Chronic HCV Carriers Research Articles

Enhanced detection of overt HBV infection in chronic HCV carriers

Enhanced detection of overt HBV infection in chronic HCV carriers

Impact of HIV-1 Infection on the Natural Progress of an Anti-HCV Positive Population in an Impoverished Village in China from 2009 to 2017.

Our study aimed to determine the impact of HIV coinfection on the natural progression of liver disease in treatment-naive HCV-infected patients. From 2009 to 2017, we tracked non-invasive markers of liver fibrosis and end-stage liver disease (ESLD)-associated mortality among HCV mono-infected and HIV/HCV coinfected patients in an impoverished village in China. The study cohort consisted of 355 HBsAg-negative and anti-HCV (+) or anti-HIV (+) patients recruited in July 2009, 164 of whom were diagnosed with HIV-1 infection. The surviving patients were re-evaluated in August 2017. During the follow-up, the disease status, liver biochemical, and non-invasive indicators of liver fibrosis (APRI and FIB-4) were measured. The transaminases ALT and AST were significantly higher in HIV-positive HCV resolvers (HIV+ HCVr) than in HIV-negative HCV resolvers (HCVr) (p = 0.019 and p < 0.0001, respectively). APRI and FIB-4 scores of HIV-positive chronic HCV carriers (HIV+ HCVc) were significantly higher than in HIV-negative chronic HCV carriers (HCVc) (p < 0.001). Similarly, APRI and FIB-4 scores were higher in the HIV+ HCVr group than in the HCVr group (ps < 0.001). From 2009 to 2017, the levels of ALT (p = 0.006), AST (p = 0.003), APRI (p = 0.015), and FIB-4 (p = 0.025) were significantly elevated in the HIV/HCV coinfected patients with CD4+ T counts below 500 cells/l. ESLD-related mortality was significantly greater in HIV/HCV-infected cases than in HCV mono-infected patients (73.3% vs. 31.3%, p = 0.009) among patients (n = 45) who died between 2009 and 2017 during follow-up. These findings suggest a higher risk of ESLD-related death and rapid progression of liver fibrosis in HIV/HCV coinfected individuals compared with HCV mono-infected patients. During HIV/HCV coinfection, HIV infection may aggravate HCV-associated liver injury.

Hepatic TLR4, MBL and CRP gene expression levels are associated with chronic hepatitis C

Contact with HCV triggers the activation of innate mechanisms responsible for initial infection control. Host cells expressed extra- or intracellularly molecules that promote recognition of pathogen-associated molecular patterns (PAMPs). Toll-like receptor 4 (TLR4), mannose-binding lectin (MBL) and C-reactive protein (CRP) are molecules available for HCV PAMP recognition. The present study evaluated TLR4, MBL and CRP gene expression in the hepatic tissue of chronic HCV carriers (n = 22) and the association of that expression with the pathogenesis of HCV as well as the progression of liver fibrosis. Liver biopsy specimens from the HCV group were divided according to the METAVIR classification: without fibrosis and/or mild fibrosis (F0-F1), moderate fibrosis (F2), and severe fibrosis and/or cirrhosis (F3-F4) and A0-A1 (absent or mild inflammation) and A2 (moderate inflammation); normal liver samples were used as a control (n = 8). The mRNA levels of the genes studied were quantified by real-time PCR, and plasma CRP and liver enzymes were measured using an automated system. CRP and MBL expression was significantly lower in the HCV group compared to that in the control group (p < .0001 and p = .0242, respectively). TLR4 expression was higher in the HCV group than in the control group (p = .0448) and was also significantly higher (p = .0314) with lower levels of necroinflammatory activity (A0-A1), with a significant correlation between the expression of MBL with TLR4 as well as a positive correlation between plasma levels and CRP expression in the HCV group (p = .0431). Hepatic TLR4, MBL and CRP expression showed no significant association with liver enzymes nor plasma viral load. Mechanisms of HCV escape seem to influence hepatic TLR4, MBL and CRP expression, resulting in a change in the transcription profile of these proteins of innate immunity, which may contribute to virus persistence, liver fibrogenesis and loss of normal liver function.

Polymorphisms in the Th17 cell-related RORC gene are associated with spontaneous clearance of HCV in Chinese women

BackgroundFemale gender and favorable IFNL3 genotypes are the primary independent predictors of spontaneous clearance of HCV infection. However, chronic hepatitis C infection occurs in numerous women carrying favorable IFNL3 genotypes, indicating that other host and/or virological factors contribute to the prognosis of infection.MethodsA cohort of 137 anti-HCV-positive female Han Chinese cases, including 64 chronic HCV carriers and 73 HCV spontaneous resolvers, was recruited in the study. 111 SNPs in 23 genes encoding HCV co-receptors, transcription factors, Toll-like receptors, co-stimulating molecules, and cytokines were selected for SNP analysis.ResultsAfter comparison of genotypes and allelotype frequencies of 111 SNPs in 23 genes in the primary cohort, the SNPs rs9826 (P = 0.024 for CC/TT/CT; P = 0.015 for C allele/T allele) and rs1521177 (P = 0.017 for GG/TT/GT; P = 0.006 for G allele/T allele) in the RORC gene were significantly associated with spontaneous HCV clearance. In the sub-cohort carrying favorable IFNL3 genotypes (rs12979860CC, rs8099917 TT, rs12980275 AA), rs1521177 (genotype: P = 0.040; allelotype: P = 0.021) remained significantly associated with spontaneous HCV clearance. Importantly, the most common RORC haplotype rs9826-T/rs1521177-T was presented at significantly different frequencies in resolvers and carriers in both the primary cohort (P = 0.0027) and the IFNL3 favorable sub-cohort (P = 0.0117).ConclusionsThis study indicates that genetic polymorphisms in human Th17-related RORC gene are associated with different natural prognosis of HCV infection. The RORC haplotype, rs9826-T/rs1521177-T, was favorable for spontaneous clearance of HCV infection.

Synergistic impact of mutations in Hepatitis B Virus genome contribute to its occult phenotype in chronic Hepatitis C Virus carriers

We characterized occult HBV (OHBV) from hepatitis B surface antigen (HBsAg)-negative chronic HCV carriers of Eastern India to explore the impact of genomic variability of HBV in causing undetectability of HBsAg and low viremia that define the occult phenomenon. Screening of sera samples revealed the presence of OHBV in 17.8% of HCV-infected patients. Determination of full-length OHBV sequences and comparison with that from HBsAg-positive carriers led to the detection of distinct substitutions/mutations in PreS2, S, P and X ORFs and in X-promoter and Enhancer-II of OHBV. These mutations were introduced in wild-type HBV and their effects were evaluated by transfection in Huh7 cells. In vitro assays demonstrated that S-substitutions resulted in antigenically modified HBsAg that escaped detection by immunoassays whereas those in ORF-P caused significant decline in viral replication. Impairment in Enhancer-II and X-promoter activities were noted due to occult-associated mutations that generated reduced pregenomic RNA and intracellular HBV-DNA. Additionally, Enhancer-II mutations altered the small to large surface protein ratio and diminished extracellular HBV-DNA and HBsAg secretion. Further, mutations in PreS2, X and enhancer-II increased Grp78-promoter activity, suggesting that OHBV could trigger endoplasmic reticulum stress. Thus viral mutations contribute synergistically towards the genesis of occult phenotype and disease progression.

Genetic variants in interferon-\u03bb 4 influences HCV clearance in Chinese Han population

Recent many studies indicated a novel dinucleotide variant in ss469415590 (TT vs. ΔG) of interferon-λ 4 (IFNL4) gene strongly associated with hepatitis C virus clearance. To evaluate the impact and clinical usefulness of IFNL4 ss469415590 genotype on predicting both spontaneous HCV clearance and response to therapy in Chinese population, we genotyped 795 chronic HCV carriers, 460 subjects with HCV natural clearance and 362 patients with pegylated interferon-α and ribavirin (PEG IFN-α/RBV) treatment. IFNL4 ss469415590 variant genotypes significantly decreased host HCV clearance, both spontaneous (dominant model: OR = 0.50, 95% CI = 0.36–0.71) and IFN-α induced (dominant model: OR = 0.32, 95% CI = 0.18–0.56). Multivariate stepwise analysis indicated that ss469415590, rs12979860, the level of baseline HCV RNA and platelet were as independent predictors for sustained virological response (SVR). But the area under the ROC curve (AUC) was only 0.58 for ss469415590, and it was elevated to 0.71 by adding rs12979860, baseline HCV RNA and platelet in the prediction model of SVR. Therefore, these findings underscore that although genetic factors of host and pathogen were commonly important during HCV clearance, ss469415590 may be also a strongly predictive marker in the Chinese population.

Dynamics of a Viral Infection Logistic Model with Delayed Nonlinear CTL Response and Periodic Immune Response

This paper investigates the global dynamics and bifurcation structure of a viral infection logistic model with delayed nonlinear CTL response and periodic immune response. It is proved that the basic reproduction numbers, $R_{0}$ and $R_{1}$, determine the outcome of viral infection. Besides changes in the amplititude of lytic component, we show, via numerical simulations, that , the birth rate of susceptible host cells and the maximum proliferation of target cells are crucial to the outcome of a viral infection. Time delay can alter the period of oscillation for the larger level of periodic forcing. Period doubling bifurcations of the system are observed via simulations. Our results can provide a possible explanation of the oscillation behaviors of virus population,which were observed in chronic HBV or HCV carriers.

Liver Damage in Patients with HCV/HIV Coinfection Is Linked to HIV-Related Oxidative Stress.

HIV infection aggravates the progression of liver damage in HCV-coinfected patients, with the underlying pathogenesis being multifactorial. Although high level of oxidative stress has been observed frequently in patients infected with HIV or HCV, the status of oxidative stress in HIV/HCV coinfection and its contribution to HCV liver damage have not been determined. This study involved 363 HBsAg-negative, anti-HCV-positive former blood donors recruited from a village in central China in July 2005; of these, 140 were positive for HIV. Of these 363 subjects, 282 were successfully followed up through July 2009. HIV/HCV-coinfected subjects had higher rates of end-stage liver disease-related death than those monoinfected with HCV. Liver ultrasound manifestations were poor in HIV-positive than in HIV-negative individuals, in both chronic HCV carriers and those with resolved HCV. Serum concentrations of total glutathione (tGSH), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), GSSG, and reduced GSH were higher in HIV-positive than HIV-negative subjects. GSSG concentrations were higher in HIV-infected subjects with abnormal ALT/AST levels than in those with normal ALT/AST levels and were associated with poorer liver ultrasound manifestations. These finding indicated that HIV infection accelerated HCV-associated liver damage in HIV/HCV-coinfected individuals. Increased oxidative stress, induced primarily by HIV coinfection, may contribute to aggravated liver damage.

Hepatitis B Hepatitis C virus and Malaria coinfection

Background: Malaria remains a major health threat worldwide. Endemic regions for malaria are endemic for other infectious diseases that might affect the malaria infection. Methods: A systematic search was conducted where it included published data about HBV, HCV and malaria. Published data on epidemiology, pathogenesis and consequences of HBV, HCV and malaria, were extracted from relevant studies. Epidemiology of co-infection has not been well studied, and studies in this concern will definitely draw the attention of decision makers towards such problem. Results: Younger age and male gender were risk factors for co-infection. There were no protective effects of HBV vaccine against malaria. The interaction between malaria parasites and HCV among chronic HCV carriers might slow the emergence of the former and that could help in determining new therapeutic approaches to defeat malaria. Conclusion: Strategies to improve currently available diagnostic techniques, researches dealing with therapeutic and prophylactic agents and protocols, vector control procedures, vaccine bringing up evolution, and other operational tools and approaches are needed.

Widespread Dystrophic-Anagen Alopecia and Drug Eruption due to Usage of PEG-IFN ?-2a /Ribavirin Combination Therapy

Chronic hepatitis C infection (CHC) is acknowledged as a major health problem all over the world. The World Health Organization estimates that 3-4 million individuals are infected each year worldwide, with a global 170 million chronic HCV carriers at risk of developing liver cirrhosis and/or liver cancer. The most experienced treatment for chronic hepatitis C is pegylated interferon (PEGINF) and ribavirin (RBV) combination therapy. A variety of conditions ranging from endocrinopathies to different skin diseases have been described in only HCV infections and/or associated with IFN based therapy. The skin lesion during anti-HCV therapy rate is 24-28%, according to randomized controlled clinical trials. The incidence of cutaneous eruptions has been estimated to be 13% to 23%. Alopecia is a frequent adverse effect of interferon and ribavirin treatment in 19% of patients treated with combination therapy. Several types of alopecia exist; telogen effluvium, localized alopecia at the injection site AA (Alopeciae Areata) and AU (Alopeciae Universalis) have been described. Telogen effluvium (TE) is characterized by an excessive loss of telogen hair. It occurs in about 30% of patients who are treated with IFN. Anagen effluvium (AE) is the non-reported case in literature in terms of the PEG-IFN and RBV combination therapy for chronic HCV infection induced anagen alopecia. Herein, we are present a case of dystrophic TE which was attributed to the INF/ribavirin combination therapy, and interpretation of the case according to hertrichogram findings. To the best of our literature search, our patient is the first case in terms of extensively interpreted with both clinical and trichogram features of a PEG-INF/ribavirin induced alopecia.

The clinical relevance of persistent recombinant immunoblot assay–indeterminate reactions: insights into the natural history of hepatitis C virus infection and implications for donor counseling

Recombinant immunoblot assay (RIBA) is used to determine the specificity of antibody to hepatitis C virus (anti-HCV). The RIBA result is recorded as positive, negative, or indeterminate. The interpretation and significance of RIBA-indeterminate reactions are unclear. We addressed the clinical relevance of these reactions in the context of the natural history of HCV infection in a prospectively followed cohort of anti-HCV-positive blood donors. Donor demographics, exposure history, and humoral and cell-mediated immunity (CMI) were compared in 15 RIBA-indeterminate subjects, nine chronic HCV carriers, and eight spontaneously recovered subjects. Serum samples were tested for anti-HCV by a quantitative, liquid luciferase immunoprecipitation system (LIPS). CMI was assessed by interferon-γ enzyme-linked immunosorbent spot assay. In the LIPS assay, the sum of antibody responses to six HCV antigens showed significant (p < 0.001) stepwise diminution progressing from chronic carriers to spontaneously recovered to RIBA-indeterminate subjects. CMI responses in RIBA-indeterminate subjects were similar to spontaneously recovered subjects and greater than chronic carriers and controls (p < 0.008). A parenteral risk factor was identified in only 13% of RIBA-indeterminate subjects compared to 89% of chronic carriers and 87% of spontaneously recovered subjects. RIBA-indeterminate donors were older than the other groups. The CMI and LIPS results suggest that persistent RIBA-indeterminate reactions represent waning anti-HCV responses in persons who have recovered from a remote HCV infection. In such cases, detectable antibody may ultimately disappear leaving no residual serologic evidence of prior HCV infection, as reported in a minority of long-term HCV-recovered subjects.

Positional effect of phosphorylation sites 266 and 267 in the cytoplasmic domain of the E2 protein of hepatitis C virus 3a genotype: Interferon Resistance analysis via Sequence Alignment

BackgroundInterferon is well thought-out as the key defence against all infections including HCV. The only treatment for HCV infection is pegylated interferon alpha (IFN-α) but unluckily more than half of the infected individuals do not act in response to the cure and become chronic HCV carriers. The mechanism how HCV induce interferon resistance is still elusive. It is recently reported that HCV envelope protein 2 interacts with PKR which is the interferon-inducible protein kinase and which in turn blocks the activity of its target molecule called eukaryotic initiation factor elF2. Sequence analysis of Envelope protein reveals it contains a domain homologous to phosphorylation sites of PKR andthe translation initiation factor eIF2alpha. Envelope protein competes for phosphorylation with PKR. Inhibition of kinase activity of PKR is postulated as a mechanism of to interferon (IFN) resistance.ResultsPresent study involves the insilico investigation of possible role of potential phosphorylation in envelope 2 protein of 3a genotype in interferon resistance. Envelope protein coding genes were isolated from local HCV isolates, cloned and sequenced. Phylogenetic analysis was done and tertiary structure of envelope gene was predicted. Visualization of phosphorylation in tertiary structure reveals that residue 266 and 267 of envelope gene 2 are surface exposed and their phosphorylation may compete with the phosphorylation of PKR protein and possibly involved in mediating Interferon Resistance.ConclusionA hybrid in-silico and wet laboratory approach of motif prediction, evolutionary and structural analysis has pointed out serine 266 and 267 of the HCV E2 gene as a hopeful claimant for the serine phosphorylation. Recognition of these nucleotide variations may assist to propose genotype precise therapy to avoid and resolve HCV infections.

Inhibition of TNFa in Patients with Concomitant HCV Infection; Molecular Insights and Safety

Chronic viral infections, such as chronic hepatitis C, are major causes of disease worldwide. They represent model systems for the study both of sophisticated ways to elute host defense mechanisms, and of mechanisms to sustain inflammation, potentially leading to autoimmune manifestations as a side effect. Cytokines are central inducers and regulators of both immune-mediated virus clearance and of immunopathology. This review describes the potential implications of TNFa in the development and clinical progression of chronic hepatitis C infection. The frequency of chronic hepatitis C, its usually indolent course, and the current application of these biological agents for the management of continuously expanding therapeutic indices, renders the study of the molecular effects and safety of TNFa antagonists in chronic HCV carriers of particular clinical significance.

Hepatitis C virus with a naturally occurring single amino-acid substitution in the E2 envelope protein escapes neutralization by naturally-induced and vaccine-induced antibodies

Mutations arising in neutralizing epitopes of hepatitis C virus may play a role in the ability of the virus to escape control by neutralizing antibodies and in the establishment of chronic infections. An amino-acid substitution, Q412H, within a major conserved neutralization epitope EP I (aa 412–426) in the E2 glycoprotein is observed in chronic HCV carriers. We found that naturally acquired polyclonal EP I-specific antibodies have an equivalent binding capacity toward either the wild type or the Q412H mutant peptide encompassing the EP I epitope. While EP I-specific antibodies neutralized J6/JFH1 virus in vitro, they did not neutralize J6/JFH1 virus containing the Q412H mutation. Furthermore, we found that plasma obtained from a chimpanzee that had anti-E1/E2 antibodies following experimental immunization, neutralized the wild type J6/JFH1 virus but failed to neutralize the mutant virus. Thus, mutation Q412H found in naturally occurring variants could represent an antibody escape mutation. These data may have important implications for vaccine design.

A viral infection model with immune circadian rhythms

A viral infection model with immune circadian rhythms is investigated in this paper. By employing the persistence theory, we establish a threshold between the extinction and the uniform persistence of the disease. These results can be used to explain the oscillation behaviors of virus population, which were observed in chronic HBV or HCV carriers. Further, numerical simulations indicate that the dynamics of the lytic component of cytotoxicity T cells (CTLs) is crucial to the outcome of a viral infection.

Structural characterisation of the hepatitis C envelope glycoprotein E1 ectodomain derived from a mammalian and a yeast expression system

The structure of the ectodomain of the hepatitis C envelope glycoprotein E1 (E1s) was characterised by spectroscopic methods. Monomeric E1s was purified from a mammalian and from a Hansenula polymorpha cell lysate, and cysteine-blocked monomers were reconstituted into stable particles. Particles from yeast E1s and mammalian E1s showed a comparable reactivity in ELISA with sera from human chronic HCV carriers, similar antibody titers in the sera of immunised mice as well as a comparable structure as analyzed by spectroscopic methods (tryptophan fluorescence, circular dichroism, and Fourier transform infrared spectroscopy). The overall secondary structure of E1s was neither influenced by the degree of glycosylation nor by the nature of cysteine modification used during purification. The structural comparability of mammalian- and H. polymorpha-expressed E1s opens new perspectives for further development of E1s-based therapeutics as yeast systems generally allow a more easy scaling up.

P.140 Anti-HCV immune response in healthy individuals in contact with chronic HCV carriers

The objective of this study was to evaluate liver fibrosis using non-invasive methods in elderly patients.In a prospective two-day study, all consecutive patients of geriatric units were examined using transient elastography (FibroScan®) and biochemical markers (Hepascore, Aspartate Transaminase (AST) to platelet ratio index [APRI], Forns score, FibroTest®). Three groups of patients were included: elderly patients without liver disease (group A, 85.2 ± 7.3 years); healthy younger control subjects without liver fibrosis (group B, 46.4 ± 15.2 years); and elderly patients with confirmed liver disease (group C, 82.4 ± 2.3 years).FibroScan® results in the elderly patients correlated well with fibrosis surrogates, but were more difficult to obtain than in the younger subjects. Mean liver stiffness was 6.1 kPa (group A) versus 4.9 kPa (group B) and versus 10.2 kPa (group C) (P < 0.0001). FibroTest® results were 0.5 in group A versus 0.2 in group B, and versus 0.6 in group C (P < 0.0001). In group A, statistical analysis showed that diabetes was associated with advanced liver fibrosis (FibroScan® ≥ 9.5 kPa). A body mass index greater than 26 kg/m2, age greater than 85 years, comorbidity score and polymedication were not associated with fibrosis.Although liver stiffness may be more difficult to assess in the elderly, FibroScan® may nevertheless serve as a new, non-invasive method for detecting liver fibrosis in this population.L’objectif de cette étude était d’évaluer la fibrose hépatique de manière non invasive chez la personne âgée hospitalisée.Une étude prospective (deux jours consécutifs) a permis d’évaluer la fibrose hépatique par élastométrie impulsionnelle (FibroScan®) et marqueurs biologiques (Hepascore, APRI, Forns score, FibroTest®) chez les patients hospitalisés en gériatrie. Trois groupes ont été analysés : patients hospitalisés en gériatrie (groupe A, 85,2 ± 7,3 ans), sujets jeunes sans fibrose hépatique (groupe B, 46,4 ± 15,2 ans) et patients âgés suivis pour hépatopathie chronique (groupe C, 82,4 ± 2,3 ans).Même si le FibroScan® était corrélé aux marqueurs biologiques de la fibrose hépatique, les taux de réussite diminuaient significativement en gériatrie. L’évaluation de la fibrose montrait une élasticité moyenne de 6,1 kPa (groupe A) versus 4,9 kPa (groupe B) et 10,2 kPa (groupe C) (p < 0,0001). Les résultats du FibroTest® étaient les suivants : 0,5 (groupe A) versus 0,2 (groupe B) et 0,6 (groupe C) (p < 0,0001). Dans le groupe A, l’élasticité hépatique supérieure à 9,5 kPa était significativement associée au diabète et non à un index de masse corporelle supérieur à 26 kg/m2, à l’âge supérieur à 85 ans, au score de comorbidités ou à la polymédication.Même si les performances de l’élastométrie diminuent en gériatrie, le FibroScan® pourrait être une méthode simple et utile à réaliser dans cette population.

P.284 Neurocognitive alterations in patients with HCV infection with and without abnormal transaminases

Background/Aims: To study whether the host's immune response determines viral clearance in chronic hepatitis C, virological markers and antigen-specific T cell reactions were analysed in 30 chronic HCV carriers followed up during interferon-α therapy, 11 untreated anti-HCV positive individuals and 10 healthy controls.Methods: Proliferative T helper cell responses to recombinant HCV core and non-structural antigens were monitored by 3H-thymidine uptake assay and compared to quantitative viraemia levels and HCV genotypes.Results: Of the 30 treated patients, six had sustained complete responses (20%), another six were transient therapy responders (20%) and 18 were non-responders (60%). Viral clearance was associated with the HCV genotype 3 and low pretreatment viral load. In a substantial proportion and complete and transient therapy responders, increased NS3-, helicase- and NS4-antigen-specific T cell responses were observed during interferon-α therapy. In non-responders and in the later clinical courses of transient therapy responders, core and NS5-specific T cell responses dominated. In addition, 11 untreated anti-HCV antibody positive individuals were studied. Two HCV-RNA negative patients who might have recovered from HCV infection showed strong persistent lymphoproliferative responses to NS3, helicase and NS4 antigens, whereas seven of the nine viraemic patients reacted with HCV core or NS5 antigens.Conclusions: Interferon-α treatment enhances NS3-, helicase- and NS4-antigen-specific T helper cell responses in patients with viral clearance, whereas viral persistence was associated with increased T cell reactivities against core and NS5 antigens. Immunogenetical, immunological and virological factors that may influence differential T cell induction in chronic hepatitis C are discussed.

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 Course of Asymptomatic Hepatitis C Virus–Infected Patients and Hepatocellular Carcinoma After Interferon Therapy

A long-term follow-up study was performed to identify the natural course of chronic HCV carriers with persistently normal serum ALT level (PNAL; < or =30 U/L) and to clarify the effect of interferon therapy on the inhibition of the development of hepatocellular carcinoma (HCC) in chronic hepatitis C patients with elevated ALT levels. One hundred twenty-nine HCV carriers with PNAL underwent liver biopsy, 69 were followed for more than 5 years, and 35 underwent serial liver biopsies. We included 1246 chronic hepatitis C patients (stage F1: 231, F2: 638, F3: 336, F4: 41) who received interferon therapy and were followed for more than 2 years (mean, 7.7 years). Approximately 90% of HCV carriers with PNAL had normal to mild liver histology, and 30% developed symptomatic chronic hepatitis C within 5 years. The frequency of steatosis and iron loading was significantly lower in these patients than in symptomatic chronic hepatitis C patients. The progression rate of fibrosis was slower than in chronic hepatitis C patients with elevated serum ALT levels. HCC was noted in 157 chronic hepatitis C patients after interferon therapy, and the development of HCC was significantly reduced in both sustained responders and transient biochemical responders compared with nonresponders. HCC in sustained responders mainly developed in male patients older than 55 years with advanced stage liver histology at entry. Approximately 30% of HCV-infected patients with PNAL become candidates for antiviral therapy within 5 years. Interferon therapy lowers the rate of the development of HCC in both sustained responders and transient biochemical responders.