Detectable Serum Hepatitis C Virus RNA Research Articles

Hepatitis C Screening in Post–Baby Boomer Generation Americans: One Size Does Not Fit All

ObjectivesTo analyze the impact of access to routine health care, as estimated by health insurance coverage, on hepatitis C virus (HCV) infection prevalence in US adults born after 1965 (post–baby boomer birth cohort [post-BBBC]) and to use the data to formulate strategies to optimize population screening for HCV. Patients and MethodsAdult examinees in the National Health and Nutrition Examination Survey with available anti-HCV data were divided into era 1 (1999-2008) and era 2 (2009-2016). The prevalence of HCV infection, as defined by detectable serum HCV RNA, was determined in post-BBBC adults. In low prevalence groups, prescreening modalities were considered to increase the pretest probability. ResultsOf 16,966 eligible post-BBBC examinees, 0.5% had HCV infection. In both eras, more than 50% had no insurance. In era 2, HCV prevalence was 0.26% and 0.83% in those with and without insurance, respectively (P<.01). As a prescreening test, low alanine aminotransferase level (<23 U/L in women and 32 U/L in men) would identify 54% of post-BBBC adults with an extremely low (0.02%) HCV prevalence. Based on these data, a tiered approach that tests all uninsured directly for HCV and prescreens the insured with alanine aminotransferase would reduce the number to test by 56.5 million while missing less than 1% infections. ConclusionFor HCV elimination, passive “universal” screening in routine health care settings is insufficient, although the efficiency of screening may be improved with alanine aminotransferase prescreening. Importantly, for individuals with limited access to health care, proactive outreach programs for HCV screening are still needed.

Real-world cure rates for hepatitis C virus treatments that include simeprevir and/or sofosbuvir are comparable to clinical trial results.

AIMTo assess the real-world effectiveness and cost of simeprevir (SMV), and/or sofosbuvir (SOF)-based therapy for chronic hepatitis C virus (HCV) infection.METHODSThe real-world performance of patients treated with SMV/SOF ± ribavirin (RBV), SOF/RBV, and SOF/RBV with pegylated-interferon (PEG) were analyzed in a consecutive series of 508 patients with chronic HCV infection treated at a single academic medical center. Patients with genotypes 1 through 4 were included. Rates of sustained virological response - the absence of a detectable serum HCV RNA 12 wk after the end of treatment [sustained virological response (SVR) 12] - were calculated on an intention-to-treat basis. Costs were calculated from the payer’s perspective using Medicare/Medicaid fees and Redbook Wholesale Acquisition Costs. Patient-related factors associated with SVR12 were identified using multivariable logistic regression.RESULTSSVR12 rates were as follows: 86% (95%CI: 80%-91%) among 178 patients on SMV/SOF ± RBV; 62% (95%CI: 55%-68%) among 234 patients on SOF/RBV; and 78% (95%CI: 68%-86%) among 96 patients on SOF/PEG/RBV. Mean costs-per-SVR12 were $174442 (standard deviation: ± $18588) for SMV/SOF ± RBV; $223003 (± $77946) for SOF/RBV; and $126496 (± $31052) for SOF/PEG/RBV. Among patients on SMV/SOF ± RBV, SVR12 was less likely in patients previously treated with a protease inhibitor [odds ratio (OR): 0.20, 95%CI: 0.06-0.56]. Higher bilirubin (OR: 0.47, 95%CI: 0.30-0.69) reduced the likelihood of SVR12 among patients on SOF/RBV, while FIB-4 score ≥ 3.25 reduced the likelihood of SVR12 (OR: 0.18, 95%CI: 0.05-0.59) among those on SOF/PEG/RBV.CONCLUSIONSVR12 rates for SMV and/or SOF-based regimens in a diverse real-world population are comparable to those in clinical trials. Treatment failure accounts for 27% of costs.

Occurrence of late relapse of hepatitis C virus confirmed by molecular analysis after sustained virologic response to interferon-ribavirin-based therapy.

The optimal duration of follow-up for patients who achieve sustained virologic responses (SVR) has become an important issue. Reports on long-term follow-up of SVR have indicated that 99% of patients maintained SVR. However, the limitations of a majority of studies include small patient numbers, short study periods, and lack of molecular analysis of hepatitis C virus (HCV) genome. The present study sought to evaluate the late relapse rate in long-term follow-up of patients who achieved SVR, with molecular analysis of HCV. A total of 224 patients with chronic hepatitis C who were treated by interferon and ribavirin-based therapy and achieved SVR were enrolled. All patients were recommended for follow-up every 6 or 12months. The mean follow-up period was 6.0years (range, 1.0-13.6years). Cumulative 5- and 10-year follow-up rates of the patients after SVR were 87.8% and 78.8%, respectively. Cumulative 5- and 10-year follow-up rates of serum HCV RNA after SVR were 85.5% and 52.6%, respectively. Two patients had detectable serum HCV RNA at 20 and 30months, respectively, after SVR. Phylogenetic analyses of core, non-structural protein 3, and 5A regions of HCV strains from late relapse patients confirmed the same strain was present at baseline and late relapse. Two of 224 patients developed late relapse of HCV by the original strain, which was confirmed by direct sequencing analysis. Although few patients may develop late relapse, SVR achieved with interferon and ribavirin-based therapy is durable for prolonged periods.

The impact of chronic hepatitis C virus infection on survival in oropharyngeal cancer patients.

e17556 Background: An association between Hepatitis C virus (HCV) infection and oropharyngeal cancers (OPCs) has been reported; however, the clinical significance of this epidemiological finding remains unknown. We therefore analyzed the oncologic outcomes of HCV-infected patients (pts) with OPCs. Methods: In this retrospective cohort study, all pts with OPCs seen at MD Anderson (1/2004-12/2015) were reviewed. HCV infection was defined as detectable HCV RNA in serum. Risk of 5-year (yr) overall survival (OS) and progression-free survival (PFS) was compared between HCV-infected (HCV+) and uninfected (HCV-) pts. OPCs that were positive for p16 by immunohistochemistry were considered HPV-related. Antiviral therapy (AVT) included either interferon (IFN)-based or IFN-free regimens. Multivariate cox proportional hazards model was used to identify independent predictors of mortality. Results: We studied 161 pts. Most of the pts were white (141; 88%), male (132; 82%) and had tumor stage 3 or 4 (147; 92%). The OPC involved tonsils (83; 52%), base of tongue (67; 42%) or soft palate (11; 7%). The median follow-up time after OPC diagnosis was 3 yrs (range: 1-13 yrs). HCV+ (n = 25) and HCV- pts (n = 136) were comparable in regards to smoking and alcohol status. In univariate analysis, HCV+ pts had more OPC progression after 1stline cancer treatment (48% vs 20.6% in HCV-, P = .0009) and were more likely to relapse (26% vs 5% in HCV-, P = .02). In multivariate analysis, HCV was associated with increased all-cause mortality [hazard ratio (HR): 2.15, 95% confidence intervals (CI): 1.08-6.85; P = .02] and risk of OPC progression [HR: 5.42, 95% CI: 2.64-11.14; P = .0008] independent of age and cirrhosis status. In HPV+ OPCs (n = 86), HCV + and HCV- pts did not have significant difference in mortality [HR: 2.03, 95% CI: 0.82-4.98; P = .12]. AVT was administered after OPC diagnosis in 8 of the 25 HCV+ pts (32%), with 6 of them receiving IFN-free AVT. HCV+ pts that received AVT had better 5 yr OS (median of 5.2 vs 2.3 yrs, P = .005) and PFS (median of 3.1 vs 0.7 yrs, P = .007) than the ones who did not. Conclusions: HCV seems to affect the oncologic outcomes of pts with OPCs and treating this infection might be beneficial. HCV screening and treatment should be considered in such pts.

Assessment of Hepatitis C Virus RNA in Peripheral Blood Mononuclear Cells as a Predictor of Response to Pegylated-Interferon and Ribavirin: A Cohort Study

Background: Sustained virologic response (SVR) to pegylated-interferon (PegIFN) and ribavirin (RBV) in hepatitis C virus (HCV)-infected patients could be predicted by detection of serum HCV RNA whereas detection of HCV RNA in other reservoirs such as peripheral blood mononuclear cells (PBMCs) for prediction of treatment response is still a mystery. Objectives: This study aimed at assessing the prediction of SVR by detection of HCV RNA in PBMCs or serum in patients during treatment. Methods: In a cohort study (2011 to 2014), 100 chronic HCV patients at Tehran Hepatitis Center were treated with PegIFN and RBV. Serum HCV RNA level was measured at baseline, 4, 12, and 24 weeks during treatment and at 24 weeks after termination of treatment. Meanwhile, HCV RNA was evaluated in PBMCs at weeks 4, 12, and 24 during the treatment. Results: Out of 100 patients treated in this study, 91 completed the course of treatment. Most patients were young males infected with HCV genotype 1. Cirrhosis and previous history of treatment was found in 16.5% and 26.5% of patients. Sustained virologic response was achieved in 65 (71.4%) patients. Among baseline parameters, only female gender was significantly associated with SVR. Undetectable serum HCV RNA at week 4 (OR = 4.74) and week 12 (OR = 11.63) of treatment predicted SVR rate while the same was not true for detection of serum HCV RNA at week 24 of treatment. Moreover, detection of HCV RNA in PBMCs at weeks 4 and 12 of treatment was not associated with the rate of SVR, while absence of HCV RNA in PBMCs at week 24 of treatment was associated with SVR (OR = 4.55). Conclusions: Detection of HCV RNA in PBMCs, especially at week 24 of treatment with PegIFN and RBV, could be considered as an additional marker for prediction of treatment response. It is recommended to assess HCV on-treatment kinetic in PBMCs of patients treated with direct-acting antiviral agents for prediction of treatment response.

Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis

Circulating mixed cryoglobulins are detected in 40%-60% of patients with hepatitis C virus (HCV) infection, and overt cryoglobulinemia vasculitis (CryoVas) develops in approximately 15% of patients. Remission of vasculitis has been associated with viral clearance, but few studies have reported the effectiveness of direct-acting antiviral drugs in these patients. We performed an open-label, prospective, multicenter study of the effectiveness and tolerance of an all-oral, interferon- and ribavirin-free regimen of sofosbuvir plus daclatasvir in patients with HCV-associated CryoVas. Forty-one consecutive patients with active HCV-associated CryoVas (median age, 56 y; 53.6% women) were recruited from hospitals in Paris, France, from 2014 through 2016. They received sofosbuvir (400 mg/day) plus daclatasvir (60 mg/day) for 12 weeks (n= 32) or 24 weeks (n= 9), and were evaluated every 4 weeks until week 24 and at week 36. Blood samples were analyzed for complete blood count, serum chemistry profile, level of alanine aminotransferase, rheumatoid factor activity, C4 fraction of complement, and cryoglobulin; peripheral blood mononuclear cells were isolated for flow cytometry analysis. Thirty-seven patients (90.2%) had a complete clinical response (defined by improvement of all the affected organs involved at baseline and no clinical relapse) after a median time of 12 weeks of therapy; all had a sustained virologic response (no detectable serum HCV RNA 12 weeks after the end of antiviral therapy). Patients' mean cryoglobulin level decreased from 0.56 ± 0.18 at baseline to 0.21 ± 0.14 g/L at week 36, and no cryoglobulin was detected in 50% of patients at this time point. After antiviral therapy, patients had increased numbers of T-regulatory cells, IgM+CD21-/low-memory B cells, CD4+CXCR5+ interleukin 21+ cells, and T-helper 17 cells, compared with before therapy. After a median follow-up period of 26 months (interquartile range, 20-30 mo), no patients had a serious adverse event or relapse of vasculitis.

Increasing prevalence of cirrhosis among U.S. adults aware or unaware of their chronic hepatitis C virus infection

Cirrhosis from hepatitis C virus (HCV) infection is a major cause of end-stage liver disease and hepatocellular carcinoma worldwide. We determine the prevalence of cirrhosis among HCV-infected American adults including those unaware of their infection. Using the National Health and Nutrition Examination Survey (NHANES) data, we identified participants aged ⩾20 years with detectable serum HCV RNA. The prevalence of advanced fibrosis and cirrhosis was determined for eras 1 (1988-94), 2 (1999-2006) and 3 (2007-2012) by using FIB-4 >3.25 and APRI >2.0, respectively. Out of 52,644 NHANES examinees, 49,429 were tested for HCV, of whom 725 met the inclusion criteria (positive HCV RNA with available data for FIB-4 and APRI). Based on APRI, 6.6% (95% confidence interval [CI]: 2.2-11.0) of HCV-infected adults in era 1, 7.6% (95% CI: 3.4-11.8) in era 2 and 17.0% (95% CI: 8.0-26.0) in era 3 had cirrhosis. In the multivariable regression analysis, this era effect was attributable to increasing age (odds ratio [OR]:1.04, 95% CI: 1.02-1.07), diabetes (OR: 2.33, 95% CI: 1.01-5.40) and obesity (OR: 2.96, 95% CI: 1.15-7.57). Cirrhosis was as common among respondents who were unaware of their infection as those who were aware (both 11%). Results were identical when FIB-4 was used. Among HCV-infected American adults, the proportion with cirrhosis has increased rapidly. Cirrhosis prevalence remains high in individuals unaware of their HCV infection. These data highlight the urgency for HCV screening regardless of symptoms, systematic assessment for liver fibrosis in those with HCV infection and institution of antivirals to prevent advanced liver disease. Chronic hepatitis C virus (HCV) infection is a major cause of cirrhosis, creating a large public health burden. Based on the U.S. National Health and Nutrition Examination Survey sample, we found the proportion of patients with cirrhosis among Americans with HCV infection increased from 6.6% to 17.0% over the past two decades. Patients who were unaware of their infection were just as likely to have cirrhosis as those who knew about their infection, which highlights the need for screening and treatment for HCV at the population level.

News and challenges in the treatment of hepatitis C in liver transplantation.

Hepatitis C virus (HCV) infection is one of the main causes of end-stage liver disease and indications for liver transplantation (LT) worldwide. HCV infection always recurs on the graft in patients who undergo LT with detectable serum HCV RNA, leading to cirrhosis in 20-30% within 5 years after transplantation. Achieving a sustained virological response (SVR) greatly improves patient and graft survival. Recently, the efficacy of therapy has radically changed and improved based on new direct acting antiviral agents (DAAs) without pegylated-interferon (PEG-IFN) and/or ribavirin (RBV), leading to SVR rates of more than 90% in transplanted patients. The safety profile in this population is also good, with limited drug-drug interactions. However, there are very few data on patients on the waiting list. Even when the results of combined DAAs are good (>80%), SVR rates are lower than in patients without cirrhosis. This review reports recent available data on the treatment of HCV infection in the transplant setting and discusses new dilemmas and challenges.

Interferon-Free Hepatitis C Treatment before and after Liver Transplantation: The Role of HCV Drug Resistance.

Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR) greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN) and ribavirin (RBV) was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs), boceprevir (BOC) or telaprevir (TVR), associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI) are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA) agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients.

New modalities in the treatment of HCV in pre and post - transplantation setting.

End-stage liver disease and hepatocellular carcinoma (HCC) secondary to hepatitis C virus (HCV) infection are the leading indications for liver transplantation (LT) in developed countries. Recurrence of HCV following LT is universal if the recipient has detectable serum HCV RNA at the time of LT. Recurrent HCV has an accelerated course and is associated with poor long term patient and graft survival. Interferon (IFN)-based regimens have achieved low Sustained Virological Rates (SVR) in this setting and are associated with a high rate of adverse events, resulting in treatment discontinuation. With advances in understanding the HCV life cycle, drugs targeting specific steps, particularly inhibiting the NS3/4A protease, NS5B RNA dependent RNA polymerase and the NS5A protein, have been developed. Sofosbuvir (SOF), a nucleotide analogue inhibitor of NS5B polymerase was the first compound to enter the market. Combinations of SOF with new HCV antivirals from other classes have allowed for IFN-free regimens with low rates of adverse events and SVR rates >90%. With the availability of newer agents, the approach to the treatment of HCV infection during the pre-and post-liver transplantation period has changed. We will hereby review the current status of HCV treatment and discuss the potential future therapies in the transplant setting.

Management of post transplant hepatitis C in the direct antiviral agents era.

Hepatitis C virus (HCV) infection is one of the main indications for liver transplantation. Viral recurrence occurs in all patients with detectable serum HCV RNA at the time of transplantation leading to cirrhosis in 20-30% of patients within 5 years. Viral eradication using antiviral therapy has been shown to improve patient and graft survival. Pegylated interferon (PEG-IFN) and ribavirin (RBV) antiviral therapy achieved SVR in around 30% of transplant recipients. In the non-transplant setting, first generation NS3/4 protease inhibitors, boceprevir or telaprevir associated with PEG-IFN and RBV, has improved the SVR rates to 75% in genotype 1 infected patients. However, tolerability and drug-drug interactions with calcineurin inhibitors are both limiting factors of their use in transplant recipients. In the non-transplant patients, using new direct-acting antiviral therapy has dramatically improved the efficacy of antiviral C therapy over recent years leading to SVR rates over 90% in phase II and III clinical trials, without PEG-IFN and/or RBV. Preliminary results in transplant patients showed better efficacy, better tolerability and less drug-drug interactions.

Management of HCV transplant patients with triple therapy

Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection. Between 20 and 30% of patients have developed cirrhosis at 5years post-LT. The outcome of transplant patients with cirrhosis on the graft is severe, with a rate of decompensation at 1year of approximately 40%. To date, retransplantation is the only option in patients with decompensated liver disease. Until 2011, standard antiviral therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV), was the only effective therapy. Obtaining a sustained virological response (SVR) in patients with LT greatly improves overall and graft survival but this only occurs in 30% of transplanted patients. Direct acting antivirals (DAAs) such as protease inhibitors (PI), polymerase or other non-structural proteins inhibitors represent a new era in HCV associated liver disease. Although their use in the field of LT will certainly be essential there are some limitations because of safety and tolerance. One limitation is the potential interaction with calcineurin inhibitors. We describe the results of triple therapy with boceprevir (BOC) or telaprevir (TVR) for efficacy and safety and comment on future therapeutic strategies in liver transplant recipients.

Sequence Analysis of Hepatitis C Virus From Patients With Relapse After a Sustained Virological Response: Relapse or Reinfection?

A sustained virological response (SVR) is the major end point of therapy for chronic hepatitis C virus (HCV) infection. Late relapse of infection is rare and poorly characterized. Three of 103 patients with a SVR treated at the National Institutes of Health had late relapse. We evaluated HCV RNA sequences in serum and liver tissue to distinguish relapse from reinfection. Per patient, 10-22 clones of amplified 5' untranslated region were evaluated in pretreatment and relapse serum specimens and in liver biopsy specimens obtained during SVR. Genotypes and sequence diversity were evaluated. Four patients whose infection relapsed before they reached a SVR (ie, the early relapse group) were used as a comparison. Results of tests for detection of serum HCV RNA in all patients with late relapse were repeatedly negative during the first 24 weeks after therapy but became positive 8, 75, and 78 months after SVR. Reinfection risk factors were absent in 2 of 3 patients. In all patients with early or late relapse, apart from minor variations, the original HCV sequence was present before treatment and after relapse. All liver biopsy specimens from patients with late relapse were HCV RNA positive at SVR, with sequences nearly identical to those of specimens obtained at other time points. Sequence comparisons suggest that reappearance of HCV RNA years after a SVR can be from relapse of the initial viral infection rather than reinfection from a different virus.

Current management and perspectives for HCV recurrence after liver transplantation

Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection. Between 20 and 30% of patients develop cirrhosis within 5 years post-LT. The outcome of transplant patients with cirrhosis on the graft is severe, with a rate of decompensation at 1 year of around 40%. To date, retransplantation is the only option for patients who develop decompensation. Until 2011, standard antiviral therapy, using pegylated interferon (PEG-IFN) and ribavirin (RBV), was the only effective therapy. Obtaining a sustained virological response (SVR) in the setting of LT greatly improves overall and graft survival, but this only concerns 30% of transplanted patients. Direct-acting antivirals (DAA) such as protease inhibitors, polymerase or other non-structural proteins inhibitors represent a new era in HCV-associated liver disease. Although their use in the field of liver transplantation seems to be essential, there are some limitations due to safety and tolerance. One limitation is the potential interaction with calcineurin inhibitors. We describe the preliminary results of triple therapy with boceprevir or telaprevir in terms of efficacy and safety in liver transplant recipients.

Hepatic steatosis and steatohepatitis in human immunodeficiency virus/hepatitis C virus–coinfected patients

Hepatic steatosis (HS) is frequent in human immunodeficiency virus (HIV)- and hepatitis C virus (HCV)-coinfected patients. Antiretroviral therapy (ART) and metabolic alterations could induce HS. However, a protective effect of ART has been reported in a paired biopsy study. Thus, our aim was to examine the changes and predictors of HS progression among HIV/HCV-coinfected patients with sequential biopsies. We also evaluated the rates of steatohepatitis and factors associated thereof. HIV-infected patients with detectable serum HCV RNA, who underwent two biopsies, separated at least by 1 year, were included in this retrospective study. HS progression was defined as increase in one or more HS grades. The median (interquartile range) time between biopsies was 3.3 (2.0-5.2) years. Among 146 individuals, HS at baseline was observed in 86 (60%) patients and in 113 (77%) in the follow-up biopsy (P < 0.001). Progression of HS was observed in 60 (40%) patients. HS regressed in 11 (8%) patients. Factors associated with HS progression were changes in fasting plasma glucose (FPG) between biopsies (per 10 mg/dL increase; odds ratio [OR] [95% confidence interval; CI] = 1.4 [1.04-1.8]; P = 0.024) and cumulative use of dideoxynucleoside analogs (per year; OR [95% CI] = 1.5 [1.2-1.8]; P = 0.001). Persistent steatohepatitis or progression to steatohepatitis between biopsies was observed in 27 (18%) patients. Persistence of or progression to steatohepatitis was associated with progression ≥ 1 fibrosis stages between biopsies (OR [95% CI] = 2.4 [1.01-5.7]; P = 0.047). HS progresses frequently and regression is rarely observed in HIV/HCV-coinfected patients, including in those on ART. Cumulative exposure to dideoxynucleoside analogs and increases in FPG are related with HS progression. Stetatohepatitis is frequently observed in these patients and is linked to fibrosis progression.

Long-term health outcomes of chronic hepatitis C patients: A review of findings from REVEAL-HCV cohort study

Chronic hepatitis C affects more than 180 million people worldwide. As one of the most important infectious diseases, it causes around 250,000 deaths per year. A long-term follow-up cohort study is essential for evaluating health outcomes associated with virus infection, and for exploring potential seromarkers that have high predictability for risk of developing various diseases. However, the prospective cohorts consisted of individuals with chronic hepatitis C virus (HCV) infection are still rare. The Risk Elevation of Viral Load Elevation and Associated Liver Disease/Cancer in HCV (REVEAL-HCV) study has followed a cohort of 1095 residents seropositive for anti-HCV antibodies lived in seven townships in Taiwan for 15 years. These anti-HCV seropositives were asymptomatic and relatively more healthy than chronic hepatitis C patients cared in clinics and hospitals. Most of them acquired HCV infection through iatrogenic transmission routes in study townships. The epidemiological characteristics of HCV infection were very similar to those in countries with high prevalence such as Japan, Korea, Italy, and India. As the participants in the REVEAL-HCV study rarely received antiviral therapies, it provided an exceptional opportunity to study the natural history of chronic HCV infection. In this review article, we describe the details of participant enrollment, laboratory tests, follow-up procedures, and major recent findings. Anti-HCV seropositives with elevated serum HCV RNA levels were found to have an increasing risk of developing hepatocellular carcinoma in a dose-response relationship. In addition to the serum HCV RNA level, serum alanine aminotransferase levels and HCV genotype also had long-term predictability for the risk of hepatocellular carcinoma. Moreover, anti-HCV seropositives with detectable serum HCV RNA levels had an increased mortality from extrahepatic diseases such as cerebrovascular and renal diseases. Our study revealed that anti-HCV seropositives with detectable serum HCV RNA levels had an increased risk of hepatic and extrahepatic diseases.

Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic Diseases: A Community-Based Long-Term Prospective Study

The study aimed to evaluate the risk of hepatitis C virus (HCV) infection on hepatic and extrahepatic deaths. A cohort of 23 820 adults aged 30-65 years old were enrolled during 1991-1992. The seromarkers hepatitis B surface antigen (HBsAg), anti-HCV, and serum HCV RNA levels at study entry were tested. The vital status was ascertained through computerized linkage with national death certification profiles from 1991 to 2008. There were 19,636 HBsAg-seronegatives, including 18,541 anti-HCV seronegatives and 1095 anti-HCV seropositives. Among anti-HCV seropositives, 69.4% had detectable serum HCV RNA levels. There were 2394 deaths that occurred during an average follow-up period of 16.2 years. Compared with anti-HCV seronegatives, anti-HCV seropositives had higher mortality from both hepatic and extrahepatic diseases, showing multivariate-adjusted hazard ratio (95% confidence interval) of 1.89 (1.66-2.15) for all causes of death; 12.48 (9.34-16.66) for hepatic diseases; 1.35 (1.15-1.57) for extrahepatic diseases; 1.50 (1.10-2.03) for circulatory diseases; 2.77 (1.49-5.15) for nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38-12.08) for esophageal cancer; 4.19 (1.18-14.94) for prostate cancer; and 8.22 (1.36-49.66) for thyroid cancer. Anti-HCV seropositives with detectable HCV RNA levels had significantly higher mortality from hepatic and extrahepatic diseases than anti-HCV seropositives with undetectable HCV RNA. Monitoring HCV RNA in anti-HCV seropositives is essential for the prediction of mortality associated with hepatitis C.

Interleukin-28and hepatitis C virus genotype-4: Treatment-induced clearance and liver fibrosis

To investigate the association between interleukin-28B (IL28B) genotype and response to treatment and hepatic fibrosis in patients with hepatitis C virus (HCV) genotype 4. Two hundred and one HCV-genotype 4 patients were included. All patients were treated with Peginterferon alph2a/Ribavirin for 48 wk. End of treatment response (ETR) was defined as loss of detectable serum HCV RNA at the end of treatment. Sustained viral response (SVR) was defined as loss of detectable serum HCV RNA at the end of 24 wk follow up. Genotyping of IL28B rs12979860 was performed using the TaqMan assay. We used logistic regression to estimate the adjusted odds ratio (aOR) and 95%CI. The study included 201 HCV-genotype 4 patients. The majority of patients were men (89.6%), with a median age of 47 years, inter-quartile range (40-51). Approximately 62.5% of patients had ETR, and 49.6% had SVR. Individuals who achieved SVR were more likely to be younger (χ(2) = 4.91, P = 0.027), and less likely to have fibrosis (χ(2) = 15.54, P < 0.0001), or inflammation (χ(2) = 7.58, P = 0.006). The genotype distribution of rs12979860 was 36.2%, 49.0% and 14.8% for genotypes CC, CT, and TT, respectively. In these participants, rs12979860 genotype distribution did not differ by gender (P = 0.466), pretreatment viral load (P = 0.600), inflammation (P = 0.435), or fibrosis (P = 0.291). The frequencies of IL28B rs12979860 genotypes were TT (14.8%), CT (49.0%), and CC (36.2%). Compared to rs12979860 genotype TT, aORs (95%CI) for ETR and SVR were: CC genotype, [17.55 (5.34-57.69) and 5.92 (2.09-16.76), respectively]; CT genotype, [5.15 (1.80-14.78) and 2.48 (0.94-6.52), respectively]. In the current study, the patients who did not achieve ETR or SVR had a lower prevalence of rs12979860 CC (17.4% and 23.3%, respectively) than individuals who had ETR or SVR (47.9% and 47.2%, respectively). Individuals with rs12979860 CC genotype had approximately 6 times the odds of SVR compared to individuals with TT genotype (aOR = 5.92; 95%CI: 2.09-16.76). Similarly, patients with CT genotype had SVR more often than patients with TT genotype (aOR = 2.48; 95%CI: 0.94-6.52). Carrying at least one copy of the C allele (genotypes CT and CC) had almost 8 times the probability of ETR compared to those with genotype rs12979860 TT (aOR = 7.87; 95%CI: 2.84-21.82), and approximately 3 times the odds of SVR compared to those with genotype rs12979860 TT (aOR = 3.46; 95%CI: 1.37-8.74). In addition, data were consistent with a significant gene-dose relationship (aOR = 4.05/allele; 95%CI: 2.27-7.22). The association between rs12979860 genotype and SVR was similar among those who achieved and those who did not achieve SVR. In HCV-genotype 4 patients, rs12979860 is a sensitive predictor of viral clearance, independent of viral load, age, gender or fibrosis, with no similar relation to severity of fibrosis.

The efficacy of extended treatment with pegylated interferon plus ribavirin in patients with HCV genotype 1 and slow virologic response in Japan

Which patients with hepatitis C virus (HCV) genotype 1 can benefit from extended treatment with pegylated interferon (Peg-IFN) plus ribavirin is unknown, although the overall sustained virologic response (SVR) rate has been shown to improve in patients with a late virologic response (LVR), defined as detectable serum HCV RNA at week 12 and undetectable at week 24. Among 1163 chronic hepatitis C patients with genotype 1 treated with Peg-IFN plus ribavirin combination therapy, 213 patients with an LVR were examined in this study. In addition, we selected 81 patients of matched sex and age from each of the 48- and 72-week treatment groups, using the propensity score, to compare the efficacy of the two treatment durations. With 72-week treatment, the timing of HCV RNA disappearance and the hemoglobin level at baseline showed a strong correlation with the SVR on multivariate analysis. Earlier HCV RNA disappearance was associated with a better SVR rate, regardless of the ribavirin dose (HCV RNA disappearance at week 16, 74%; at week 20, 52%; and at week 24, 31%, p=0.01). The SVR rate with 72-week treatment was higher than that with 48-week treatment, irrespective of age, sex, or the platelet value, and, especially in aged patients (≥65years old), the SVR rate increased markedly with 72-week treatment (48weeks, 25% vs. 72weeks, 56%; p<0.05). An earlier response predicts a higher SVR rate in patients with an LVR given 72-week treatment. Extended treatment with Peg-IFN plus ribavirin for patients with an LVR improved the treatment efficacy, even for aged patients.

Hepatitis C virus RNA detection in serum and peripheral blood mononuclear cells of patients with hepatitis C.

To investigate the existence and clinical significance of hepatitis C virus (HCV) RNA in the serum and peripheral blood mononuclear cells (PBMC) of patients with hepatitis C. HCV RNA was detected by nested polymerase chain reaction (Nested PCR) in serum and in PBMC of 46 patients with acute hepatitis C (AHC) and in 42 patients with chronic hepatitis C (CHC). The positive rate of HCV RNA in PBMC of patients with CHC was markedly higher than that of patients with AHC (P < 0.01). The positive rates of HCV RNA in serum of patients with AHC and CHC and in PBMC of patients with CHC were significantly higher than those of anti-HCV positive patients with normal alanine aminotransferase (ALT) levels (P < 0.01). HCV RNA was negative in the serum of two patients, but could be detected in PBMC. In 12 patients, anti HCV was negative while HCV RNA was positive in serum. (1) detection of serum HCV RNA by nested PCR might be helpful in the early diagnosis of anti-HCV negative hepatitis C; (2) liver damage in patients with hepatitis C might be correlated with HCV-viremia; (3) infection of PBMC by HCV might play an important role in chronic liver damage in patients with HCV and in the chronicity of its clinical course; and (4) PBMC might be considered as a "reservoir" for HCV.