HCV Clearance Research Articles

Impaired Toll-Like Receptor 3-Mediated Immune Responses from Macrophages of Patients Chronically Infected with Hepatitis C Virus

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with the majority of patients becoming chronically infected and a subset (20%) progressing to cirrhosis and hepatocellular carcinoma. Individual variations in immune responses may help define successful resistance to infection with HCV. We have compared the immune response in primary macrophages from patients who have spontaneously cleared HCV (viral load negative [VL-], n = 37) to that of primary macrophages from HCV genotype 1 chronically infected (VL+) subjects (n = 32) and found that macrophages from VL- subjects have an elevated baseline expression of Toll-like receptor 3 (TLR3). Macrophages from HCV patients were stimulated ex vivo through the TLR3 pathway and assessed using gene expression arrays and pathway analysis. We found elevated TLR3 response genes and pathway activity from VL- subjects. Furthermore, macrophages from VL- subjects showed higher production of beta interferon (IFN-β) and related IFN response genes by quantitative PCR (Q-PCR) and increased phosphorylation of STAT-1 by immunoblotting. Analysis of polymorphisms in TLR3 revealed a significant association of intronic TLR3 polymorphism (rs13126816) with the clearance of HCV and the expression of TLR3. Of note, peripheral blood mononuclear cells (PBMCs) from the same donors showed opposite changes in gene expression, suggesting ongoing inflammatory responses in PBMCs from VL+ HCV patients. Our results suggest that an elevated innate immune response enhances HCV clearance mechanisms and may offer a potential therapeutic approach to increase viral clearance.

The Impact of Ethnicity on Hepatitis C Virus Treatment Decisions and Outcomes

Hepatitis C virus infection is a major public health concern. Approximately 4 million people are reported to be infected with the virus in the United States, and the annual death rate due to HCV-associated decompensated liver failure or hepatocellular carcinoma is estimated to be approximately 18,000 within the next decade. Therapeutic success, as measured by a sustained virologic response, is approximately 50% in G1 patients with pegylated-interferon/ribavirin-based therapies. Independent studies have reported significant variation in response rates depending on the ethnicity or race of the patient, though the underlying reasons are not well understood. Historically, ethnic populations have been underrepresented in most large clinical trials of HCV therapies, even though these populations have disproportionately high rates of HCV infection. Recent clinical trials have investigated genetic variations in key biological pathways that may underlie the mechanisms responsible for the different rates of HCV clearance and treatment outcomes in ethnic populations treated with pegylated-interferon/ribavirin. However, as novel direct-acting antiviral drugs are added to, and eventually replace, existing treatment regimens, the role of the innate immune response in determining treatment outcomes will diminish. Socioeconomic and biological factors can impact rates of HCV infection, disease progression, and treatment outcomes in minority populations. Improved access to health care, novel antiviral treatments, and a better understanding of the host factors that contribute to disparities in treatment outcomes are expected to result in optimized treatment paradigms that directly target the virus, leading to improved outcomes for all patients.

Spontaneous Clearance of HCV in HIV–Hepatitis C Virus Coinfected Liver Transplant Patients: Prospective Study

BackgroundHepatitis C virus (HCV) clearance is an independent predictive factor for long-term survival in HIV-HCV liver transplantation patients. After 46 months of antiviral therapy it is achieved in up to 80% of cases. Little is known, however, about spontaneous viral clearance. We performed prospective study of HIV-HCV coinfected liver transplant patients. MethodsBetween January 1, 2001, and December 31, 2011, we analyzed the parameters from among HIV-HCV coinfected liver transplant patients of donor and recipient ages, transplant cause, Model for End-Stage Liver Disease (MELD) score, donor and recipient serology, transplant date, viral load before and after transplantation, immunosuppressive therapy, HCV recurrence, HCV viral clearance (spontaneous and duration), retransplant cause, and viral load before and after retransplant, as well as survival. ResultsThe seven transplanted HIV-HCV coinfected patients had most commonly HCV-related hepatocarcinoma (n = 5, 71.42%). Three subjects (42.85%) developed HCV recurrences. Two patients (28.57%) were retransplanted, both due to HCV recurrence with one of them developing a spontaneous clearance of HCV (14.28%). This patient showed a preoperative HIV viral load < 50 copies IU/mL, CD4+ count 486/μL, HCV-RNA 2564 IU copies/mL, Anti-HBc+, and MELD 30. The donor was an 81-year-old female who was Anti-HBc+. Immunosuppressive therapy consisted of cyclosporine, mycophenolate, and prednisone. One month after transplantation, the patient developed an acute cellular rejection episode with progression of liver disease secondary to the HCV recurrence (56.5 × 105 copies IU/mL). He started antiviral treatment (α-interferon and ribavirin), but due to side effects and interactions with the antiretrovirals, they were stopped after four doses. The viral load decreased spontaneously and progressively until it became negative at 146 days after transplantation; he was retransplanted and HCV-RNA has continued to be negative after 772 days. ConclusionSpontaneous clearance of HCV among HIV-HCV coinfected liver transplant patients is possible. Despite no treatment, one patient still has no detectable HCV viral load after retransplantation.

Susceptibility to chronic hepatitis C virus infection is influenced by sequence differences in immunodominant CD8+ T cell epitopes

The antiviral immune response against HCV by CD8+ T cells plays a central role in viral containment. In a large HCV genotype 1b outbreak in Ireland, HLA-B(∗)08 was identified as a risk allele for chronic infection and HLA-A(∗)03 and HLA-B(∗)27 were associated with higher clearance rates. Here we took advantage of a similar large common source HCV genotype 1b outbreak (East-German cohort) to determine the role of HLA class I alleles and the sequence of the infection source, in immunodominant CD8+ T cell epitopes for disease outcome. HLA-type and IL28B genotype were determined in 216 patients with chronic and 95 with spontaneously resolved HCV infection. The viral sequence in immunodominant epitopes was determined in the infection source and in patients with chronic infection. In contrast to the Irish cohort, HLA-B(∗)08, HLA-A(∗)03 and HLA-B(∗)27 were neutral for disease outcome even when the cohort was stratified for the IL28B genotype. Sequence analysis of the immunodominant epitopes revealed that pre-existing substitutions in the infection source of both cohorts influenced the impact of the corresponding HLA-allele. The immunodominant epitopes presented by the "protective" alleles HLA-A(∗)03 and -B(∗)27 in the Irish cohort contained substitutions in the source virus of the East-German outbreak. Importantly, the pre-existing substitutions altered subsequent selection pressure and viral evolution in the East-German cohort. This study highlights that subtle sequence differences in the infection source may have profound effects on the ability to clear HCV infection in the presence of particular HLA class I alleles.

Genetic polymorphism of IL28B in hepatitis C‐infected haemophilia patients in Israel

Single-nucleotide polymorphisms (SNPs) near the IL28B gene were identified as major predictors of treatment response (sustained virologic response--SVR) and spontaneous clearance of HCV. Haemophilia patients have the highest prevalence of HCV, and are a unique target for genetic studies. The Israeli population is ethnically heterogeneous; therefore, genetic variability is anticipated. To determine the IL28B haplotypes in HCV-infected haemophilia patients and association with SVR and spontaneous viral clearance. IL28B polymorphism at SNPs rs12979860 and rs8099917 was determined in sera obtained from 130 HCV-infected haemophilia patients. The frequency of the various haplotypes was analysed according to treatment response, spontaneous HCV clearance, viral load and degree of fibrosis. The CC haplotype at SNP rs12979860 was found in 31% of patients, whereas the TT genotype at SNP rs8099917 was detected in 57% of cases. SVR was achieved in 70% of patients carrying the CC haplotype (P = 0.0196 vs. CT/TT), and 50% of the TT genotype at SNP rs8099917 (P = 0.0227 vs. TG/GG). Thirty-five percent of patients carrying the CC haplotype and 26% with the TT genotype at SNP rs8099917 showed spontaneous clearance of HCV infection (P = 0.00262 vs. CT/TT; and P = 0.00371 vs. TG/GG respectively). The C-allele frequency was exceptionally high (71%) in immigrants from the Asian republics of Russia. In HCV-infected haemophilia patients, SVR was more commonly achieved among patients who had the CC (rs12979860) or TT (rs8099917) genotype. Likewise, patients who possess harbour the CC or TT genotypes were more likely to clear HCV infection spontaneously. A unique distribution of the CC genotype was observed in some ethnic groups.

New therapies against HCV: Expected risks and challenges associated with their use in the liver transplant setting

Current approaches to anti-viral therapy (AVT) in the setting of liver transplantation are based on the use of pegylated interferon in combination with ribavirin (PegIFN/RBV). Attempts to clear HCV pretransplant have been successful in about 15–20% of the patients with genotype 1 infection and about 20–35% with genotype 3 [1,2] Such patients usually have relatively lower MELD scores (<18) than many other patients listed for transplant. Despite this AVT is associated with an increased risk of serious bacterial infections [3]. Sustained viral response (SVR) pretransplant is associated with lack of viral recurrence post-transplant [1,2] Early post-transplant AVT is not thought to be useful due to lack of efficacy and poor tolerability [4,5]. The commencement of AVT is usually considered at about the 12-month mark based on protocol biopsies. Patients with either F2 or F1 with significant portal inflammation (stage P to 2) are usually considered for AVT6.-8. SVRs in the range of 20–30% for patients with HCV genotype 1 (G1) and 40–50% for patients with HCV G3 are obtained [6–8]. SVR post-transplant has been linked to both donor and recipient IL28 polymorphisms [9–11]. Achievement of SVR in the post-transplant setting is associated with improved survival compared to patients who do not achieve an SVR [6–8]. Given the importance of viral clearance in the pre and posttransplant setting, such results have been thought to be somewhat unsatisfactory and the liver transplant community has been eagerly awaiting new anti-HCV therapies.

In Vitro Antigen-Specific Induction of IL-22 in Human Subjects that Resolved HCV Infection

AIMS: To determine if in vitro production of IL-22 and IL-17 correlated with resolution of HCV infection. MATERIALS #ENTITYSTARTX00026; METHODS: Human peripheral blood cells isolated from a well-defined cohort of resolved and chronic HCV-infected subjects were used to measure HCV-, influenza- and mitogen-activated T-cell proliferation. In addition, IL-22 and IL-17 production was measured via ELISAs and flow cytometry. RESULTS: Resolved HCV subjects had a significantly higher T-cell proliferative response to recombinant NS3 protein compared with chronic HCV subjects. Resolved subjects had a dose-dependent IL-22 response to recombinant NS3 compared with chronic HCV subjects. CONCLUSION: IL-22 production is associated with antigen-specific induction of CD4 (+) T cells in individuals that resolved HCV infection, suggesting a potential role for IL-22 in HCV clearance.

Low reduction of HCV-RNA level at week 4 in HIV-1 infected patients with acute HCV Infection

The epidemic of acute Hepatitis C-virus infection (AHC) is an on-going issue, especially among MSM patients. Spontaneous HCV clearance rates have been estimated to be between 5-40%, with lower rates among HIV-1 co-infected patients. High rates of sustained virological response have been observed (60-80%) when patients are treated within 24 weeks of AHC diagnosis. Moreover, a spontaneous 2log reduction in HCV-RNA might be a good predictor of spontaneous HCV-RNA clearance in HIV-1 co-infected patients. The aim of this study is to analyse the incidence of 2-log-HCV-RNA spontaneous reduction in AHC in HIV-1 infected patients.

The in vivo antiviral state is dependent on IFNγ (170.5)

Abstract Since the discovery of interferons 50 years ago their potential therapeutic use has been a source of active research. Thus far, the most successful interferon therapy has been use of IFNα2 in combination with Ribavirin to treat Hepatitis C (HCV). The success rate for this therapy is only about a 50%. A recent case study showed that adding IFNγ to the standard IFNα/Ribavirin therapy regimen led to clearance of HCV in a patient that had failed the standard therapy. The idea that IFNγ is important for successful therapy against HCV is supported by several in vitro and in vivo studies. Using the well-established mouse model of chronic viral infection, LCMV, we have found that the natural in vivo antiviral state is dependent on interferon gamma (IFNγ). In our whole-organism model early production of IFNγ by CD8+ cells within days of a primary LCMV infection creates an antiviral environment capable of preventing secondary viral infections, whereas IFN-I signaling is surprisingly dispensable. The clearance of the secondary infection is not antigen specific since an acquired immune response to the second infection is not induced. Further, this block is transient and the mice eventually become susceptible to the secondary infection. Finally, the IFNγ induced antiviral state is effective regardless of the route of secondary viral entry. Therefore, a naturally induced sustained antiviral state is dependent on IFNγ production.

Interleukin 28B Gene Polymorphism and Association with Chronic Hepatitis C Therapy Results in Latvia

Introduction. With the standard treatment of chronic hepatitis C, sustained virological response (SVR) can be achieved only in half of all patients. Interleukin-28B appears to be involved in the control of HCV infection, and the genetic polymorphism of the encoding IL-28B gene may determine the efficacy of clearance of HCV. The aim of this paper was to detect IL-28B gene polymorphism in Latvia and to analyze therapy results. This is the first study on IL-28B gene polymorphism in Latvia. Material and Methods. There were 159 chronic viral hepatitis C patients included in the study. In order to detect IL-28B gene polymorphism, we used molecular biology techniques and methods: classical DNA separation, amplification by PCR, and standard sequencing. Genotype was defined as CC, CT, TC, or TT type. 142 patients were treated with the standard of care treatment. Results were analyzed according to IL-28B polymorphism. Results. There were 53 patients (33%) with CC genotype, 84 patients (53%) with CT/TC genotype, and 22 patients (14%) with TT genotype. 34 patients (74%) in CC genotype subgroup achieved SVR versus 50 patients (52%) in non-CC subgroups. In patients with genotype 1, SVR was achieved in 16 patients (84%) in CC subgroup versus 30 patients (47.6%) in non-CC subgroups, P = 0.007. Conclusions. The most common genotype of IL28B in Latvia is CT/TC, with an incidence of 53%. Patients with CC genotype achieved SVR more often than CT or TT subgroups. IL28B gene polymorphism therefore is a strong predictor of treatment result.

Immediate vs. delayed treatment in patients with acute hepatitis C based on IL28B polymorphism: A model-based analysis

Timing of treatment initiation in acute hepatitis C (AHC) patients is unclear. Spontaneous viral clearance argues for a "watch-and-wait" strategy. However, early initiation of treatment could increase the sustained virological response (SVR) rate. We compared three different HCV treatment initiation strategies in patients with AHC according to presence of clinical symptoms and IL28B polymorphism: (1) within 2 months after transmission (immediate initiation), (2) at 3 months (early initiation), and (3) at 4/5 months (delayed initiation). We calculated spontaneous HCV clearance probability based on the symptomatic (sAHC) and asymptomatic (aAHC) nature of disease and C/C or non-C/C genotype. We used different SVR probabilities according to delay between transmission and treatment. We estimated the probability of developing chronic hepatitis C (CHC). The probability of developing CHC was lower for immediate treatment initiation (7.1% in C/C and 7.3% in non-C/C patients with sAHC; 6.6% in C/C and 7.1% in non-C/C patients with aAHC) than for delayed initiation (13.5% in C/C and 18.0% in non-C/C patients with sAHC; 14.6% in C/C and 18.5% in non-C/C patients with aAHC) regardless of the presence of symptoms or IL28B genotype. In patients such as health care workers, in whom HCV is detected ≤ 2 months following transmission, treatment should be immediately initiated regardless of clinical symptoms and IL28B polymorphism. In those in whom HCV is detected>2 months after transmission, treatment 4/5 months after may be preferable because of a higher rate of spontaneous HCV clearance after 2 months and a poor HCV treatment efficacy's differential between months 3 and 4/5.

Study of diabetes mellitus among patients with hepatitis C virus

Abstract Introduction Hepatitis C virus (HCV) infection and type 2 diabetes are two common disorders with high impact on health worldwide. There is growing evidence to support the concept that HCV is associated with type 2 diabetes. Purpose This work aimed to study the clinical phenotype of type 2 diabetes in HCV patients. Patients and methods Our study was conducted upon 100 nonobese, noncirrhotic hepatitis C positive patients who were classified into two groups according to homeostatic model assessment (HOMA) test for insulin resistance (HOMA IR). This study also included 15 nonobese type 2 diabetic patients negative for HCV and hepatitis B virus infection classified as control groups. We excluded alcoholics and drug addicts and patients with conditions that affect blood glucose such as endocrine diseases associated with disordered glucose metabolism and use of drugs. All participants were subjected to full history taking and complete clinical examination including BMI and the following investigations: complete blood count, fasting blood sugar, 2 h postprandial blood sugar, glycosylated hemoglobin, fasting insulin level, cholesterol level, HDL, LDL, triglyceride, serum urea, creatinine, complete urine analysis, liver function tests: total bilirubin, alkaline phosphatase, albumin, prothrombin time, INR, SGOT, SGPT, quantitative PCR for determination of HCV-RNA, surface antigen (HbsAg), abdominal ultrasonography, liver biopsy when needed and possible for HCV patients, and ECG. Results In this study, we found that the prevalence of type 2 diabetes in group I is 24%. HCV can independently contribute to IR with viral genotypes 1 or 4. We noticed significant positive correlation between fasting insulin and HOMA IR in hepatitis C +ve patients. IR in HCV-infected patients is high irrespective of the degree of liver injury even before a minimal fibrosis is present. Both IR and diabetes can adversely affect the course of chronic hepatitis C, leading to enhanced steatosis and liver fibrosis, and even increase the risk of hepatocellular carcinoma. A significant correlation between HOMA IR and steatosis, a significant positive correlation between fasting insulin and steatosis and a negative correlation between steatosis and BMI in HCV patients was found. No correlation was found between HOMA IR and the viral load (quantitative HCV RNA). Conclusion We can concluded that diabetic HCV patients had intermediate clinical phenotype lower BMI and LDL than control and development of type 2 diabetes mellitus in HCV patients was significantly higher in nontreated patients than treated patients. Antiviral therapy and clearance of HCV improves IR, β-cell function, the blood glucose abnormalities.

Lack of full CD8 functional restoration after antiviral treatment for acute and chronic hepatitis C virus infection

BackgroundHepatitis C virus (HCV) persistence is associated with impaired CD8 functions. Whether functional restoration of CD8 T cells chronically exposed to antigen can be obtained once the antigen is removed...

Acute hepatitis C in Spain: a retrospective study of 131 cases

The management of acute hepatitis C (AHC) is controversial. We have conducted a retrospective study to determine the epidemiological and biochemical aspects, the genotypes, the spontaneous clearance of HCV (SVC), and the treatment responses in patients with AHC. We have retrospectively collected data from 131 patients with AHC from 18 Spanish hospitals. The mean age was 43 ± 16 years (17-83), 69% were symptomatic. The causes of infection were nosocomial in 40% and intravenous drug users in 20%. Eighty two percent had genotype 1. The delay from symptoms-onset to HCV-RNA confirmation was 50 ± 68 days (range, 11-350 days) and to treatment (in 59%) 14±1 3 weeks (range, 2-58 days). In the treated group, 80% achieved sustained virological response (SVR) versus 57% SVC in untreated patients (p = 0.004). Up to 96% of those treated within the first 12 weeks had SVR versus 86% of those treated later (p = 0.04). Patients with HCV-RNA(-) at week 4 resolved with or without treatment more frequently than those HCV-RNA(+) (98% versus 69%, p = 0.005). The treatment was not beneficial if HCV-RNA was undetectable at week 12. No differences in SVR were found in genotype 1 patients treated for 24 or 48 weeks. Patients with low baseline viral load achieved higher SVC and SVR. The SVC in patients with bilirubin > 5 mg/dL was 78 versus 40% in those with lower values (p = 0.004). The most common transmission route was nosocomial. SVR was higher in patients treated than SVC in non-treated.Early treatment (before week 12) achieved the highest response rate. SVC and SVR were more common in patients with a low baseline viral load. Undetectable HCV-RNA at week 4 was associated with high SVR and SVC rates. Jaundice was related with SVC.

Vertical genotype 1 HCV infection treated successfully in the second year of life: A case report

SummaryBackgroundPerinatal HCV transmission appears to be an important cause of HCV in children. Treatment of chronic hepatitis C in young children is controversial because of spontaneous HCV clearance and possible adverse events.Case ReportVertical HCV genotype 1 infection was diagnosed in a 3-month-old infant. In the subsequent clinical examination we still observed hepatomegaly, fluctuations of ALT, AST and GGT activity, with the highest values 2206 U/L, 1319 U/L, and 297 U/L, respectively. In qPCR, HCV RNA was >700.000 IU/ml. In the 42nd week of observation, liver biopsy was performed with Grade 1 grading and Grade 1 staging. At age 12 months, interferon-alpha2b (1.5 MU 3 times a week) and ribavirin (2×80 mg daily) were administered for 48 weeks. At the beginning of the treatment we observed fever after IFN injection. In the 12th week of therapy, HCV RNA disappeared followed by SVR, and it was sustained for 6 years. To our knowledge, this is the first report of a pediatric (1-year-old) patient treated with combined IFN alpha-2b and ribavirin therapy.ConclusionsThis case report confirms the possibility of successful anti-HCV treatment in a young child, with 6-year sustained virological response without significant adverse events.

IL28B genetic polymorphism testing in the era of direct acting antivirals therapy for chronic hepatitis C: ten years too late?

An association between variations at the IL28B gene locus and HCV clearance (spontaneous recovery or sustained virological response under pegylated interferon (PEG-IFN) and ribavirin (RBV) has been extensively described. In genotype 1-infected patients, the new direct antiviral agents (DAA) including the two approved protease inhibitors boceprevir and telaprevir, in association with the PEG-IFN/RBV combination is the new standard of care making it necessary to redefine the interest of the IL28B genotype in the decision to treat and how to treat genotype 1-infected patients. In treatment-naïve patients, IL28B status can certainly identify those with a high probability of achieving SVR with response guided therapy and probably in whom the duration of treatment can be markedly reduced. In experienced patients, the impact of IL28B genotypes is limited and cancelled by early viral kinetics. However, the decision to initiate or withhold therapy remains a clinical one. In summary, although it was a major milestone in the treatment of patients with PEG-IFN/RBV, IL28B polymorphism testing entered the clinical arena almost 10 years too late.

Il28B Cc-Genotype Association with Hla-Dqb1*0301 Allele Increases the Prediction of Spontaneous HCV RNA Clearance in Thalassaemic HCV-Infected Patients

A single nucleotide polymorphism (SNP), upstream of the IL28B gene has been recently associated with natural clearance of HCV. In a well-characterized cohort of patients with thalassaemia major exposed to the risk of acquiring HCV infection by blood transfusions, we aimed to replicate this finding and to evaluate whether combining the IL28B genotype and HLA class II alleles allow viral clearance to be accurately predicted. Of 168 patients, 130 with complete clinical history were included in the analysis. According with their HCV antibodies status 13 were defined HCV resistant, and 117 infected. Infected patients were subdivided, giving 49 with self-limiting and 68 with ongoing infection. IL28B CC-genotype was observed in 32 patients with self-limiting and in 23 with ongoing infection (64% versus 34%; P=0.004). HLA DQB1*0301 allele was associated with viral clearance in 36 cases (73%; P<0.0001). Both DQB1*0301 and IL28B CC-genotype were found to be independent predictors of HCV clearance (OR=5.64, 95% CI 1.52-20.9 and OR=5.76, 95% CI 2.16-15.33, respectively). With the addition of DQB1*0301, the accuracy of the prediction increased from 63% to 69%. In addition to IL28B CC-genotype, HLA DQB1*0301 helps in predicting natural clearance of HCV after acute infection.

HIV/HCV-Coinfected Natural Viral Suppressors Have Better Virologic Responses to PEG-IFN and Ribavirin Than ARV-Treated HIV/HCV Patients

Less than 1% of HIV patients control HIV replication to an almost undetectable level without the aid of antiretroviral therapy (ARV), and are termed natural viral suppressors (NVSs)1. A recent study demonstrated that NVSs demonstrate immunological control toward HIV and not HCV or other chronic viral infections similar to HCV 2. The impact of effective immunological control of HIV replication in NVSs on response to Interferon-based immune therapy in HCV has not been studied. Studies have demonstrated that induction of host immunity is a key phenomenon associated with virologic response to IFN and ribavirin (RBV) treatment 3. In this regard, HIV/HCV co-infected patients have significantly lower host immune response and rates of sustained virologic response (SVR) to IFN/RBV compared to HIV negative, HCV infected patients4. Our study compares the effect of superior immunological control of HIV replication in NVSs to that in patients with chronic HIV (CHIV) on the clearance of HCV after treatment with IFN/RBV.

Sustained HCV Clearance by Interferon-Based Therapy Reduces Hepatocellular Carcinoma in Hepatitis B and C Dually-Infected Patients

Recent studies have indicated that interferon (IFN) or pegylated interferon (PEG-IFN) plus ribavirin therapy can achieve sustained virological response (SVR) against HCV equally in dual HBV-HCV infection and in HCV monoinfection. Whether these therapies can reduce hepatocellular carcinoma (HCC) development in dual HBV-HCV infection remains unclear. A total of 135 dually-infected patients with active hepatitis C receiving IFN or PEG-IFN plus ribavirin therapy were enrolled. The cumulative incidence of HCC was compared to that in 1,470 HCV-monoinfected patients. Based on the Cox proportional hazards model, dual infection was an independent factor for HCC development in all 1,605 chronic hepatitis C patients with or without positive hepatitis B surface antigen receiving IFN or PEG-IFN plus ribavirin (hazard ratio (HR)=1.864, 95% CI 1.052-3.303; P=0.033). In dually-infected patients, HCC developed in 4 of 96 with HCV SVR and 11 of 39 without HCV SVR (P < 0.001) after a median follow-up of 4.6 years. Age (HR=1.175, 95% CI 1.070-1.291; P=0.001) and non-HCV-SVR (HR=7.874, 95% CI 2.375-26.32; P=0.001) were independent factors for HCC development. Subgroup analysis showed that HCC occurrence was lower in patients with HCV SVR and HBV DNA levels < 2,000 IU/ml at the end of treatment or follow-up compared to those with HCV SVR and HBV DNA levels ≥ 2,000 IU/ml (P=0.034) and those without HCV SVR (P<0.001). Sustained HCV clearance by IFN or PEG-IFN plus ribavirin therapy may significantly reduce HCC in HBV-HCV dually-infected patients, whereas persistence or reactivation of HBV decreases the benefit of HCV SVR.

P45 Natural killer cell cytotoxicity is enhanced in injection drug users with apparent resistance to hepatitis C virus infection

IntroductionWe have identified a cohort of injection drug users (IDU) who, despite long-term high risk sharing of drug injection equipment, remain seronegative and aviraemic for HCV. These exposed uninfected (EU)...