Clinical Course of Chronic Hepatitis C Virus Infection Is Not Influenced by Concurrent Hepatitis G Virus Infection

To determine the effects of hepatitis G virus(HGV) infection on chronic hepatitis C virus infection(HCV) and to evaluate HGV response to interferon, weinvestigated HGV RNA by polymerase chain reaction in 247 Japanese patients with chronic HCVinfection (166 men and 81 women; 124 had chronichepatitis and 26 cirrhosis, and 97 hepatocellularcarcinoma). HGV RNA was detectable in 22 (8.9%)patients, among whom 21 were men: this male predominance wasstatistically significant (P < 0.01). There were nodifferences in age, aminotransferase level, stage ofliver disease, HCV RNA level by competitive polymerase chain reaction, genotype, or interferonresponse to HCV RNA between patients with HCV infectionalone or with HCV/HGV coinfection. Sustained eliminationof HGV RNA was found in 28.6% of the 14 treated patients with HCV/HGV coinfection. In the 14 treatedpatients, sustained elimination of both viruses was seenin two, HCV alone was eliminated in two, and HGV alonewas eliminated in two. Aminotransferase level improvement by interferon treatment wasassociated with clearance of HCV, but not of HGV. Thus,HGV infection had no apparent effects on HCV infection,and the sensitivity of HGV to interferon is comparable to but independent of HCV.     

No Significant Changes in Levels of Hepatitis C Virus (HCV) RNA by HCV Infection Competitive Polymerase Chain Reaction in Blood Samples from Patients with Chronic

To determine if levels of hepatitis C virus(HCV) RNA change over a several-year period, wequantified the amount of HCV RNA by competitivepolymerase chain reaction. The population studiedincluded 44 residents of a rural area with chronic HCVinfection, 39 had chronic hepatitis C and 37 werepatients on hemodialysis. All these Japanese patientshad HCV RNA of genotype II. Blood samples were collected once a year from 1992 to 1995. From 1993 to1995 between the groups, there was no significantdifference in change of HCV RNA levels of 44 residentswith chronic HCV infection, with and without liverdysfunction, nor was there any change in the 31 hemodialysispatients from 1992 to 1995. The HCV RNA levels in the 25with chronic hepatitis who did not respond tointerferon-alpha during 1992-1993 returned topretreatment levels after the cessation of interferontreatment. In two of six hemodialysis patients who wereinfected with HCV during this observation period, HCVRNA was eliminated within one year, and the remaining four became HCV carriers. HCV RNA levels in thelatter rose rapidly after infection and were sustainedat a high level throughout the study period. Thus, HCVRNA level did not change remarkably during a three-year period, a finding which supportsthat it does not correlate with deterioration of liverdamage and aging of HCV carriers.     

Correlation Between Relative Number of Circulating Low-Density Hepatitis C Virus Particles and Disease Activity in Patients with Chronic Hepatitis C

Hepatitis C virus (HCV) circulates as particleshaving differing buoyant densities. Changes in therelative proportions of virus particles of differentdensities were examined in 19 patients with chronic hepatitis C: 6 without (group A) and 13 with(group B) abnormal serum alanine aminotransferase (ALT)levels. High- and low-density virus particles wereseparated by differential flotation centrifugation. The numbers of high-density particlesconsistently exceeded that of low-density particles inall patients in group A, whereas the titers of bothtypes of particles were the same at least once in 7 of10 patients sampled at two time points in group B.The ALT level significantly increased, <2 monthslater (P < 0.05) when the titers of both types ofparticles were the same in patients in group B. Thus, we found a correlation between the relativenumbers of circulating low-density HCV particles anddisease activity in chronic hepatitis Cpatients.     

HCV Infection in Egyptian Patients with Acute Hepatitis

The diagnostics of community-acquired acute HCVhepatitis in an endemic area was studied in 110 Egyptianpatients with acute jaundice. In the first week of thejaundiced period 30 of 110 patients (27.3%) had anti-HCVantibodies. The majority already showed high levels ofanti-HCV IgG (25/30), associated with anti-HCV IgM innine of them. Five patients showed only an HCV IgMreactivity. Seven had also anti-HEV and/or anti-HBV: their jaundice couldthen be related to an acute infection caused by thoseviruses. All patients were infected with genotype 4a, inthree associated with the 3a. During the follow-up five patients seroconverted for IgG, whiletheir anti-HCV IgM did not show a uniform pattern ofreactivity. Patients with positive serology suspected ofan acute HCV infection were older than the patients with other acute hepatitis and showed a lowerpeak of ALT level. Seroconversion during acute hepatitisstrongly indicated HCV as the etiologic agent. However,the detection of anti-HCV IgG antibodies in the jaundiced period showed that the majorityof patients had already seroconverted to anti-HCVantibodies; in most of them it is possible tohypothesize a reactivation of a chronic HCVinfection.     

Hepatitis G Virus Infection Among Liver Graft Recipients: Anatomoclinical Correlations

Hepatitis G virus (HGV) causes persistent infection in man, but its disease association is controversial. We studied the HGV disease association in 25 liver transplantation (LT) recipients without evidence of hepatitis B and C infection. HGV RNA was tested by semiquantitative RT-PCR in serial serum samples and its presence was correlated with the biochemical and histological evidence of liver damage. The overall prevalence of HGV infection in this population was 9/25 (36%), one patient being HGV RNA positive since before LT, while the other eight apparently acquired de novo infections after LT. In five cases, appearance of HGV was followed by biochemical and histological evidence of liver damage: the liver biopsy showed acute rejection in two cases, acute cholangitis in two, and acute hepatitis in one. At the end of follow-up, histological evidence of chronic hepatitis was found in one HGV-positive patient but also in three HGV-negative patients, whereas the only patient with acute hepatitis at the time HGV RNA was first detected in serum developed an intralobular gigantocellular granuloma. In conclusion, HGV infection after LT may be seldom associated with acute and chronic liver damage, but comparable histological features can be observed also among HGV-negative controls.     

Viral and Host Factors in Determining Response of Relapsers with Chronic Hepatitis C to Retreatment with Interferon

In chronic hepatitis C the rate of relapse afteran end-of-treatment response to interferon may exceed50%. The usefulness of retreatment of relapsers withinterferon in obtaining a complete sustained response and the role of clinical, virological andimmunological features in determining long-term efficacyof retreatment are unclear. We aimed to assess theefficacy of interferon retreatment in obtaining acomplete sustained response, to evaluate whetherincreasing the dose may enhance responsiveness, and toidentify possible predictors of sustained response. Weenrolled 42 patients with biopsy-proven chronichepatitis C without cirrhosis who had previouslyresponded to a six-month course ofInterferon-_2b (total dose: group A, 22patients, 234 MU; group B, 20 patients, 468 MU) and thenrelapsed. All, except one, were HCV-RNA negative at the end of first cycle ofinterferon; most (31/42, 74%) were infected by HCV 1b.Subjects were randomly allocated to receive anothercycle of interferon either at the original dose (group A₁: 234 MU, 11 patients; groupB 468 MU, 10 patient) or twice the original dose (groupA₂: 468 MU, 11 patients; group B : 936 MU, 10patients). At the end of the second cycle of interferon,24 subjects (57%) had normal ALT and were HCV-RNAnegative, and 16 (39%) had normal ALT, but were HCV-RNApositive. A complete sustained response was obtained ineight patients (19%), at a similar rate in all treatment groups. Complete sustainedresponders were different from the other patients interms of age (35.9 ± 10.4 vs 44.1 ± 8.8,P = 0.027), rate of infection with non-1b HCV (6/8 vs5/34, P = 0.0005), serum HCV-RNA (74,016 vs 321,428median copies/ml, P = 0.037) and serum levels of90K/MAC-2 BP (5.76 ± 3.01 vs 10.25 ± 5.16units/ml, P = 0.02), an N-glycoprotein implicated incellular defense functions. Multivariate logistic analysisvalidated age and HCV genotype as independent predictorsof CSR. Among noncirrhotic relapsers who received atotal interferon dose 234 MU in the first cycle,retreatment usually induced end-of-treatment response. Acomplete sustained response was obtained in only one ofevery five subjects. Increasing the dose of interferonabove that of the first cycle did not enhance the rate of sustained response. In conclusionwe might assert that young subjects infected by non-1bHCV and with low levels of HCV-RNA and of 90K/MAC-2 BPare the best candidates for retreatment.     

Comparison of HCV RNA Levels by Branched DNA Probe Assay and by Competitive Polymerase Chain Reaction to Predict Effectiveness of Interferon Treatment for Patients with Chronic Hepatitis C Virus

To compare hepatitis C virus (HCV) RNA levelsdetermined by branched DNA probe assay and bycompetitive polymerase chain reaction (PCR) aspredictive markers of the response to interferon fortreatment of patients with chronic HCV infection, westudied data on 140 patients treated for six months withnatural interferon-alpha. Serum samples were tested forHCV RNA by PCR. HCV RNA was grouped into four genotypes by PCR with type-specific primers,and HCV RNA level was measured by branched DNA probeassay and by competitive PCR. HCV RNA was detected inall patients prior to initiation of the treatment. A complete response, sustained elimination ofHCV RNA, occurred in 51 patients (36.4%). With multiplelogistic regression analysis assessment, when usingcompetitive PCR, a low level of HCV RNA (P < 0.0001), younger age (P = 0.0054) and genotype 2a and 2b(P < 0.0158) were significant predictive markers fora complete response to interferon treatment. When usingbranched DNA probe assay, a low level of HCV RNA (P < 0.0001) and age (P = 0.0089) werepredictive markers, but genotype was not. The branchedDNA probe assay had a narrower linear range forquantitation of HCV RNA level than competitive PCR. In conclusion, HCV RNA level determined bybranched DNA probe assay proved to be useful forprediction of effects of interferon and it is costeffective as a marker of complete response to interferontreatment for patients with chronic HCVinfection.     

Serum Soluble Interleukin-2 Receptor Levels Before and During Interferon Treatment in Patients with Chronic Hepatitis B Virus Infection

To determine the role of serum solubleinterleukin-2 receptor (sIL-2R) in chronic hepatitis Bvirus (HBV) infection, the level of serum sIL-2R wasmeasured in sera of 105 patients with chronic HBVinfection and in 21 healthy controls, using enzyme-linkedimmunosorbent assay. Serum sIL-2R levels weresignificantly higher in chronic HBV-infected patientswith chronic hepatitis (508 ± 310 units/ml) andliver cirrhosis (543 ± 283 units/ml) than inhealthy controls (331 ± 106 units/ml, P <0.05). Moreover, serum sIL-2R levels were significantlyhigher in patients with chronic hepatitis or livercirrhosis than in asymptomatic HBV carriers (341 ±150 units/ml, P < 0.01). There was no difference inserum sIL-2R levels between asymptomatic HBV carriersand healthy controls or between patients with chronic hepatitis and liver cirrhosis. A significantrelationship was found between serum sIL-2R and ALTlevels (P < 0.05) in patients with chronic HBVinfection, although there was no correlation betweensIL-2R and HBV DNA levels. Serum sIL-2R levels in mostpatients decreased to the same level as asymptomatic HBVcarriers and healthy controls at 48 weeks after the endof treatment, and serum ALT and HBV DNA levels were decreased to within the normal range at 96weeks. Thus, serum sIL-2R levels indicate the degree ofliver damage among patients with chronic HBV infection.The serum sIL-2R levels one year after interferon administration may be a useful marker ofdetermined at the effectiveness by thistreatment.     

Serum Pancreatic Enzyme Concentrations in Chronic Viral Liver Diseases

Serum amylase and lipase concentrations weredetermined in 78 patients with chronic liver diseases[26 chronic active hepatitis (CAH) and 52 livercirrhosis] and in 15 healthy subjects. Pancreaticisoamylase concentrations and macroamylase complexes wereassayed in hyperamylasemic sera. Serum amylase levelswere abnormally elevated in 27 patients (35%; 22 livercirrhosis, 5 CAH), whereas serum lipase levels were elevated in 16 patients (21%; 15 livercirrhosis, 1 CAH). In 9 of the 27 hyperamylasemicpatients, the hyperamylasemia was of pancreatic type.Macroamylasemic complexes were not detected inhyperamylasemic sera. Patients with liver cirrhosis had serumlevels of amylase and lipase significantly higher thanboth the healthy subjects and the patients with CAH,while no significant differences were found in serum levels of these enzymes in patients with CAH ascompared to the healthy subjects. A decreased livermetabolism of serum amylase and lipase in patients withchronic infective liver disease, especially in those having liver cirrhosis, may lead to anaccumulation of these enzymes in the blood.     

Phenotyping of Intrahepatic and Peripheral Blood Lymphocytes in Patients with Chronic Hepatitis C

The host immune responses have been suggested toplay a role in liver injury occurring in patients withchronic hepatitis C. In order to explore therelationship between the relative proportions ofintrahepatic and peripheral blood lymphocytes (IHL, PBL),the levels of viremia, and the histological hepatitisactivity score, three-color fluorescence-activatedcytometric analysis was performed for 36 patients with chronic hepatitis C and six control subjectswithout chronic hepatitis. The liver biopsy wasperformed before any antiviral therapy. Each liverspecimen was divided into two parts: one forhistological examination and one for immunological analysis.Tricolor CD45 was used to improvelymphogating. Fluorescein isothiocyanate-or phycoerythrin-conjugated monoclonal antibodies withspecificity for CD3, CD4, CD8, and CD20 (lymphocyte subpopulations),for CD69 (activated lymphocytes), and for CD16/56(natural killer cells) were used. The livers of patientswith chronic hepatitis C contained a greater proportion of CD4⁺ lymphocytes that exhibitedmarked expression of CD69 than in control subjects (20.7± 7.3% vs 10.2 ± 4.6%, P = 0.027).Moreover, in patients with chronic hepatitis C, theproportion of CD4⁺ IHL correlated with the histological hepatitisactivity evaluated by the Knodell score (r = 0.48, P =0.004). No correlation was found between the percentageof CD4⁺ IHL and the level of viremia ortransaminase activities. Our findings clearly indicate thata cellular immune response does take place inHCV-infected livers and could thus contribute to theoutcome of hepatitis C virus infection.     

Diversity of Nucleotide Sequences in Hypervariable Region 1 of Hepatitis C Virus in Japanese Patients with Chronic Hepatitis C of Unknown Mode of Transmission

We evaluated the sequence diversity of thehypervariable region 1 (HVR1) of hepatitis C virus (HCV)in HCV-infected patients in whom the mode oftransmission is unknown. The sequence diversity of HVR1in 26 Japanese patients with chronic HCV infectionof unknown mode of transmission (UT) was compared with17 patients with chronic posttransfusion hepatitis C inwhom only a single HCV infection had occurred (PH), and with 18 patients with hemophilia withchronic HCV infection who might have been multiplyinfected with HCV (HE). The diversity of HVR1 wasevaluated by direct sequencing after PCR amplification of HVR1. The sequence diversity of HVR1 was10.1 ± 7.7% in UT, 2.7 ± 2.8% in PH, and14.6 ± 6.9% in HE. The diversity of the patientswith unknown transmission was greater than that of theposttransfusion hepatitis patients, and in some patients it wassimilar to that of multitransfused hemophiliac patients(UT vs PH, P = 0.0004; UT vs HE, P = 0.04; and HE vs PH,P < 0.0001). Multiple infections with HCV could have occurred frequently in patientswith chronic HCV infection in whom the mode oftransmission was unknown, which increased the sequencediversity of HVR1 of these patients.     

Serum HCV-RNA and Liver Histologic Findings in Patients with Long-Term Normal Transaminases

In this study we aimed to correlate liverhistology and the presence of hepatitis C virus (HCV)viremia, genotype, and quantity of HCV genome in 19positive and 11 RIBA II indeterminate patientspresenting persistently normal ALT values over 24 monthsbefore biopsy. In addition, after biopsy serum ALTvalues were monitored monthly for a mean follow-upperiod of 24.8 months, after which patients werereevaluated for RIBA II and the presence of viremia.Sixteen patients (53%) were serum HCV-RNA-positive; 13of them (68%) were confirmed positive and 3 (27%)indeterminate on RIBA II. Histology of the HCV-RNA-positive patients showed eight cases of CPH (one case ofgenotype 1a; four cases type 1b; three cases type 2),six cases of CAH (three cases type 1b, three cases type2), one case of CLH (type not determined), and one case of normal liver (NL) (type 1b).Histology of the HCV-RNA-negative patients showed fourcases of CPH, one case of CAH, two cases of CLH, andseven cases of NL. During the follow-up period ninepatients (30%) presented slight increases in ALT values(<2 × N), and in particular, flares of ALT wereobserved four times in the CAH and five times in the CPHpatients, who were all viremic, but never in the NL subjects. These results indicate that subjectspositive on RIBA II, but with persistently normal ALTvalues, had a high probability of being serumHCV-RNA-positive and that almost all these viremicsubjects presented histologic signs of liver disease. Incontrast, RIBA II indeterminate subjects had a moderateprobability of being HCV-RNA-positive, but a number ofthese may present signs of liver disease. In both cases there was no association withgenotype or HCV-RNA serum levels. The other nonviremiccases included subjects with hepatic changes goingtoward resolution or with normal liver in whom hepatic biopsy can be avoided. Only one case was a truecarrier since he was viremic with normal liver andpersistently normal ALT values.     

Prevalence of Mutations in Core Promoter/Precore Region in Japanese Patients with Chronic Hepatitis B Virus Infection

We examined the frequency and significance ofmutations in the core promoter and precore region in 103Japanese patients with chronic hepatitis B virus (HBV)infection. HBV DNAs from the patients' sera were amplified by polymerase chain reaction andwere directly sequenced. A double mutation(T¹⁷⁶² A¹⁷⁶⁴) in the core promoterwas frequently observed in the patients regardless ofHBeAg status except for asymptomatic carriers with HBeAg. Furthermore,a mutation at nucleotide 1753 from T to C or G wasfrequently found in anti-HBe positive patients and wasoften accompanied by the double mutation. TheA¹⁸⁹⁶ mutation was found in only about onefourth of the patients with anti-HBe. These data suggestthat the patients with chronic liver diseases frequentlyhad a double mutation regardless of HBeAg status and a mutation at nucleotide 1753 might beassociated with HBeAg-negative chronic hepatitis B virusinfection.     

Portohepatic Gradient and Portal Hemodynamics in Patients with Cirrhosis Due to Hepatitis C Virus Infection

We evaluated the agreement between wedgedhepatic vein pressure (WHVP), portal vein pressure(PVP), and its relationship with portal hemodynamics in21 patients with HCVrelated cirrhosis with esophageal varices. Direct measurements of theportohepatic gradient (HVPG) were obtained byultrasound-guided fine needle puncture of the righthepatic and the portal veins. In five cases PVP was6.4-10.4 mm Hg higher than WHVP. In 12 cases measurements weresimilar (WHVP-PVP 3 mm Hg). In the remaining fourcases WHVP was 3.6-9.6 mm Hg higher than PVP. WHVP andPVP agreement was not related to HVPG mean value,Child-Pugh score, or grading of esophageal varices. Bycontrast, the difference between WHVP and PVP wasinversely related to the portal flow velocity (P =0.053) and directly related to the portal vascularresistance (P = 0.02). Whereas the portal branches werevisualized in patients with WHVP lower or similar toPVP, a predominant left portosystemic collateral flowwas observed in patients with WHVP > PVP. Our data point out that, in patients with cirrhosis dueto hepatitis C virus infection, discrepant HVPG valuesreflect true hemodynamic differences.     

Frequent Detection of Hepatitis B Virus X-Gene DNA in Hepatocellular Carcinoma and Adjacent Liver Tissue in Hepatitis B Surface Antigen-Negative Patients

Hepatitis B virus is associated with humanhepatocellular carcinoma. We performed polymerase chainreaction for the X, C, S, and preS2/S regions of theviral genome in 23 hepatitis B surface antigen-negative hepatocellular carcinomas and adjacent liver.Hepatitis B viral genomes were detected in 17 of 23tumors and adjacent tissues (73.9%). Among recognizedtransactivators, the X gene was present in 16 (69.6%) cases of hepatocellular carcinoma, but preS2/Swas detected in only 7 (30.4%). Hepatitis B virus C andS regions were detected in 3 (13.0%) and 9 (39.1%)hepatocellular carcinomas, respectively. Serologic study revealed antibodies to hepatitis Bsurface antigen, hepatitis B core antigen, and hepatitisB e antigen in 14 patients; among these, X-gene DNA wasdetected in 12 of 14 tumors (85.7%). The X gene was also detected in 4 of 9 tumors ofseronegative patients. The X gene, present in manyhepatocellular carcinomas, may promote hepatocellularcarcinoma in hepatitis B surface antigen-negativepatients.     

Markers of apoptosis and proliferation related gene products as predictors of treatment outcome in childhood acute lymphoblastic leukemia

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is a major problem for hemophiliacs treated before 1985 with non-virally inactivated factor concentrates. However, as HIV infection has been effectively controlled by highly active antiretroviral therapy (HAART), HCV eradication has become a primary goal in co-infected individuals in order to prevent the progression to cirrhosis and end-stage liver failure and the development of hepatocellular carcinoma. In this concise review, the current knowledge as regards the management of HCV infection in HIV co-infected hemophiliacs is analyzed.     

Hepatitis G and C Viruses Respond to Interferon-α with Different Virologic Kinetics

The aim of this work was to specify the timecourse of response to interferon (IFN) of hepatitis Gvirus (HGV) and hepatitis C virus (HCV) in coinfectedindividuals. A group of 33 patients, undergoing 12 months of IFN therapy for chronic hepatitis C,was screened for the presence of both HGV and HCV RNAsto select seven coinfected patients. Spontaneousrecovery from HGV infection was excluded through the detection of antibodies to the envelope-2protein of HGV and HCV isolates were genotyped. Withinthree months of treatment, we found that HGV RNA wastransiently cleared in 6/7 patients, but the rate of long-term favorable response was very low(1/7). In addition, considering the same individualsseparately, it was shown that HGV and HCV responded toIFN with different kinetics in 5/7 patients. Takentogether, these results underscore the importance of thevirological basis of the resistance to IFNtreatment.