents reported 188 patients who met the criteria for HBV reactivation. Forty-one practised outside the United States, and most were hepatologists (n = 71) or gastroenterologists (n = 12). One hundred and twenty-six patients had haematologic malignancies, of which 88 (70%) had lymphoma. Seventy-five patients (40%) had screening for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc), and an additional 24 patients (13%) had HBsAg screening alone. Prophylactic antiviral therapy was reported in only 18 patients (10%). Chemotherapy was interrupted in 52 patients (41%) with haematologic malignancies and 26 of 41 patients (63%) with solid tumours (P = 0.01). Rituximab-treated patients (n = 66) required hospitalization more frequently (P = 0.04), but their overall survival did not differ from individuals not treated with rituximab. Death due to liver failure was reported in 43 patients overall (23%). Underutilization of prophylactic antiviral therapy occured in a substantial number of patients who were found to be HBV infected prior to the initiation of cancer chemotherapy. The reasons for this need further exploration because reactivation results in serious yet preventable outcomes.

PCDH20 functions as a tumour-suppressor gene through antagonizing the Wnt/β-catenin signalling pathway in hepatocellular carcinoma.

Abstract: Several members of protocadherins have been found involved in human carcinogenesis, but little is known about PCDH20 in HCC. Here in this study, using quantitative real-time RT-PCR assay, we demonstrated the downregulation of PCDH20 expression in 6 of 7 HCC cell lines tested. Similarly, PCDH20 expression in primary HCC tissues was also significantly downregulated in comparison with that in either disease-free normal liver tissues or the adjacent nontumour liver tissues (P < 0.001, respectively). Among HCC tumour tissues studied, about 48% (51/107) of them showed reduced PCDH20 mRNA level. Further statistic analysis revealed that the reduced PCDH20 mRNA level in tumour tissues was much more common in younger patients group (aged <50 years) than that in older group (≥50 years) (60% vs 33%, P = 0.0303). Loss of heterozygosity (LOH) and promoter hypermethylation analysis revealed that deletion and/or aberrant epigenetic modulation of PCDH20 gene account for its downregulation, at least in a fraction of tumour specimens. Moreover, ectopic expression of PCDH20 in HCC cells significantly suppressed cell proliferation, clonogenicity, migration and tumour formation. Notably, we proved for the first time that, via activating GSK-3β, PCDH20 could inhibit Wnt/β-catenin signalling pathway. Furthermore, our data suggest that PCDH20 may conduct its Wnt/β-catenin signalling antagonizing function through suppressing Akt and Erk activities and promoting GSK-3β signalling activities. However, the detailed mechanism remained undiscovered. In conclusion, our data here strongly suggested that PCDH20 may act as a candidate tumour suppressor in HCC.

Treating Immune-tolerant Hepatitis B

Abstract: Hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma worldwide. On the basis of virus-host interactions, the natural history of HBV carriers can be divided into four chronological phases. In the first immune tolerance phase, HBV carriers are positive for hepatitis B e antigen (HBeAg) and have high HBV replication activity, normal ALT levels as well as minimal liver disease. Ample evidence has shown that patients in the immune tolerance phase have very low viral evolution and minimal risk of fibrosis progression. However, recent immunological studies argued that HBV-specific immune responses already exist in a proportion of immune-tolerant patients and the immune activities are comparable to those in the immune clearance phase. Regarding antiviral therapy, whether these immune-tolerant patients are indicated for treatment remains debated. Previous studies showed that HBeAg-positive patients with normal or near-normal ALT levels, who are assumed to be in the immune tolerance phase, have a lower HBeAg seroconversion rate receiving either pegylated interferon or nucleos(t)ide analogue treatment. The latest clinical trial focusing on-treatment response of immune-tolerant patients with tenofovir disoproxil fumarate-based therapy also confirmed the results. The HBeAg seroconversion rates are <5% at 4 years of treatment. Considering the minimal risk of disease progression and low treatment response rates in immune-tolerant patients, current antiviral therapy should not be recommended unless the patients have advanced liver fibrosis. In addition, novel agents targeting the HBV template known as covalently closed circular DNA and aiming to reduce or eliminate it are urgently required.

Risk of all-type cancer, hepatocellular carcinoma, non-Hodgkin lymphoma and pancreatic cancer in patients infected with hepatitis B virus

Abstract: The increased risk of hepatocellular carcinoma (HCC) among patients infected with hepatitis B virus (HBV) is well established; however, long-term risk estimates are needed. Recently, it has been suggested that HBV is associated with non-Hodgkin lymphoma (NHL) and pancreatic cancer (PC). The aim of this Danish nationwide cohort study was to evaluate the association between HBV infection and all-type cancer, HCC, NHL and PC. A cohort of patients infected with HBV (n = 4345) and an age- and sex-matched population-based comparison cohort of individuals (n = 26,070) without a positive test for HBV were linked to The Danish Cancer Registry to compare the risk of all-type cancer, HCC, NHL and PC among the two groups. The median observation period was 8.0 years. Overall, the incidence rate ratio (IRR) for all-type cancer among HBV-infected patients was 1.1 (95% confidence intervals (CI) 0.9-1.3). The IRR of HCC was 17.4 (CI 5.5-54.5), whereas the IRR of PC and NHL was 0.9 (CI 0.3-2.5) and 1.2 (CI 0.4-3.6), respectively. HBV-infected patients had a 10-year risk of 0.24% (Cl 0.12-0.44) for HCC, whereas the comparison cohort had a 10-year risk of 0.03% (Cl 0.02-0.07) for HCC. The risk of all-type cancer, NHL and PC was not higher in the HBV-infected cohort compared to non-HBV infected. We found a 17-fold higher risk of HCC for HBV-infected individuals.

Expression of microRNA-155 correlates positively with the expression of Toll-like receptor 7 and modulates hepatitis B virus via C/EBP-β in hepatocytes

Abstract: Effective recognition of viral infection and successive activation of antiviral innate immune responses are vital for host antiviral defence, which largely depends on multiple regulators, including Toll-like receptors (TLRs) and microRNAs. Several early reports suggest that specific TLR-mediated immune responses can control hepatitis B virus (HBV) replication and express differentially with disease outcome. Considering the versatile function of miR-155 in the TLR-mediated innate immune response, we aimed to study the association between miR-155 and TLRs and their subsequent impact on HBV replication using both a HBV-replicating stable cell line (HepG2.2.15) and HBV-infected liver biopsy and serum samples. Our results showed that miR-155 was suppressed during HBV infection and a subsequent positive correlation of miR-155 with TLR7 activation was noted. Further, ectopic expression of miR-155 in vitro reduced HBV load as evidenced from reduced viral DNA, mRNA and subsequently reduced level of secreted viral antigens (HBsAg and HBeAg). Our results further suggested that CCAAT/enhancer-binding protein-β (C/EBP-β), a positive regulator of HBV transcription, was inhibited by miR-155. Taken together, our study established a correlation between miR-155 and TLR7 during HBV infection and also demonstrated in vitro that increased miR-155 level could help to reduce HBV viral load by targeting C/EBP-β.