HCV Clearance Research Articles

Virological Pattern in Plasma, Peripheral Blood Mononuclear Cells and Liver Tissue and Clinical Outcome in Chronic Hepatitis B and C virus Coinfection

We aim to evaluate in chronic hepatitis B virus-hepatitis C virus (HBV-HCV) coinfection the interplay of these viruses in liver tissue, peripheral blood mononuclear cells (PBMC), and plasma and to analyze the effect on disease course and response to treatment. We enrolled 19 patients with chronic HBV-HCV coinfection, 20 with chronic HCV and 20 with chronic HBV infection at their first liver biopsy, all were naive for antiviral therapy. The patients' plasma, PBMC and liver biopsy samples were tested for HBV DNA and/or HCV RNA by real-time PCR, according to the presence/absence of hepatitis B surface antigen and antibodies against HCV in the serum. Contemporary presence of HBV DNA and HCV RNA was rare in plasma (5.3% of cases) and PBMC (10.6%), but frequent in liver tissue (52.6%). Of 10 cases circulating only HCV RNA and treated with pegylated interferon (PEG-IFN) plus ribavirin for 12 months, two showed a sustained response, and eight cleared HCV RNA but became HBV-DNA-positive in plasma; these eight had detectable HBV DNA in liver at baseline. One patient, who was plasma HBV-DNA-positive/HCV-RNA-negative at baseline, showed a sustained response after 18 months of PEG-IFN treatment; another, who was plasma HBV-DNA/HCV-RNA-positive at baseline, cleared only HCV RNA during 12 months of PEG-IFN plus ribavirin treatment. Seven cases remained untreated. Despite a reciprocal inhibition in plasma, HBV and HCV frequently coexist in liver tissue, a condition to be taken into consideration when deciding therapy.

187 PRE-EMPTIVE DIAGNOSTIC AND THERAPEUTIC APPROACH OF ANASTOMOTIC BILIARY STRICTURES AFTER PEDIATRIC LIVER TRANSPLANTATION

infection who undergo immuno-suppressive therapies. It is still believed to be rare in HIV infection. However, it is potentially life-threatening. We aimed to analyze the clinico-virological factors associated with HBV-SRR in 5 HIV-1-seropositive patients and the HBV serological background for such event in the Marseilles public hospitals HIV cohort. Methods: HBVDNA was quantified using Roche Cobas Ampliprep/TaqMan assay. Direct HBVDNA amplification/sequencing was performed from serum using in-house protocols. HBV serologies were performed using Axsym Abbott assays. HBV-SRR was defined as evolution from re-appearence of HBsAg and serum HBVDNA in anti-HBc antibodies (Ab)+ patients, concomitantly with a dramatic ALT rise. Results: 1,076 HIV+ patients had HBV serology during the 2 past years. 67 (6.2%) were HBsAg+, 473 (44%) had serology indicating past-HBV infection, among whom 248 had an anti-HBs antibodies (Ab) titer 100 IU/L in 55% and 60% of patients with a serology indicating past infection or VI, respectively. HBsAg-/anti-HBcAb+ and HBsAg/anti-HBcAb+/anti-HBsAb patterns were significantly more frequent in male (P< 10−5 and 0.018, respectively). 4/5 patients presenting HBVSRR were male, mean age = 49 y, mean ALT = 1704 IU/L (1477–1931), mean prothrombin index = 68% (45−93), mean serum HBVDNA = 9 log10 copies/mL (6.9−9.5), mean HIV load = 4.5 log (<1.6−4.9), mean CD4 = 220/mm3 (154–308). Acute hepatitis E or transient spontaneous HCV clearance were observed in 2 patients. All patients interrupted anti-HIV/HBV drugs (TDF, 3TC, and/or FTC) prior to HBV-SRR. HBV genotype was A in 3 patients, and D in 2. Amino acid substitutions within HBsAg “a” determinant were found at positions 133 and/or 144 from 2/5 patients. Neither HBV drug-resistance mutations nor pre-core/core promoter mutations were observed. Conclusions: Our data highlight that a substantial proportion of HIV infected patients are at risk of HBV-SRR. This latter diagnosis should be considered in HIV-infected patients with unexplained severe ALT rise. Our results suggest that male might be at higher risk of HBV-SRR. HBV VI should be proposed to HBV-seronegative HIV-infected patients.

HCV relapse after peg-interferon (IFN) plus ribavirin (RBV) therapy: is 12-week follow-up enough to determine sustained HCV clearance?

Methods Retrospective analysis of all IFN-naive patients with chronic hepatitis C who received a full course of 48 weeks of pegIFN (alpha 2a or 2b, at standard doses) plus weightadjusted RBV (~13 mg/kg, 1,000–1,200 mg/day) therapy and had negative serum HCV-RNA at the end of treatment (EOT). Incidence and timing for HCV relapse were analyzed separately in HIV-pos and HIV-neg patients. Serum HCV-RNA was measured at EOT and every 3 months thereafter during the next year using a real-time PCR assay (Cobas Taqman, Roche), which has a lower limit of detection of 10 IU/mL.

The scavenger receptor BI and its ligand, HDL: partners in crime against HCV neutralizing antibodies

Better knowledge of the viral and host factors that determine HCV clearance vs. persistence at the acute stage of infection is needed in order to improve antiviral therapy and develop efficient vaccines. Spontaneous HCV clearance is associated with a strong, early and broad cellular immune response. Yet, several observations suggest that antibody-mediated neutralisation occurs during HCV infection in vivo and that polyclonal antibodies to HCV can be protective. The recent development of HCV infection assays has confirmed that sera from HCV-infected patients neutralise infection in vitro. Recent studies have demonstrated that Nt-antibodies, of narrow specificity, are induced during the early phase of infection and could play a role in controlling viral infection or clearance. Yet, high-titre, broadly cross-reacting Nt-antibodies are readily detected in chronically infected patients, suggesting that their effectiveness is limited in patients who do not resolve the disease. The factors that mitigate the impact of the Nt-antibody response need to be clarified. Here we review some essential features of the Nt-antibody responses to HCV. We then discuss an original mechanism that HCV may use in vivo to attenuate Nt-antibodies, which involves the hyper-variable region-1 of the HCV-E2 glycoprotein, high-density lipoprotein (HDL) and the physiologic activity of the scavenger receptor BI, a receptor shared by both HCV and HDL.

Recognition of Hepatitis C Virus Coinfection in HIV-Positive Injecting Drug Users in Asia

HIV and hepatitis C (HCV) are readily transmitted by the sharing of injecting equipment. It has been estimated that there are 2 to 9 million injecting drug users (IDUs) in the Asia Pacific region of whom approximately 750000 are living with HIV. Injecting drug use is a major mode of HIV transmission in many Asian countries accounting for more than 30% of infections in Myanmar; 40% in China; and most infections in Vietnam Indonesia and Malaysia. This is superimposed on a geographically varied high population prevalence of HCV. Prevalence across Asia can be explained by unsterile medical injections contaminated transfusions traditional cultural practices6 and more recently injecting drug use. There are few studies on the prevalence of HCV and HIV coinfection in Asia although all demonstrate almost universal HCV infection in HIV-infected IDUs. Increasing coinfection as a proportion of HIV infections in some countries indicates that although sexual transmission of HIV may be reducing transmission through sharing injecting equipment continues. A Thai study found that although the prevalence of HIV in military recruits (a marker of population HIV prevalence) decreased from 2.4% to 1.1% between 1995 and 2000 the proportion coinfected increased from 20.8% to 49.5% during the same period. (excerpt)

ペグインターフェロン&alpha;2b/リバビリン投与開始後5&sim;24週目にHCV RNAが陰性化したC型慢性肝炎例に対する爾後一律44週間継続投与の有用性

Patients with chronic hepatitis C who do not respond rapidly to therapy have a low chance of acquiring sustained virological response (SVR). We tried a new regimen of treatment with peginterferon α2b plus ribavirin, arranged to continue it for 44 weeks after HCV RNA has disappeared in the patient's circulation. Subjects were 17 consecutive patients with chronic hepatitis C (50.8 [21-68] years of age, 10 females and 7 males, HCV genotype 1, HCV RNA>100KIU/ml) whose serum HCV RNA remained positive at week 4 but became undetectable between weeks 5 and 24 of treatment. SVR rate for all patients enrolled in this study was 76.5%. Among patients with HCV clearance between weeks 5 and 12 (n=13), SVR rate was 76.9% (10/13), and among those with HCV clearance between weeks 13 and 24 (n=4), SVR rate was 75.0% (3/4). These data suggest that this prolonged therapy (i.e., 5∼24+44=49∼68 weeks in total) will be of use in patients who first cleared HCV RNA between weeks 5 and 24, though a larger number of patients should be examined to clarify whether this therapy is really superior to the current standard 48-week treatment.

Low incidence of HCV reinfection

We read with interest the report wherein Grebely and colleagues found lower incidence of HCV reinfection following natural HCV clearance than incidence of initial HCV infection within a Vancouver, Canada, community-based cohort.1 These findings are given as evidence of protective immunity provided by prior HCV infection. However, the comparison of initial HCV infection and HCV reinfection incidence has several inherent methodological difficulties, particularly when conducted retrospectively. First, demographic and behavioral characteristics generally differ among the denominator populations: uninfected individuals for initial HCV infection and previously infected individuals with viral clearance for HCV reinfection. The latter group is often older and may have reduced risk behavior after HCV diagnosis. Adjustment for baseline characteristics as performed by Grebely et al. reduces but does not remove this concern. Second, longitudinal reporting of injection risk behavior may not be available to cover the at-risk study period. Third, the HCV testing interval is generally heterogeneous and may be relatively broad. Variability in testing interval is a minor issue for determination of incidence of initial HCV infection, because long-lasting seroconversion to anti-HCV antibody following infection supports detection of all new cases. However, an incident case of HCV reinfection requires detection of new HCV viremia, which is dependent on the proportion of cases with persistent viremia, duration of viremia in clearance cases and interval of HCV RNA testing. A previous study of HCV reinfection demonstrated that HCV viremia in the setting of HCV reinfection was at a lower level, generally transient, and shorter in duration compared to initial HCV viremia.2 The duration of HCV viremia among individuals with natural HCV clearance following initial HCV infection is generally less than 12 weeks.3 Thus, a testing interval for HCV RNA longer than 12 weeks in an HCV reinfection cohort where a majority of new viremic cases could be expected to clear viremia may miss many HCV reinfection cases. Studies of HCV reinfection from community-based and primary care–based cohorts in Baltimore,2 Vancouver,1 and Sydney4 are outlined in Table 1. In contrast to the findings in Vancouver and Baltimore, we found no evidence for lower incidence of HCV reinfection compared to initial infection. Key features of our study were a young aged cohort, with the same median age in both uninfected and previously infected subgroups, high rate of frequent (daily) injection drug use, and a relatively short interval for HCV RNA testing. An evaluation of the HCV RNA testing interval within the Vancouver study, including a comparison among HCV reinfection cases and noncases in the previously infected group, may provide some explanation for the apparent lower incidence of HCV reinfection. A relatively long testing interval (greater than 6 months) would suggest than many HCV reinfection cases may have been undetected. The absence of persistent HCV viremia following HCV reinfection may reflect partial protective immunity, but alternatively could relate to the same host factors that influenced viral clearance following initial HCV infection.5, 6 As suggested by Grebely et al., prospective studies of HCV clearance, reinfection, and potential protective immunity are crucial to advance the understanding of early HCV immunopathogenesis. Gregory J. Dore*, Joanne Micallef*, * National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Darlinghurst, NSW, Australia.

Impact of aboriginal ethnicity on HCV core-induced IL-10 synthesis: Interaction with IL-10 gene polymorphisms

The host immune response is a critical determinant in viral infection outcome. Epidemiological studies indicate that North American indigenous peoples are more resistant to chronic HCV infection than other populations. Due to the prominence of IL-10 in chronic HCV infection, we investigated the genetic tendency to produce IL-10 in Caucasian (CA) and First Nation (FN) populations. Peripheral blood mononuclear cells (PBMCs) from CA subjects had a greater tendency to produce IL-10 defined by allelic polymorphisms, as well as genotypes and haplotypes, at the -1082, -819, and -592 positions of the IL-10 promoter. More importantly, we directly evaluated the influence of ethnicity on the ability of HCV core protein to induce IL-10 synthesis and found significantly higher IL-10 production by PBMCs isolated from healthy CA subjects compared with FN subjects. Further examination of the underlying relationship between core-induced IL-10 with the high, intermediate, and low phenotypes at the -1082, -819, and -592 position revealed that spontaneous and core-induced IL-10 synthesis tended to interact negatively with defined polymorphisms. This was particularly evident for the FN cohort, in which the relationship was strengthened by a stronger interaction of core with the low-IL-10-producing phenotypes. As with previous studies, concanavalin A induced IL-10 synthesis from the CA cohort positively associated with defined genetic phenotypes. Cells from FN subjects had a reduced capacity to produce IL-10 in response to HCV core protein, suggesting that reduced susceptibility of FN immunity to virally induced IL-10 synthesis might contribute to epidemiological observations of enhanced HCV clearance.

A comparative review of HLA associations with hepatitis B and C viral infections across global populations

Hepatitis B (HBV) and hepatitis C (HCV) viral infection or co-infection leads to risk of development of chronic infection, cirrhosis and hepatocellular carcinoma (HCC). Immigration and globalization have added to the challenges of public health concerns regarding chronic HBV and HCV infections worldwide. The aim of this study is to review existing global literature across ethnic populations on HBV and HCV related human leukocyte antigen (HLA) associations in relation to susceptibility, viral persistence and treatment. Extensive literature search was conducted to explore the HLA associations in HBV and HCV infections reported across global populations over the past decade to understand the knowledge status, weaknesses and strengths of this information in different ethnic populations. HLA DR13 is consistently associated with HBV clearance globally. HLADRB1*11/*12 alleles and DQB1*0301 are associated with HBV persistence but with HCV clearance worldwide. Consistent association of DRB1*03 and *07 is observed with HCV susceptibility and non-responsiveness to HBV vaccination across the population. HLA DR13 is protective for vertical HBV and HCV transmission in Chinese and Italian neonates, but different alleles are associated with their susceptibility in these populations. HLA class I molecule interactions with Killer cell immunoglobulin like receptors (KIR) of natural killer (NK) cells modulate HCV infection outcome via regulating immune regulatory cells and molecules. HLA associations with HBV vaccination, interferon therapy in HBV and HCV, and with extra hepatic manifestations of viral hepatitis are also discussed. Systematic studies in compliance with global regulatory standards are required to identify the HLA specific viral epitope, stage specific T cell populations interacting with different HLA alleles during disease progression and viral clearance of chronic HBV or HCV infections among different ethnic populations. These studies would facilitate stage specific therapeutic strategies for clearance of HBV and HCV infections or co-infections across global populations and aid in identification of HBV-HCV combined vaccine. HLA associations of chronic HBV or HCV development with confounding host factors including alcohol, drug abuse, insulin resistance, age and gender are lacking and warrant detailed investigation across global populations.

Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity

Broad T cell and B cell responses to multiple HCV antigens are observed early in individuals who control or clear HCV infection. The prevailing hypothesis has been that similar immune responses induced by prophylactic immunization would reduce acute virus replication and protect exposed individuals from chronic infection. Here, we demonstrate that immunization of naïve chimpanzees with a multicomponent HCV vaccine induced robust HCV-specific immune responses, and that all vaccinees exposed to heterologous chimpanzee-adapted HCV 1b J4 significantly reduced viral RNA in serum by 84%, and in liver by 99% as compared to controls (P=0.024 and 0.028, respectively). However, despite control of HCV in plasma and liver in the acute period, in the chronic phase, 3 of 4 vaccinated animals developed persistent infection. Analysis of expression levels of proinflammatory cytokines in serial hepatic biopsies failed to reveal an association with vaccine outcome. However, expression of IDO, CTLA-4 [corrected] and PD-1 levels in liver correlated with clearance or chronicity. Despite early control of virus load, a virus-associated tolerogenic-like state can develop in certain individuals independent of vaccination history.

Long-Term Outcome after Interferon Therapy in Elderly Patients with Chronic Hepatitis C

Objective: The purpose of this study was to elucidate the long-term outcome after interferon (IFN) therapy in chronic hepatitis C elderly patients. Methods: We studied the incidence of hepatocellular carcinoma (HCC) and survival probability after the initiation of IFN therapy in 500 Japanese chronic hepatitis C patients >60 years. The mean age of initiation of IFN was 63 years and the mean follow-up period was 7.4 years. Cox proportional hazard regression analysis was used to evaluate the long-term outcome after initiation of IFN therapy.Sustained virological response (SVR) was defined as negative HCV-RNA by RT-nested PCR 6 months after the completion of long-term IFN therapy. Non-response (NR) was applied to patients who did not show SVR. Hepatic fibrosis was defined as the fibrosis score (score 0–4) according to Knodell et al. Results: 140 patients (28%) had an SVR and 360 patients (72%) had an NR. 71 of 500 patients developed HCC during follow-up. The cumulative incidence of HCC was 9.6% at the 5th year, 17.4% at the 10th year, and 31.3% at the 15th year. HCC developed with significance when: (1) HCV was not cleared after IFN therapy (p < 0.0001), (2) sex was male (p < 0.0001), and (3) staging of liver fibrosis was >2 (p = 0.008). 53 of the patients died. The cumulative survival probability was 95.7% at the 5th year, 86.4% at the 10th year, and 78% at the 15th year. Patients achieved a long survival with significance when: (1) staging of liver fibrosis was 1 (p < 0.0001), (2) HCV was cleared after IFN therapy (p = 0.034), and (3) sex was female (p = 0.015). Conclusion: Chronic hepatitis C patients with clearance of HCV after IFN therapy had a significantly reduced risk of HCC appearance and achieved prolonged survival even if they are ≧60 years.

Gender-dependent association of CTLA4 polymorphisms with resolution of hepatitis C virus infection

A vigorous T-cell response is essential for the resolution of HCV infection. It is modified by co-stimulatory molecules that attenuate T-lymphocyte responses by binding to CTLA4. We investigated whether CTLA4 single nucleotide polymorphisms are associated with the resolution of infection or with the course of disease. We enrolled 127 individuals with self-limited and 947 patients with chronic HCV infection, of whom 560 were treated with interferon-alpha-based therapies, and 200 healthy controls. We analyzed CTLA4 polymorphisms -318C>T and +49A>G by melting curve analysis and reconstructed haplotypes. CTLA4 haplotypes were distributed differently between men but not women with self-limited and chronic infection (p=0.043) but were not predictive of the stage of fibrosis in chronic carriers. Haplotypes were distributed differently between male but not female end-of-treatment responders and non-responders (p=0.025). The influence of CTLA4 haplotypes was more pronounced in "hard-to-treat" situations, i.e., treatment with interferon-alpha monotherapy or infection with HCV genotypes 1/4. Logistic regression analysis confirmed gender-specific risk factors for a virological non-response. CTLA4 polymorphisms are associated with the resolution of HCV infection. This study underlines the role of an efficient T-cell response in the clearance of HCV and sheds light on a gender-dependent difference of immune regulation.

Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: A controlled study

To evaluate long-term outcomes in decompensated HCV-related cirrhotic patients treated with antiviral therapy. Of 129 eligible patients, 66 received peginterferon alfa-2b and ribavirin for 24 weeks, and 63 were controls. Survival and recurrence of liver failure events after therapy were main outcomes. Therapy was tolerated by 27 patients, dose reduced in 26 for toxicity, and discontinued in 13 for intolerance. End-of-therapy and sustained virological response (SVR) rates were 82.6% and 43.5% for HCV 2/3 patients, and 30.2% and 7.0% for HCV 1/4 patients. During therapy, odds ratios for severe infections or deaths due to infection were 2.95 (95% C.I. 0.93-9.3) and 1.97 (95% C.I. 0.40-9.51) in treated patients as compared with controls. During a follow-up of 30 months off-therapy, decompensated events occurred in 52, 33, and 3 of controls, non-responders, and SVR patients. Odds ratios for ascites, encephalopathy, and oesophageal bleeding in treated patients significantly decreased as compared with controls. Annualized incidence of death was 2.34, 1.91, and 0 per 1000 patient-years, respectively, in controls, non-responders, and SVR patients. Survival curves showed early separation of SVR patients from both non-responders and controls at approximately 6 months. In decompensated cirrhotics, HCV clearance by therapy is life-saving and reduces disease progression.

Hepatitis A virus infection suppresses hepatitis C virus replication and may lead to clearance of HCV

The significance of hepatitis A virus (HAV) super-infection in patients with chronic hepatitis C had been a matter of debate. While some studies suggested an incidence of fulminant hepatitis A of up to 35%, this could not be confirmed by others. We identified 17 anti-HCV-positive patients with acute hepatitis A from a cohort of 3170 anti-HCV-positive patients recruited at a single center over a period of 12 years. Importantly, none of the anti-HCV-positive patients had a fulminant course of hepatitis A. HCV-RNA was detected by PCR in 84% of the anti-HCV-positive/anti-HAV-IgM-negative patients but only in 65% of anti-HCV-positive patients with acute hepatitis A (p=0.03), indicating suppression of HCV replication during hepatitis A. Previous HAV infection had no effect on HCV replication. After recovery from hepatitis A, an increased HCV replication could be demonstrated for 6 out of 9 patients with serial quantitative HCV-RNA values available while 2 patients remained HCV-RNA negative after clearance of HAV throughout follow-up of at least 2 years. HAV super-infection is associated with decreased HCV-RNA replication which may lead to recovery from HCV in some individuals. Fulminant hepatitis A is not frequent in patients with chronic hepatitis C recruited at a tertiary referral center.

744 Sustained virologic response (SVR) to interferon-alpha-2b +/- ribavirin therapy at 6 months reliably predicts long-term clearance of HCV at 5-year follow-up

744 Sustained virologic response (SVR) to interferon-alpha-2b +/- ribavirin therapy at 6 months reliably predicts long-term clearance of HCV at 5-year follow-up

Prospective study of viral clearance and CD4 + T-cell response in acute hepatitis C primary infection and reinfection

Background The outcome of acute hepatitis C is determined by early host–virus interactions, particularly involving the antiviral T-cell response. Objectives To identify early prognostic markers of spontaneous resolution of acute hepatitis C by performing a comprehensive analysis of viral and immunological factors during the natural course of acute HCV infection and reinfection. Study design 20 patients were investigated prospectively during acute HC or confirmed reinfection and 18 of them during follow up after spontaneous or treatment-induced elimination of the virus and resolution of the disease. Multiparameter flow cytometry was used to functionally characterize virus-specific CD4 + T-cell responses relative to the virologic outcome. Results Parallel immunologic and virologic monitoring of patients with acute HC identified distinct patterns of host–virus interaction related to HCV persistence or clearance. The highest frequency of antiviral Th1 cytokine-producing CD4 + T-cells was observed in patients with HCV reinfection, preceding rapid viral clearance within 3 weeks after disease onset. In all patients who subsequently cleared viremia, CD4 + T-cells produced Th1 cytokines following stimulation with non-structural HCV antigens (NS3 and NS4). In contrast, a chronic course of disease was associated with the absence of antiviral Th1 cytokine producing cells from the first weeks after onset of disease (acute persistent HC), or with fluctuating RNA levels (yo-yo pattern) and gradual waning of antiviral Th1 cells. Conclusions The results highlight the variability of immune response pattern in acute hepatitis C. Most importantly, “acute persistent hepatitis C” and a lack of TH1 effector cells within the first months of acute hepatitis C represent efficacious predictors of viral persistence and could thus be used as criteria in selecting candidates for early antiviral treatment.

Hepatitis C virus reinfection in injection drug users

Spontaneous clearance of hepatitis C (HCV) may provide protection against reinfection. In a large community-based cohort study of 3,553 inner-city residents (mainly injection drug users), we identified HCV-infected individuals in whom virological clearance had occurred and compared the rate of reinfection in this group with that observed in previously uninfected members of the same cohort. We identified 926 HCV-uninfected and 658 HCV-infected viremic subjects at baseline, with 152 of 658 (23.1%) spontaneously clearing viremia over a median follow-up of 5.2 years (IQR, 2.8-7.4). At baseline, individuals with HCV clearance were more likely to be HIV coinfected (P < .001) and to be engaged in frequent illicit drug use (P = .004) and injection drug use (P < .001). The occurrence of HCV infection was lower in individuals with previous infection (14/152, 9.2%) compared with that in those without previous infection (172/926, 18.6%), with incidence rates of 1.8 (95% CI, 0.9-3.0 cases/100 person-years) and 8.1 (95% CI, 6.9-9.4 cases/100 person-years) cases/100 person-years, respectively, after accounting for follow-up. In a logistic regression analysis, with previous HCV infection assessed as a covariate with other potential confounding variables (age, sex, ethnicity, HIV infection, housing status, and illicit and injection drug use), individuals with previous HCV infection and viral clearance were 4 times less likely to develop infection than those infected for the first time (adjusted odds ratio, 0.23; 95% CI, 0.10-0.51, P < .001). In conclusion, individuals with clearance of HCV infection may have a lower risk of acquiring HCV than individuals who have never been infected, despite ongoing exposure to HCV.

Hepatology highlights

Hepatology highlights

Characteristics and Prospects for Hepatitis C Therapy of an HIV-HCV Coinfected Population Followed at a Reference HIV Center

Purpose: A cross-sectional study was performed during 2004 at a large HIV clinic in Spain to identify HIV-HCV coinfected individuals who might be candidates for HCV therapy. Method: Plasma HCV RNA levels were measured in 405 anti-HCV antibody positive patients. Spontaneous HCV clearance had occurred in 11.4%. Overall, 165 (40.1%) of HCV-HIV coinfected patients had already been exposed to interferon (IFN)-based therapies. Excluding those currently on treatment, the majority of them had either failed (64/142; 45.1%) or not completed therapy (25/142; 17.6%). Other 103 (25.4%) chronic HCV carriers refused treatment or were not considered as appropriate candidates, most often due to low CD4 counts or severe neuropsychiatric conditions. Treatment was deemed feasible and planned in the near future in 91 (22.5%) patients. Unfavorable HCV genotypes (1 and 4) were significantly more frequent in this group of individuals ready for HCV treatment compared to those who had cleared HCV in the past following IFN-based therapies. Results: Spontaneous clearance of the HCV infection was low in HIV-coinfected patients. One third of our HIV-HCV coinfected population had already been exposed to HCV therapy, but only a minority had achieved sustained HCV clearance. Half of patients with active HCV replication never exposed to IFN were not considered as appropriate candidates for HCV therapy. Conclusion: More flexible criteria would considerably increase the number of patients to be treated with IFN-based therapy. The majority of patients ready to initiate HCV therapy have a poor therapeutic profile.

Natural Killer Cells in Hepatitis C Virus Infection: From Innate Immunity to Adaptive Immunity

Natural killer (NK) cells are specialized lymphocytes that provide a first line of defense through their ability to kill pathogen-infected cells and transformed cells. The function of NK cells is regulated by a fine balance of inhibitory and activating signals, which are mediated by a diverse array of cell-surface receptors. We recently found that expression of the inhibitory receptor CD94/NKG2A is up-regulated on NK cells in patients with chronic hepatitis C. HLA-E, a ligand for NKG2A, was expressed in all human hepatoma cell lines tested as well as in nontransformed hepatocytes, but not in K562 cells, a classic NK-sensitive target. NK cells isolated from patients with chronic hepatitis C (HCV-NK) were less capable of killing hepatoma cells and of producing interferon-gamma in response to hepatoma cells than those from healthy donors, whereas there was no significant difference in NK responsiveness toward K562 cells. Of note is the finding that maturation and activation of monocyte-derived dendritic cells were negatively modulated in the presence of HCV-NK and hepatoma cells, which were restored by the addition of anti-NKG2A antibody during the coculture of HCV-NK and hepatoma cells. Research revealed that dendritic cells recognize danger signals from microorganisms by monitoring pathogen-associated molecular patterns via Toll-like receptors. Our findings have shed light on NK receptors as an important interface that transmits danger signals from abnormal cells to immune systems. Aberrant expression of CD94/NKG2A should have negative impact on innate resistance and subsequent adaptive immunity toward HCV-infected or transformed cells in chronic hepatitis C.