High Hepatitis C Virus Research Articles

Patterns of longitudinal change in hepatitis C virus neutralization titers correlate with the outcome of peginterferon and ribavirin combination therapy.

In chronic hepatitis C virus (HCV) infection, combination therapy of peginterferon and ribavirin does not guarantee viral eradication. Among factors relevant to therapeutic efficacy, the role of humoral immunity has not been examined thoroughly. In the current study, HCV pseudoparticles (HCVpp) were first generated with 80 patient-derived full-length HCV envelope clones, followed by detailed characterization with regard to virus productivity, infectivity and neutralizing activity. Selective HCVpp were used to measure HCV neutralization titers in two independent patient cohorts consisting of 102 patients undergoing antiviral therapy. The HCV neutralization titers at the baseline fitted with a power-law distribution among patients. Pretreatment neutralization titers in both patient cohorts were not correlated with treatment outcomes. In the patient cohort 2 (n = 28) that had samples available at multiple time points, however, HCV neutralization titers displayed clearly distinct patterns over therapeutic course and follow-up. No virological responders (n = 10) had neutralization titers stabilized at low level while it was increased significantly in both sustained virological responders (n = 10) and relapsers (n = 8). High HCV neutralization titers were maintained only in sustained virological responders but not in relapsers after treatment cessation. Therefore, patterns of longitudinal change of HCV neutralization titers, but not pretreatment titers, correlate with the treatment outcome in patients undergoing peginterferon and ribavirin combination therapy.

Estimation of hepatitis C virus infections resulting from vertical transmission in Egypt.

Despite having the highest hepatitis C virus (HCV) prevalence in the world, the ongoing level of HCV incidence in Egypt and its drivers are poorly understood. Whereas HCV mother-to-child infection is a well-established transmission route, there are no estimates of HCV infections resulting from vertical transmission for any country, including Egypt. The aim of this study was to estimate the absolute number of new HCV infections resulting from vertical transmission in Egypt. We developed a conceptual framework of HCV vertical transmission, expressed in terms of a mathematical model and based on maternal HCV antibody and viremia. The mathematical model estimated the number of HCV vertical infections nationally and for six subnational areas. Applying two vertical transmission risk estimates to the 2008 Egyptian birth cohort, we estimated that between 3,080 and 5,167 HCV infections resulted from vertical transmission among children born in 2008. HCV vertical transmission may account for half of incident cases in the <5-year age group. Disproportionately higher proportions of vertical infections were estimated in Lower Rural and Upper Rural subnational areas. This geographical clustering was a result of higher-area-level HCV prevalence among women and higher fertility rates. Conclusion: Vertical transmission is one of the primary HCV infection routes among children <5 years in Egypt. The absolute number of vertical transmissions and the young age at infection highlight a public health concern. These findings also emphasize the need to quantify the relative contributions of other transmission routes to HCV incidence in Egypt. (Hepatology 2015;61:834–842)

Diagnosis and Management of Hepatitis C Virus Infection.

The hepatitis C virus (HCV) infects more than 200 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to chronic liver disease, creating a heavy economic burden on resource-poor countries and lowering patient quality of life. Effective HCV diagnosis, treatment selection, and treatment monitoring are important in stopping disease progression. Serological assays, which detect anti-HCV antibodies in the patient after seroconversion, are used for initial HCV diagnosis. Qualitative and quantitative molecular assays are used to confirm initial diagnosis, determine viral load, and genotype the dominant strain. Viral load and genotype information are used to guide appropriate treatment. Various other biomarker assays are performed to assess liver function and enable disease staging. Most of these diagnostic methods are mature and routinely used in high-resource countries with well-developed laboratory infrastructure. Few technologies, however, are available that address the needs of low-resource areas with high HCV prevalence, such as Africa and Southeast Asia.

Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study.

Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co-infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co-infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co-infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.

Hepatitis C virus-associated B-cell non-Hodgkin lymphomas.

Epidemiological studies have demonstrated an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. However, the strength of the association shows great geographic discrepancies, with higher relative risk in countries with high HCV prevalence. It remains unclear whether additional environmental and genetic factors are involved or if the international variability is simply a consequence of the variable infection prevalence. Therefore, a causal relationship remains controversial. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used, and the year of publication. The most convincing proof is the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after HCV eradication with IFN and ribavirin. However, the molecular mechanisms of the HCV-induced lymphomagenesis are mainly hypothetical. According to the model considered to be most plausible, lymphoma growth is a consequence of the continuous antigenic stimulation of the B-cell immunologic response induced by the chronic viral infection. This review summarizes the current epidemiological and biological evidence of a role of HCV in lymphomagenesis, describing the putative mechanisms for a causative relationship. The clinical characteristics and management difficulties of the HCV-associated lymphomas are also discussed. HCV treatment with IFN cannot be given safely in concomitance with cytotoxic lymphoma treatment because of hematological and liver toxicity. However, novel and better tolerated antiviral regimens are under development and will hopefully make the treatment of both lymphoma and hepatitis easier in the future.

Targeted hepatitis C antibody testing interventions: a systematic review and meta-analysis.

Testing for hepatitis C virus (HCV) infection may reduce the risk of liver-related morbidity, by facilitating earlier access to treatment and care. This review investigated the effectiveness of targeted testing interventions on HCV case detection, treatment uptake, and prevention of liver-related morbidity. A literature search identified studies published up to 2013 that compared a targeted HCV testing intervention (targeting individuals or groups at increased risk of HCV) with no targeted intervention, and results were synthesised using meta-analysis. Exposure to a targeted testing intervention, compared to no targeted intervention, was associated with increased cases detected [number of studies (n) = 14; pooled relative risk (RR) 1.7, 95 % CI 1.3, 2.2] and patients commencing therapy (n = 4; RR 3.3, 95 % CI 1.1, 10.0). Practitioner-based interventions increased test uptake and cases detected (n = 12; RR 3.5, 95 % CI 2.5, 4.8; and n = 10; RR 2.2, 95 % CI 1.4, 3.5, respectively), whereas media/information-based interventions were less effective (n = 4; RR 1.5, 95 % CI 0.7, 3.0; and n = 4; RR 1.3, 95 % CI 1.0, 1.6, respectively). This meta-analysis provides for the first time a quantitative assessment of targeted HCV testing interventions, demonstrating that these strategies were effective in diagnosing cases and increasing treatment uptake. Strategies involving practitioner-based interventions yielded the most favourable outcomes. It is recommended that testing should be targeted at and offered to individuals who are part of a population with high HCV prevalence, or who have a history of HCV risk behaviour.Electronic supplementary materialThe online version of this article (doi:10.1007/s10654-014-9958-4) contains supplementary material, which is available to authorized users.

Is screening baby boomers for HCV enough? A call to screen for hepatitis C virus in persons from countries of high endemicity

Is screening baby boomers for <scp>HCV</scp> enough? A call to screen for hepatitis C virus in persons from countries of high endemicity

Impact of alloimmune T cell responses on hepatitis C virus replication in liver transplant recipients

We investigated the influence of alloimmune T cell responses on hepatitis C virus (HCV) replication in HCV-infected patients after liver transplantation (LT). To monitor the immune-status in 27 HCV-infected LT recipients, we routinely performed mixed lymphocyte reaction (MLR) assays within 4weeks after LT. HCV RNA titers in most patients fluctuated in inverse proportion to the stimulation index (SI) of anti-donor reactive T cells early after LT. Two weeks after LT, recipients with high HCV RNA titers (>1000KIU/mL) displayed a significantly lower SI for anti-donor reactive T cells than recipients with low HCV RNA titers did (<1000KIU/mL). An in vitro transwell assay mimicking the anatomical features of the interaction between HCV-infected hepatocytes and alloreactive T cells in allograft livers demonstrated that interferon (IFN)-γ was necessary to suppress HCV replication. This study proves the significant impact of alloimmune T cell responses on HCV replication in HCV-infected LT recipients.

Spontaneous Clearance of Chronic HCV Infection: An Unusual Phenomenon

Introduction: In acute hepatitis C virus (HCV) infection, only about 25% of patients clear the infection through an immune response. Once chronic HCV infection is established in the remaining 75% of patients, spontaneous clearance of HCV infection is extremely uncommon. We present to you 5 such cases. We describe 5 consecutive patients at the Bronx VA Medical Center that spontaneously cleared chronic HCV infection within the last 10 years. The results are as follows: 3 out of 5 patients were chronically infected with HCV genotype 1. Spontaneous clearance occurred in 3 different scenarios: 1.) Two patients were HIV and HCV-co-infected (HIV infection was suppressed with antiretroviral therapy) and were never treated for hepatitis C. After many years of chronic HCV viremia, they spontaneously became HCV RNA undetectable and remained undetectable for up to 4 years. 2.) Two patients with chronic HCV mono-infection were each treated with antiviral therapy, which resulted in undetectable HCV RNA. After the end of therapy, they relapsed to high-level viremia and high ALT level, but spontaneously cleared HCV RNA to undetectable levels and a normal ALT. However, they relapsed again to high HCV RNA and high ALT. One patient subsequently cleared again and relapsed again. 3.) One HCV-mono-infected patient had received a liver transplant and was on immunosuppressive therapy. He never received HCV antiviral therapy. Two years after the liver transplant, his HCV RNA became undetectable, and it has remained undetectable since 3 years ago. Spontaneous clearance of chronic HCV infection is a very rare phenomenon, but we present 5 subjects in 1 medical center over a span of 10 years that exhibit this rare phenomenon, and in different scenarios: 1.) after relapse from antiviral therapy, 2.) post-liver transplantation, and 3.) in HIV/HCV co-infection.

The successful implementation of Scotland's Hepatitis C Action Plan: what can other European stakeholders learn from the experience? A Scottish voluntary sector perspective.

The successful implementation of Scotland's Hepatitis C Action Plan: what can other European stakeholders learn from the experience? A Scottish voluntary sector perspective.

Improved hepatitis C screening and treatment in people who inject drugs should be a priority in Europe.

Since its launch in 2005, the European Liver Patients’ Association (ELPA) has worked to promote the interests of people with all forms of liver disease. Despite improvements in medical treatment, and despite the recent publication of WHO guidelines for screening, the overall situation of hepatitis C virus (HCV) transmission in Europe is a growing concern for ELPA. Many patients who are infected with HCV can carry the infection for many years before developing symptoms [1], and people who currently have chronic HCV will represent a heavy disease burden in the coming years [2]. The World Health Organization (WHO) estimates that more than 19 million people in Europe are infected with Hepatitis C, and states that transmission is mainly concentrated in people who inject drugs (PWID), who globally have 67% HCV prevalence [3]. Since there is no vaccine for Hepatitis C, prevention efforts must concentrate on health education programmes targeting high-risk populations and on public awareness campaigns that seek to improve testing and case finding in the general community [1]. On 1 December 2010, World AIDS Day, the European Monitoring Centre for Drugs and Drug Addiction published guidelines on testing for HIV, viral hepatitis and other infectious diseases in PWID. The new guidelines recommended a strategy to increase the uptake of testing among PWID in Europe and beyond. This would enable earlier treatment of infected individuals and reduce the further spread of the disease [4]. Two years later, the Euro Hepatitis Care Index called attention to the need for screening programs in risk populations to be improved in all countries, noting that in order to increase testing in drug users it is important to make the services as reachable and convenient as possible [1]. More recently, WHO recommended screening to identify persons with HCV infection, and also recommended that HCV testing be offered to individuals who have a history of HCV risk behaviour or who belong to populations with high HCV prevalence [3]. There is evidence that where HCV screening of PWID is implemented, it can be cost-effective [5] and screening programmes can be successful [6]. However it is not clear which countries have adopted these guidelines and there are still relatively few published reports on best practices. Identifying infected patients through screening programmes is only part of the solution, and ELPA continues to be concerned about the slow introduction of new drugs for HCV treatment. The Euro Hepatitis Care Index showed that general access to the direct-acting antiviral drugs telaprevir and boceprevir only existed in five European countries, and that one-third of countries were not providing these new drugs at all [1]. WHO states that avoiding discrimination or stigmatisation of PWID is essential, and reports that treatment for HCV infection is both efficacious and cost-effective in PWID. WHO recommends that all adults and children with chronic HCV infection, including PWID, be assessed for antiviral treatment. WHO also notes that treatment may be effective as prevention due to a reduction in transmission [3]. In order to bring about change and to ensure that guidelines and effective treatment programmes are implemented in Europe, ELPA will continue to call for the reporting of additional data on HCV screening and treatment measures. We look forward to further changes being made in European policies and healthcare strategies which lead to success in tackling this chronic disease.

Active co-infection with HBV and/or HCV in South African HIV positive patients due for cancer therapy.

Human immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV) share routes of transmission. There is limited data on the incidence of active co-infection with HBV and/or HCV in cancer patients infected with HIV in Africa. This was a prospective study based on 34 patients with varied cancer diagnosis, infected with HIV and awaiting cancer therapy in South Africa. HIV viral load, CD4+ cell counts, Alanine-aminotransferase and aspartate aminotransferase levels were tested. Exposure to HBV and HCV was assessed serologically using commercial kits. Active HBV and/or HCV co-infection was detected using viral specific nested PCR assays. HCV 5'-UTR PCR products were sequenced to confirm active HCV infection. Active viral infection was detected in 64.7% of patients for HBV, 38.2% for HCV, and 29.4% for both HBV and HCV. Occult HBV infection was observed in 63.6% of the patients, while seronegative HCV infection was found in 30.8% of patients. In addition, CD4+ cell count < 350 cells/µl was not a risk factor for increased active HBV, HCV or both HBV and HCV co-infections. A total of 72.7%, 18.2% and 9.1% of the HCV sequences were assigned genotype 5, 1 and 4 respectively.The study revealed for the first time a high active HBV and/or HCV co-infection rate in cancer patients infected with HIV. The findings call for HBV and HCV testing in such patients, and where feasible, appropriate antiviral treatment be indicated, as chemotherapy or radiotherapy has been associated with reactivation of viral hepatitis and termination of cancer therapy.

Spatial epidemiology of hepatitis C virus infection in Egypt: Analyses and implications

Egypt has the highest hepatitis C virus (HCV) prevalence in the world (14.7%). The drivers of the HCV epidemic in Egypt are not well understood, but the mass parenteral antischistosomal therapy (PAT) campaigns in the second half of the 20th century are believed to be the determinant of the high prevalence. We studied HCV exposure in Egypt at a microscale through spatial mapping and epidemiological description of HCV clustering. The source of data was the 2008 Egypt Demographic and Health Survey. We identified clusters with high and low HCV prevalence and high and low PAT exposure using Kulldorff spatial scan statistics. Correlations across clusters were estimated, and each cluster age-specific HCV prevalence was described. We identified six clusters of high HCV prevalence, three clusters of low HCV prevalence, five clusters of high PAT exposure, and four clusters of low PAT exposure. HCV prevalence and PAT exposure were not significantly associated across clusters (Pearson correlation coefficient [PCC] = 0.36; 95% confidence interval [CI] −0.12 to 0.71). Meanwhile, there was a strong association between HCV prevalence in individuals older than 30 years of age (who could have been exposed to PAT) and HCV prevalence in individuals 30 years of age or younger (who could not have been exposed to PAT) (PCC = 0.81; 95% CI 0.55-0.93). Conclusion: The findings illustrate a spatial variation in HCV exposure in Egypt. The observed clustering was suggestive of an array of iatrogenic risk factors, besides past PAT exposure, and ongoing transmission. The role of PAT exposure in the HCV epidemic could have been overstated. Our findings support the rationale for spatially prioritized interventions. (Hepatology 2014;60:1150–1159)

Assessing the feasibility of hepatitis C virus vaccine trials: Results from the Hepatitis C Incidence and Transmission Study-community (HITS-c) vaccine preparedness study

Efficacy trials of preventive hepatitis C virus (HCV) vaccine candidates raise challenging scientific and ethical issues. Based on data from the first 3years of a community-based prospective observational study – the Hepatitis C Incidence and Transmission Study-community (HITS-c) – this paper examines the feasibility of conducting trials of candidate HCV vaccines with people who inject drugs (PWID) in Sydney, Australia. Of the 166 PWID confirmed HCV antibody negative and eligible for enrolment, 156 (94%) completed baseline procedures. Retention was high, with 89% of participants retained at 48weeks and 76% of participants completing at least 75% of study visits within 2weeks of schedule. The rate of primary HCV infection was 7.9/100py (95% CI 4.9, 12.7). Of the 17 incident cases, 16 completed at least one follow-up assessment and 12 (75%) had evidence of chronic viraemia with progression to chronic HCV infection estimated to be 6/100py. Power calculations suggest a chronic HCV infection rate of at least 12/100py (primary HCV infection rate 16/100py) will be required for stand-alone trials of highly efficacious candidates designed to prevent chronic infection. However, elevated primary HCV infection was observed among participants not receiving opioid substitution therapy who reported heroin as the main drug injected (26.9/100py, 95% CI 14.5, 50.0) and those who reported unstable housing (23.5/100py, 95% CI 7.6, 72.8), daily or more frequent injecting (22.7/100py, 95% CI 12.2, 42.2) and receptive syringe sharing (23.6/100py, 95% CI 9.8, 56.7) in the 6months prior to baseline. These data suggest that it is possible to recruit and retain at-risk PWID who adhere to study protocols and that modification of eligibility criteria may identify populations with sufficiently high HCV incidence. Results support the feasibility of large multi-centre HCV vaccine trials, including in the Australian setting.

Factors associated with sustained virological response in 24‐week telaprevir‐based triple therapy for chronic hepatitis C genotype 1b patients with the IL28B minor genotype

Single nucleotide polymorphisms (SNP) near the interleukin-28B (IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus (HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. Pretreatment and on-treatment factors associated with sustained virological response (SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non-TT). Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response (P = 0.0041), high fasting serum low-density lipoprotein cholesterol (LDL-C) concentration (P = 0.0068) and low serum HCV RNA levels (P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response (RVR) were significantly and independently associated with SVR (P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response (P = 0.0018), low pretreatment serum fasting LDL-C (P = 0.0062) and achieving RVR (P = 0.0021) were significantly and independently associated with SVR. In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL-C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy.

Occult Hepatitis C Virus Infection in Haemodialysis Unit : A Single-Center Experience

Background & Aims: Detection of hepatitis C virus RNA in peripheral blood mononuclear cells (PBMC) and/or hepatocytes in the absence of HCV RNA in serum, designated as ‘occult HCV infection’, has been a matter of controversy in the recent years. Occult hepatitis C virus (HCV) infection has not been investigated in haemodialysis patients. We investigated for the first time the prevalence of occult HCV infection in large cohorts of chronic hemodialysis (CHD) patients in a single heamodialysis center at Al-Taif, KSA. Methods: We enrolled 84 CHD patients, whose sera are negative for HCV markers. HCV RNA was tested in PBMC using a sensitive commercial real time assay. In this study, real-time PCR was used to test for the presence of genomic HCV-RNA in peripheral blood mononuclear cells of all of these patients. For comparison, 20 patients on HD with evidence of chronic hepatitis C virus infection were included as a control group. Results: In CHD patients, occult HCV infection, determined by the presence of genomic HCV-RNA in peripheral blood mononuclear cells (PBMNCs), was found in 13.4 % of the patients; 83 % of these patients had ongoing HCV replication, indicated by the presence of HCV-RNA. Patients with occult HCV infection had spent a significantly longer time on heamodialysis and had significantly higher mean alanine aminotransferase levels during the 3 months before study entry. Compared to CHCV patients, those with occult HCV have less elevated bilirubin, AST and ALT. Conclusions: The prevalence of occult HCV infection was moderate in our CHD patients, and it did not appear to be clinically relevant. Further studies in other geographic populations with high HCV endemicity are required to clarify the significance of occult HCV infection in these patient groups. Abbreviations HCV, Hepatitis C Virus ; antibody against HCV; PBMC, peripheral blood mononuclear cells; rRT-PCR, real time reverse transcriptase polymerase chain reaction; CHD, chronic hemodialysis.

Hepatitis C virus NS3 mutations in haemophiliacs

Haemophiliacs have high hepatitis C virus (HCV) exposure risk from blood products that did not undergo heat inactivation or disease-specific screening prior to 1987. Repeated exposure to infected factor concentrates predisposes haemophiliacs to higher likelihood of HCV from multiple sources. HIV coinfection could result in impaired clearance of less fit variants resulting in enrichment of quasispecies carrying resistance mutations. We postulated that haemophiliacs demonstrate increased prevalence of baseline signature mutations in the HCV NS3/4 serine protease coding domain. We examined the prevalence of putative HCV protease inhibitor mutations, mutations, subclassified into dominant mutations if changes conferred resistance, and minor variants not associated with drug resistance, in patients with haemophilia A or B, infected with HCV or HCV/HIV, prior to HCV PI exposure. A total of 151 subjects were evaluated, including 22 haemophiliacs and 129 non-haemophilic controls. Of the 58 mutations detected, 55 (95%) were resistance mutations and three (5%) were minor variants. Dominant mutations were detected in 10 (45.5%) haemophiliacs and in 43 (33.3%) controls (OR 1.67, 95% CI 0.67-4.16). There was no statistical difference in proportion of dominant mutations (P=0.27) or minor variants (P=0.47) between groups, despite adjustment for HIV status (P=0.44). No significant differences in dominant or minor resistance mutations between haemophiliacs and non-haemophiliacs were observed. HIV presence or prior HAART exposure did not affect baseline distribution. We conclude that haemophiliacs are not at higher risk for pre-existing HCV PI mutations, and prospective studies of response to PI-based regimens with HCV activity are indicated.

A preliminary assessment of the clinical utility of measuring hepatitis C virus antibody to evaluate infection status

To investigate the potential of hepatitis C virus (HCV) antibody measurement as a clinical approach to determine the infection status and potential for spontaneous-resolution among patients with HCV mono-infection and HCV/human immunodeficiency virus (HIV) co-infection. A total of 340 individuals who tested positive for serum anti-HCV antibodies and/or serum anti-HW antibodies were enrolled for study in 2009 from a single village in central China. Markers of liver function (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) and infection (anti-HCV antibodies, CD4⁺ T cell counts, HCV genotype, and HCV viral load) were measured at baseline and follow-up (in July 2012). At follow-up,the subjects were grouped according to ongoing HCV mono-infection (n=129), ongoing HCV/HIV co-infection (n=98), spontaneously resolved (SR)-HCV in mono-infection (n=65), and SR-HCV in HCV/HIV co-infection (n=48) for statistical analysis. Almost all of the subjects in the ongoing HCV mono-infection group showed high levels of HCV antibodies (S/CO more than or equal to 10), but the majority of the subjects in the SR-HCV in mono-infection group and in the ongoing HCV/HIV co-infection group. The SR-HCV mono-infection group showed a remarkable decrease in HCV antibodies from 2009 (HIV:7.75 ± 3.8; HIV+:7.61 ± 3.47) to 2012 (HIV:5.51 ± 3.67; HIW:4.93 ± 3.35) (HIV:t =10.67, P less than 0.01; HIV+:t =9.52, P less than 0.01). The ongoing HCV/HIV co-infection group showed a positive correlation between HCV antibodies S/CO ratio and CD4⁺ T cell count (r=028, P=0.008). In the ongoing HCV mono-infection group,the levels of HCV antibodies were significantly higher in individuals infected with HCV-1b than in those with HCV-2a (14.74 ± 1.68 vs.14.08 ± 1.44, t=2.20, P=0.03). In the ongoing HCV/HIV co-infection group, the numbers of subjects with elevated (more than 40 U/L) liver function markers were significantly different according to the HCV genotype infection:HCV-1b:ALT, 25/42 vs.16/56 (x²=9.45, P=0.002); HCV2a:AST, 28/42 vs.18/56 (x²=11.49, P=0.001). The HCV RNA positive rate was significantly higher in subjects with high HCV antibody cutoff values (S/CO more than or equal to 10) than in those with low HCV antibody (S/CO less than 10) (HIV:128/151 vs.1/43, x²=102.11, P less than 0.01; HIV+:88/98 vs.10/48, x²=69.44, P less than 0.01), regardless of HIV co-infection. Significantly more subjects in the ongoing HCV mono-infection group had elevated (more than 40 U/L) ALT or AST than the subjects in the SR-HCV mono-infection group with high levels of HCV antibody (S/CO more than or equal to 10) (ALT:57/128 vs.2/23, x²=10.52, P=0.001; AST:57/128 vs.0/23, x²=16.45, P less than 0.01). Serum HCV antibody levels, in combination with other clinical information such as liver function and HIV infection status, may aid in the preliminarily evaluation of an individual's HCV infection status and likelihood for spontaneous resolution. Low levels of HCV antibody (S/CO less than 10) may indicate a better chance of SR-HCV, after ruling out the possibility of suffering from immunosuppressive diseases such as HIV infection.

Disease progression during advanced fibrosis:IL28Bgenotype or HCV RNA levels?

We read with interest the article from Noureddin et al.1 demonstrating that interleukin-28B (IL28B) CC genotype was associated with greater hepatic inflammation, higher alanine aminotransferase (ALT), and worse clinical outcomes in patients with chronic hepatitis C virus (HCV) infection. However, we wonder whether the authors considered adjusting for HCV RNA levels? The hypothesis would be that the relationship between IL28B CC genotype and increased disease progression may be confounded by HCV RNA levels in those with the IL28B CC genotype. Individuals with the IL28B CC genotype have higher HCV RNA levels during acute2 and chronic3 infection. In the InC3 Study, a collaborative of nine prospective international cohorts of acute HCV infection,4 among those with untreated persistent HCV infection and HCV RNA levels 12 months following infection (n = 224), male gender (versus female, adjusted odds ratio [AOR] = 2.38; 95% confidence interval [CI] = 1.19-4.76; P = 0.02), IL28B CC genotype (versus TT/CT, AOR = 2.26; 95% CI = 1.21-4.20; P = 0.03), and HCV genotype 1 (versus genotype 3, AOR = 2.13; 95% CI = 1.03-4.55; P = 0.04) were independently associated with high HCV RNA levels at 12 months following infection. Although studies have suggested that HCV RNA levels are not associated with disease progression,5 HCV RNA may mediate liver disease progression by cumulative HCV RNA exposure (over the duration of infection) or by absolute HCV RNA levels (by way of immune responses and/or hepatic inflammation). It is possible that HCV RNA levels have greater clinical effect in later stages of liver disease. To better understand the independent effect of IL28B genotype on HCV natural history, the impact of HCV RNA levels should be considered as a potential confounder which may partially explain or contribute to the observed associations or lack thereof. This important work could shed light on whether increased HCV RNA levels or cumulative HCV RNA exposure among those with IL28B CC genotype has any impact on HCV natural history during advanced disease. We urge the authors to assess whether HCV RNA levels and duration of infection were associated with outcomes measured in their study and whether this varied by IL28B genotype. The InC3 Study is supported by the National Institute on Drug Abuse Award Number R01DA031056. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. JGr is supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship. GD is supported by an NHMRC Practitioner Research Fellowship. Jason Grebely, Ph.D.1 Bart Grady, M.D.2 Behzad Hajarizadeh, M.D.1 Kimberly Page, Ph.D.3 Gregory J. Dore, B.Sc., MBBS, MPH, Ph.D.1On Behalf of the InC3 Study Group 1The Kirby Institute The University of New South Wales Sydney, Australia 2GGD Public Health Service of Amsterdam Amsterdam, The Netherlands 3Department of Epidemiology and Biostatistics University of California, San Francisco San Francisco, CA, USA

Outcomes of hepatitis C screening programs targeted at risk groups hidden in the general population: a systematic review.

BackgroundEffective screening programs are urgently needed to provide undiagnosed hepatitis C virus (HCV)-infected individuals with therapy. This systematic review of characteristics and outcomes of screening programs for HCV focuses on strategies to identify HCV risk groups hidden in the general population.MethodsWe conducted a comprehensive search of MEDLINE and EMBASE databases for articles published between 1991–2010, including studies that screened the general population using either a newly developed (nonintegrated) screening program or one integrated in existing health care facilities. Look-back studies, prevalence studies, and programs targeting high-risk groups in care (e.g., current drug users) were excluded.ResultsAfter reviewing 7052 studies, we identified 67 screening programs: 24 nonintegrated; 41 programs integrated in a variety of health care facilities (e.g., general practitioner); and 2 programs with both integrated and nonintegrated strategies. Together, these programs identified approximately 25,700 HCV-infected individuals. In general, higher HCV prevalence was found in programs in countries with intermediate to high HCV prevalence, in psychiatric clinics, and in programs that used a prescreening selection based on HCV risk factors. Only 6 programs used a comparison group for evaluation purposes, and 1 program used theory about effective promotion for screening. Comparison of the programs and their effectiveness was hampered by lack of reported data on program characteristics, clinical follow-up, and type of diagnostic test.ConclusionsA prescreening selection based on risk factors can increase the efficiency of screening in low-prevalence populations, and we need programs with comparison groups to evaluate effectiveness. Also, program characteristics such as type of diagnostic test, screening uptake, and clinical outcomes should be reported systematically.