Showing papers in "Journal of Viral Hepatitis in 2003"
TL;DR: Peginterferon α‐2a (40 kDa) is superior to conventional interferonα‐2A in the treatment of chronic hepatitis C, and this is the first report on peginterferon β‐1a ( 40 kDa) in the Treatment of CHB.
Abstract: Current therapies for chronic hepatitis B (CHB) have a number of limitations, and better treatment options are needed. Peginterferon alpha-2a (40 kDa) is superior to conventional interferon alpha-2a in the treatment of chronic hepatitis C. This is the first report on peginterferon alpha-2a (40 kDa) in the treatment of CHB. In this phase II study, 194 patients with CHB not previously treated with conventional interferon-alpha were randomized to receive weekly subcutaneous doses of peginterferon alpha-2a (40 kDa) 90, 180 or 270 microg, or conventional interferon alpha-2a 4.5 MIU three times weekly. Twenty-four weeks of therapy were followed by 24 weeks of treatment-free follow-up. All subjects were assessed for loss of hepatitis B e antigen (HBeAg), presence of hepatitis B antibody (anti-HBe), suppression of hepatitis B virus (HBV) DNA, and normalization of serum alanine transaminase (ALT) after follow-up. At the end of follow-up, HBeAg was cleared in 37, 35 and 29% of patients receiving peginterferon alpha-2a (40 kDa) 90, 180 and 270 microg, respectively, compared with 25% of patients on conventional interferon alpha-2a. The combined response (HBeAg loss, HBV DNA suppression, and ALT normalization) of all peginterferon alpha-2a (40 kDa) doses combined was twice that achieved with conventional interferon alpha-2a (24%vs 12%; P = 0.036). All treatment groups were similar with respect to frequency and severity of adverse events. These results indicate that peginterferon alpha-2a (40 kDa) is superior in efficacy to conventional interferon alpha-2a in chronic hepatitis B based on clearance of HBeAg, suppression of HBV DNA, and normalization of ALT.
476 citations
TL;DR: FHF in pregnant women caused by HEV was an explosive disease with short pre‐ encephalopathy period, rapid development of cerebral oedema and high occurrence of disseminated intravascular coagulation and may represent a severe manifestation of a Schwartzmann‐like phenomenon.
Abstract: Hepatitis E causes large-scale epidemics in endemic areas. The disease, during epidemics, has increased incidence and severity in pregnant women. Sporadic acute viral hepatitis (AVH) is common in endemic areas. The relationship of sporadic AVH and pregnancy has not been well studied. Over a 3-year period we prospectively studied 76 pregnant women and 337 non-pregnant women of childbearing age with sporadic acute viral hepatitis for aetiology, clinical course and outcome of disease. The aetiology in sporadic AVH was hepatitis A virus (HAV) in six (1.5%), hepatitis B virus (HBV) in 62 (15%), hepatitis C virus (HCV) in seven (1.7%), hepatitis D virus (HDV) co-infection in six (1.5%), hepatitis E virus (HEV) in 205 (49.6%), and hepatitis non-A-to-E (HNAE) in 127 (30.7%). Sixty-five (85.5%) pregnant women and 140 (41.5%) nonpregnant women had hepatitis E. The proportion of pregnant women was 31.7% in HEV group and 5.3% in non-HEV group [P < 0.001; OR=8.3 (95%C1 4.2-16.3)]. The prevalence of HEV in pregnant women in first trimester (76.9%), second trimester (88.9%), third trimester (83.8%) and puerperium (100%) did not differ significantly (P=0.09). Forty-seven (61.8%) of the 76 pregnant women developed fulminant hepatic failure (FHF), 69.2% in HEV group and 10% in non-HEV group (P < 0.001). Thirty-four (10.1%) nonpregnant women developed fulminant hepatic failure, 10% in HEV group and 9.7% in non-HEV group (P=0.86). FHF had occurred in four (40%) of 10 patients with HE in first trimester as against 41 (74.5%) of 55 patients in second trimester and beyond (P=0.015). Amongst the major complications of fulminant hepatic failure, cerebral oedema (53.2%) and disseminated intravascular coagulation (21.3%) occurred more often in pregnant women than in nonpregnant women (29.4% and 2.8%; P=0.03 and 0.016, respectively) while infections occurred more often in nonpregnant women (36.1%) than in pregnant women (10.6%; P=0.003). Fifty (61.7%) patients with FHF died [25 (53.2%) pregnant women and 25 (69.5%) nonpregnant women (P=0.06)]. Cerebral oedema and HEV aetiology were independent variables of survival in patients with FHF. Patients with cerebral oedema had worse prognosis and patients with HEV aetiology had best chances of survival. Hence HEV was the most common cause of sporadic AVH in this endemic area. High proportion of pregnant women and increased severity of disease in pregnancy were limited to patients with hepatitis E. Sporadic AVH caused by agents other than HEV did not show any special predilection to or increased severity in pregnancy. FHF in pregnant women caused by HEV was an explosive disease with short pre- encephalopathy period, rapid development of cerebral oedema and high occurrence of disseminated intravascular coagulation and may represent a severe manifestation of a Schwartzmann-like phenomenon.
305 citations
TL;DR: In highly viraemic HBsAg‐positive mothers, reduction of viraemia by lamivudine therapy in the last month of pregnancy may be an effective and safe measure to reduce the risk of child vaccination breakthrough.
Abstract: Vertical transmission of hepatitis B virus (HBV) can occur occasionally despite vaccination of the child. This vaccination breakthrough has been associated with high maternal viraemia. We treated eight highly viraemic (HBV-DNA >/= 1.2 x 10(9) geq/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. HBV-DNA, hepatitis B surface antigen (HBsAg), anti-HBs and anti-HBc of their offspring were measured at birth and at 3, 6 and 12 months, respectively. Twenty-four children, born to untreated HBsAg-positive mothers with HBV-DNA levels >/=1.2 x 10(9) geq/mL served as historical controls. All children received passive-active immunization at birth and were followed-up for 12 months. In the lamivudine group one of the eight children (12.5%) was still HBsAg and HBV-DNA positive at the age of 12 months. All other children seroconverted to anti-HBs and maintained seroprotection. In three children, HBV-DNA was temporarily detected by polymerase chain reaction. In the untreated historical control group, perinatal transmission occurred in seven of 25 children (28%). In highly viraemic HBsAg-positive mothers, reduction of viraemia by lamivudine therapy in the last month of pregnancy may be an effective and safe measure to reduce the risk of child vaccination breakthrough. This approach should be evaluated in a large controlled trial.
285 citations
TL;DR: The accumulated data from studies assessed indicate that protection is dependent on immune memory, rather than declining anti‐HBs responses and add additional weight to the European Consensus recommendations that following a complete course of vaccination, booster doses are unnecessary in immunocompetent persons.
Abstract: This review analyses the cumulated data from a number of long-term follow-up studies among infants, children and adults vaccinated against hepatitis B in industrialised and developing countries. Despite low or undetectable antibody responses years after vaccination, the development of HBsAg was a rarity and, if present, only transient. Some vaccinees developed anti-HBc responses but none developed an HB carrier state or clinical manifestations of disease. Studies demonstrating anamnestic responses among those with low or undetectable anti-HBs levels following challenge with HB vaccine, together with the production of anti-HBs in circulating B-cells by spot ELISA, confirmed the presence of immune memory among vaccinees. Anamnestic anti-HBs responses all correlate close in kinetics and magnitude with proliferative T-cell responses. The accumulated data from studies assessed in this Review indicate that protection is dependent on immune memory, rather than declining anti-HBs responses and add additional weight to the European Consensus recommendations (12) that following a complete course of vaccination, booster doses are unnecessary in immunocompetent persons. If implemented, this recommendation will have considerable cost benefits world-wide.
181 citations
TL;DR: The sensitivity and specificity of significant prognostic factors was assessed and significant factors on univariate analysis were entered into a stepwise logistic regression analysis to identify independent variables of prognosis.
Abstract: The early prognostic indicators for acute liver failure in endemic zones for hepatitis E virus have not been determined. All consecutive patients with acute liver failure from a geographically defined region endemic for hepatitis E virus were studied over the period April 1989-April 1996. Demographic, clinical and biochemical parameters were recorded at presentation and serum samples were analysed for known viral hepatitis (A-E) markers. Multiple parameters were compared in survivors and non-survivors in a univariate analysis. All significant factors on univariate analysis were entered into a stepwise logistic regression analysis to identify independent variables of prognosis. The sensitivity and specificity of significant prognostic factors was then assessed. A total of 180 [69 males and 111 females: age (mean +/- SD) 31.1 +/- 14.7 years] with acute liver failure were studied. Of these, 131 (72.8%) patients died. Hepatitis E virus was the aetiological cause in 79 (43.9%) patients, while hepatitis A virus, hepatitis B virus, hepatitis C virus and non-A, non-E agent/'s could be incriminated in four (2.1%), 25 (13.9%), 13 (7.2%) and 56 (31.1%) patients respectively. Of 83 women in childbearing age, 49 (59.0%) were pregnant, 33 (67.3%) of these were in the third trimester. Forty-seven (95.8%) pregnant women had HEV infection. Nine variables differed significantly between survivors and non-survivors on univariate analysis. Of these, four variables which predicted the adverse outcome on multivariate analysis were non-hepatitis-E aetiology, prothrombin time >30 s, grade of coma >2 and age >40 years in that order of significance. Pregnancy per se or duration of gestation did not adversely affect the prognosis. In endemic areas, hepatitis E virus is the commonest cause of acute liver failure. Acute liver failure occurs in a high proportion of pregnant women, mostly in third trimester. Early predictors of a poor outcome are non-E aetiology, prothrombin time >30 s, grade of coma >2 and age >40 years.
147 citations
TL;DR: There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, coexistent depression or hepatic encephalopathy, which may in part account for the reductions in quality of life.
Abstract: A number of studies have reported an association between chronic hepatitis C (HCV) infection and significant impairments in health-related quality of life (QOL), which are independent of the severity of liver disease. There are numerous reports documenting the prevalence of symptoms such as fatigue and depression in chronic HCV infection, which may in part account for the reductions in quality of life. Although there are a large number of potential explanations for these symptoms, including depression and anxiety associated with the diagnosis of HCV infection or substance abuse, there has been recent interest in the possibility of a biological effect of HCV infection on cerebral function. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, coexistent depression or hepatic encephalopathy. In vivo magnetic resonance spectroscopy and neurophysiological studies have suggested that a biological mechanism may underlie these cognitive findings. The recent detection of HCV genetic sequences in post mortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.
120 citations
TL;DR: Administration of the antiapoptotic ursodeoxycholic acid in HCV infection is compatible with the notion that apoptosis may represent a mechanism for viral shedding rather than for viral elimination, thereby raising the concept that inhibition of apoptosis could ameliorate hepatitis C.
Abstract: The apoptotic process appears to be a host defence mechanism against viral infections and tumourigenesis. However, many viral genomes encode proteins, which repress apoptosis so as to escape from immune attack by the host. Therefore, virus-host interactions may determine viral persistence, extent and severity of liver inflammation and possibly viral hepatocarcinogenesis. Apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. Pathomorphologic features of increased apoptosis include shrinkage and fragmentation of nuclei/cytoplasm in piecemeal necrosis areas, acidophilic bodies, and focal cell dropout in the liver lobule. The hepatitis C virus (HCV) core protein exhibits both proapoptotic or antiapoptotic actions. Modulation of apoptosis may involve binding of HCV core protein to the intracellular signal transducing portion of death receptors and displacement of signalling molecules. Apoptosis may occur in the absence of significant transaminase elevation, thereby explaining the lack of correlation between biochemical activity and liver cell histological injury. Monitoring caspase activation might provide a reliable tool to estimate the efficacy of HCV therapy, and might open challenging therapeutic strategies in HCV infection. The antiviral effect of interferon may be mediated through induction of apoptosis. Lastly, administration of the antiapoptotic ursodeoxycholic acid in HCV infection is compatible with the notion that apoptosis may represent a mechanism for viral shedding rather than for viral elimination, thereby raising the concept that inhibition of apoptosis could ameliorate hepatitis C.
110 citations
TL;DR: ART should be a priority in HIV/HCV co‐infected patients eligible for anti‐HCV treatment as it is a protective factor for liver fibrosis, according to the multivariate analysis time on ART.
Abstract: To assess the factors associated with liver fibrosis in human immunodeficiency virus and hepatitis C virus (HIV/HCV) co-infected patients eligible for anti-HCV therapy, we performed an observational, single-centred, cross-sectional study of 180 HIV/HCV co-infected patients who underwent liver biopsy between May 1998 and November 2001. A total of 126 patients with a known date of HCV infection were evaluated. Liver fibrosis was defined as a Knodell stage of fibrosis 1-4. The mean age was 36.7 (3.8) years, 81% were male and had a mean age of 20.5 (3.8) years at HCV infection. Mean CD4 cell count and plasma HIV-1 RNA load at the time of biopsy were 552 cell/mm3 (239) and 2.5 log10 (0.9), respectively; 118 patients had been on antiretroviral therapy (ART) for a median of 45 months (Q1-Q3: 21-75) and 84 on protease inhibitor for a median of 12.0 months (Q1-Q3: 0-29.5); 55 had an AIDS event or a CD4 cell count nadir 50 g/day) (OR: 2.73, 95% CI: 1.108-6.731) were associated with liver fibrosis. Hence ART should be a priority in HIV/HCV co-infected patients eligible for anti-HCV treatment as it is a protective factor for liver fibrosis.
108 citations
TL;DR: A systematic evaluation of published studies was undertaken to identify factors associated with accelerated fibrosis progression in patients with chronic hepatitis C virus (HCV) infection and an algorithm to predict the risk of subsequently developing cirrhosis was presented.
Abstract: A systematic evaluation of published studies was undertaken to identify factors associated with accelerated fibrosis progression in patients with chronic hepatitis C virus (HCV) infection. An ecologic analysis was used to estimate relative risk (RR) of cirrhosis across four study methodologies: liver clinic series, post-transfusion cohorts, community-based studies and blood donor series. In each study category, the following factors were independently associated with disease progression: male sex (RR = 1.08); heavy alcohol consumption (RR = 1.61); elevated serum ALT levels (RR = 1.23) and histology demonstrating high-grade necro-inflammatory activity. After adjusting for these cofactors, older age at HCV infection and acquisition of HCV through blood transfusion were not implicated in influencing disease outcome. Although not able to be examined in this study,co-infection with HIV, and to a lesser extent HBV, is also likely to result in worse outcomes for patients with chronic HCV infection. Virological factors such as HCV genotype, viral load and quasispecies diversity are less likely to be important. A Weibull distribution was used to model disease progression at a population level. The influence of cofactors on individual prognosis was examined and an algorithm to predict the risk of subsequently developing cirrhosis is presented.
92 citations
TL;DR: The HBcrAg assay is a sensitive and useful test for the assessment of a patient's HBV load and provides a viral marker which is independent of HBV DNA when monitoring the anti‐viral effect of lamivudine.
Abstract: We aimed to assess the clinical performance of a newly developed chemiluminescence enzyme immunoassay (CLEIA) for the detection of hepatitis B virus (HBV) core-related antigen (HBcrAg) in patients with chronic HBV infection. A total of 82 patients with chronic HBV infection and 167 HBV-negative controls were studied. HBcrAg was measured by CLEIA with monoclonal antibodies to hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg), and HBV DNA was measured by transcription-mediated amplification assay (TMA) and in-house real-time detection polymerase chain reaction (RTD-PCR). The HBcrAg assay detected viremia in 189 of 216 samples (88%) collected from 72 patients whilst the TMA assay detected viremia in 178 of the 216 samples (82%) (P = 0.019). The HBcrAg concentration correlated linearly with the HBV DNA concentration (P < 0.001) over a range which varied 100 000-fold. The accuracy in the measurement of the patients' HBV load obtained using the HBcrAg assay was not affected by the absence of hepatitis B e antigen from the serum or the presence of precore mutations in the HBV genome. In patients without anti-viral drugs, changes in their serum HBcrAg concentration over time corresponded to their HBV DNA concentration. In six additional patients who were later treated with lamivudine, HBV DNA concentration declined more rapidly than their HBcrAg concentration. Three months after treatment commenced, the ratio of HBcrAg: HBV DNA had increased in all six patients (P = 0.031). The HBcrAg assay is a sensitive and useful test for the assessment of a patient's HBV load. When monitoring the anti-viral effect of lamivudine, HBcrAg provides a viral marker which is independent of HBV DNA.
90 citations
TL;DR: To achieve continuous drug exposure and to improve initial viral clearance, peginterferon‐α‐2b has to be given at least two times weekly.
Abstract: The decline in hepatitis C viral load on treatment with peginterferon-alpha-2b is not continuous. The aim of this study was to investigate whether twice weekly dosing of peginterferon-alpha-2b may improve viral kinetics. Ten interferon-naive patients with chronic hepatitis C (genotype 1a or b) were randomized to receive either 1.0 microg/kg peginterferon-alpha-2b once (group A) or twice weekly (group B) for 4 weeks. Viral load and serum concentrations of peginterferon-alpha-2b were measured. Peginterferon-alpha-2b reached maximal blood concentrations 24 h after the first dose, followed by a linear decline during the subsequent days. On the day before administration of the next dose, peginterferon-alpha-2b was undetectable in nine patients in group A (once weekly dosing). The same pattern was observed during the next 3 weeks of therapy. In group B (twice weekly dosing) peginterferon-alpha-2b was detectable at any given time point and higher than in group A (P between 0.01 and <0.0001). Viral load decreased in all patients within 2 days after the first dose of peginterferon-alpha-2b, but increased again on day 3. In group A, it further increased until day 7. A similar pattern was observed in the second week. In contrast, in group B, viral load decreased again on day 4 and remained lower until the end of the study (P < 0.001). To achieve continuous drug exposure and to improve initial viral clearance, peginterferon-alpha-2b has to be given at least two times weekly.
TL;DR: It is suggested that person‐to‐person transmission is uncommon in sporadic hepatitis E, although a majority lacked IgG antibodies to hepatitis E virus and were likely to be susceptible.
Abstract: Summary. Intrafamilial transmission is rare in epidemic hepatitis E; its frequency in sporadic hepatitis E is not known. We followed up 86 household contacts (age range 4–75 years, mean ± SD 32.4 ± 15.8; 49 males), who were family members of patients with acute sporadic hepatitis E. Of the 86 contacts, 68 (79%) tested negative for IgG anti-hepatitis E virus antibodies. Four (4.7%) had IgM anti-hepatitis E virus antibodies at the time of diagnosis of hepatitis E in the index case; two of these contacts possibly had hepatitis E virus infection acquired simultaneously with that in the index case, and two could have had intrafamilial transmission. None developed serological evidence of hepatitis E virus infection over a period of 49 ± 18 days after the diagnosis of index case, although a majority lacked IgG antibodies to hepatitis E virus and were likely to be susceptible. This suggests that person-to-person transmission is uncommon in sporadic hepatitis E.
TL;DR: The results suggest that patient‐to‐patient transmission occurred in both episodes via contamination of intravenous anaesthetic ampoules with HCV used on multiple patients, and should not be used for more than one patient.
Abstract: Two separate cases of acute hepatitis C virus (HCV) infection following medical procedures, arthroscopy and colonoscopy, are reported. In both episodes, patient risk factors were reviewed, and staff and other patients' sera were tested for HCV antibodies and RNA. HCV RNA positive samples were genotyped, sequenced, and subjected to phylogenetic analysis. No risk factors for HCV infection were identified for either case except for medical procedures. HCV RNA positive patients were identified preceding both cases on the respective theatre lists. HCV infection in a second low risk patient was also identified. Nucleic acid sequencing and phylogenetic analysis of HCV from the two putative source patients and the three recipient patients demonstrated a high degree of relatedness respectively. The results suggest that patient-to-patient transmission occurred in both episodes via contamination of intravenous anaesthetic ampoules with HCV used on multiple patients. Injectable medication ampoules should not be used for more than one patient.
TL;DR: In vitro transfection studies confirmed that the YSDD strain is resistant to lamivudine, and HBV‐specific sequences were amplified by polymerase chain reaction (PCR) from sera of patients with breakthrough virus.
Abstract: The emergence of drug-resistant virus in hepatitis B virus (HBV) patients treated with lamivudine is well documented. In this study, we determined the mutations occurring in the tyrosine-methionine-aspartate-aspartate (YMDD) amino acid motif of the HBV DNA polymerase gene, as well as upstream and downstream of this region, in patients with breakthrough virus during lamivudine therapy. Thirty-one Turkish patients (20 patients HBeAg positive, 11 patients HBeAg negative and anti-HBe positive) with chronic HBV infection who completed at least 104 weeks of lamivudine treatment were investigated. All patients received lamivudine, (150 mg/day), for 104 weeks, with or without 4 months of interferon (IFN) combination. HBV-specific sequences were amplified by polymerase chain reaction (PCR) from sera of patients with breakthrough virus, and the PCR products were directly analysed by sequencing. Breakthrough virus was detected in seven of the 31 patients (22.6%) between 9 and 18 months of therapy. Of the seven patients, six were HBeAg positive at baseline, and four had a double mutation consisting of rtM204V and rtL180M, while two had an rtM204I change. In one patient, two base substitutions at rt204 (ATG --> AGT; T to G and G to T) lead to a methionine to serine change (YMDD --> YSDD). This novel DNA pol mutation was detected at month 18 of lamivudine treatment. In addition, this new variant had the rtL180M mutation and a 12 base pair deletion in the pre-S1 region between nucleotides 43-54. The YSDD mutation was still present 6 months after lamivudine discontinuation. In vitro transfection studies also confirmed that the YSDD strain is resistant to lamivudine. In conclusion, the results indicate that, in addition to a Met --> Val and Met --> Ile change in YMDD, a Met --> Ser change at rt204 (YMDD --> YSDD) associated with the rtL180M change can also emerge during lamivudine treatment, which confers lamivudine resistance in vivo and in vitro, leading to virological breakthrough and ALT increases.
TL;DR: Data show that the prevalence rates of HBV and HCV were similar with prevalence rates detected in randomized blood donors showing that universal infection‐control precautions and encouraging HBV vaccination reduces HCW infection with hepatotropic viruses.
Abstract: We determined the seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) among health care workers (HCWs) at Gulhane Military Medical Academy, Haydarpasa Training Hospital in Istanbul, Turkey. Between April 1998 and September 2000, 702 HCWs were included in the study. The blood samples were tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs) and HCV antibody (anti-HCV) using third-generation tests, with confirmation by reverse transcriptase-polymerase chain reaction. Seroprevalence rates were compared with those detected in 5670 blood donors during the same period. HBsAg, anti-HBs and anti-HCV were detected in 21 (3.0%), in 480 (68.4%) and in 2 (0.3%) of 702 HCWs respectively. HBsAg and anti-HCV rates were 2.1 and 0.4% in blood donors, respectively. These data show that the prevalence rates of HBV and HCV were similar with prevalence rates detected in randomized blood donors showing that universal infection-control precautions and encouraging HBV vaccination reduces HCW infection with hepatotropic viruses.
TL;DR: In chronic HBV infection, low viral replication and HBeAg negativity is related to increased presence of intralobular CD8+ T‐lymphocytes, but of Fas‐L expression by Kupffer cells and increased cytolytic activity of cells in portal areas may be caused by the absence of cells producing anti‐viral cytokines in the liver.
Abstract: Cytotoxic T lymphocytes (CTL) and Kupffer cells play an important role in the immune control of hepatitis B virus (HBV), but may also induce liver injury during infection. We investigated the intrahepatic immune response in liver biopsies of chronic HBV patients in relation to inflammatory liver injury and viral control. Forty-seven liver biopsies from patients with chronic HBV with varying degrees of inflammation (ALT values) were selected. Acute hepatitis and normal liver specimens served as controls. Immune effector cells, cytotoxic effector molecules and cytokine producing cells were quantified after immunohistochemical staining in lobular and portal areas of the biopsies. The intralobular number of CD8+ T-lymphocytes was significantly decreased in biopsies of patients with high ALT (r = -0.54; P < 0.001). Higher ALT-values were correlated with increased numbers of granzyme+ cells in portal areas (r = 0.65; P < 0.001) and higher numbers of intralobular Fas-L+ cells (r = 0.32; P = 0.05). Fas-L was expressed on Kupffer and lymphoid cells. More intralobular CD8+ T-lymphocytes were found in HBeAg- than in HBeAg+ patients (P = 0.002). But IFN-gamma and TNF-alpha producing cells were observed sporadically in chronic HBV patients. Hence, in chronic HBV infection, low viral replication and HBeAg negativity is related to increased presence of intralobular CD8+ T-lymphocytes. Persistence of the virus may be caused by the absence of cells producing anti-viral cytokines in the liver. Inflammatory liver injury during chronic HBV infection is probably not the result of increased numbers of infiltrating CD8+ T-lymphocytes, but of Fas-L expression by Kupffer cells and increased cytolytic activity of cells in portal areas.
TL;DR: The rate of fibrosis progression is an independent predictor of SVR to IFN‐based therapy in patients with chronic hepatitis C, and should be considered in economic models evaluating this condition.
Abstract: summary. The response to antiviral therapy and the rate of fibrosis progression in chronic hepatitis C virus (HCV) infection are related to common factors, including age and gender. The aim of this study was to evaluate the relationship between the rate of fibrosis progression and the sustained virologic response (SVR) to interferon (IFN)-based treatment. A total of 332 patients treated for chronic HCV infection were evaluated. Using multivariate logistic regression analysis, the impact of the rate of fibrosis progression (defined as the stage of liver fibrosis according to the Metavir system/duration of infection) on the rate of SVR (negative HCV RNA at least 6 months following the end of treatment), was determined. The median age of the patients was 44 (range 25–77) years, 64% were male, and 66% were infected with genotypes 1, 4, 5 or 6. The median rate of fibrosis progression was 0.083 (range 0–2) Metavir units/year; 158 patients (48%) had F2–F4 fibrosis. After a median of 48 (range 2–126) weeks of therapy (IFN, n=190; IFN and ribavirin, n=96; pegylated IFN, n=20; pegylated IFN and ribavirin, n=26), 93 patients (28%) achieved an SVR. In univariate analysis, the rate of SVR was higher in slow [< 0.083 Metavir units/year (n=162)] than rapid progressors [≥ 0.083 Metavir units/year (n=170)] (35%vs 22%, P=0.01). After controlling for age, gender, genotype, viral load, and treatment regimen and duration, the rate of fibrosis progression remained an independent predictor of SVR (slow vs rapid progressors, OR 2.74; 95% CI 1.27–5.92; P=0.01). Hence the rate of fibrosis progression is an independent predictor of SVR to IFN-based therapy in patients with chronic hepatitis C. This additional factor should be considered in economic models evaluating this condition.
TL;DR: Among chronic hepatitis C patients treated with IFN, those with a 12‐month sustained response, unlike those who relapse, have a long‐term progressive reduction and, in some cases, a complete regression of liver histological damage.
Abstract: A retrospective multicentre survey was conducted to evaluate, in patients with chronic hepatitis C, the long-term liver histological changes induced by interferon (IFN). A total of 112 patients (mean age 46.4 years) were studied. All patients had received a 6-12-month IFN-alpha course (6-18 MU/week) and had successively undergone clinical, biochemical and virological follow-up for at least 36 months (range: 36-76). In each patient, two liver biopsies had been performed: 1-6 months before treatment and, 12-76 months after its completion. In 87 patients with biochemical and virological sustained response persisting for 12 months after therapy, post-treatment liver necroinflammation and fibrosis mean(+/-SD) scores (Knodell index) were significantly lower than pretreatment scores (2.9 +/- 2.2 vs 6.8 +/- 2.9 and 0.8 +/- 1.0 vs 1.2 +/- 1.1, respectively; P 0.05). On an individual basis, necroinflammation decreased in 87% of sustained responders but only in 36% of relapsers (P < 0.001), whereas fibrosis decreased in 44% of sustained responders but only in 14% of relapsers (P < 0.001). In sustained responders with biopsies performed 12-23 months (n=34), 24-35 months (n=26) or more than 36 months (n=27) after treatment, a progressive decrease of mean necroinflammatory score was observed (-2.6 +/- 2.1, -4.1 +/- 3.4 and -5.2 +/- 3.7 points, respectively; P < 0.01). A similar pattern was observed in fibrosis score (-0.3 +/- 0.6, -0.3 +/- 0.7 and -0.7 +/- 0.9 points, respectively; P < 0.05). Hence, among chronic hepatitis C patients treated with IFN, those with a 12-month sustained response, unlike those who relapse, have a long-term progressive reduction and, in some cases, a complete regression of liver histological damage.
TL;DR: It was shown that NS5A–ISDR mutations were correlated with the SVR to combination therapy in chronic HCV‐1b patients in Taiwan.
Abstract: Nonstructural 5A (NS5A) and the second envelope (E2) proteins of hepatitis C virus (HCV) have the potential to block interferon (IFN)-induced RNA-dependent protein kinase (PKR) and may therefore interfere with the response to IFN therapy, but controversy still exists regarding the relevance of this. This study aimed to assess whether mutations in these regions correlated with the response to combination therapy, IFN and ribavirin. Pretreatment parameters were analysed in 57 HCV-1b patients who had received IFN-alpha2b (3 or 5 MU three times weekly) and ribavirin (800-1200 mg per day) for 24 weeks. The amino acid sequences of the NS5A and PKR-eIF2alpha phosphorylation homology domain (E2-PePHD) were deduced from the corresponding coding sequence, which were determinated by direct sequencing of the HCV genome amplified by the polymerase chain reaction. Twenty (36%) patients achieved a sustained virological response (SVR). The mean number of amino acid substitutions in the NS5A-PKR binding domain (2209-2274), interferon sensitivity-determining region (ISDR) (2209-2248), and E2-PePHD sequence (659-670) in patients with and without SVR were 4.53 +/- 3.31 vs 2.83 +/- 1.78 (P = 0.094), 2.45 +/- 2.74 vs 1.03 +/- 1.32 (P = 0.042) and 0.25 +/- 0.70 vs 0.03 +/- 0.17 (P = 0.109), respectively. Patients with a mutant-type (>/= 4) NS5A-ISDR had a higher rate of SVR (six of nine, 67%) than those with wild-type (five of 22, 23%) (P = 0.038). Stepwise multiple logistic regression analysis of the factors (age, gender, viral load, cirrhosis rate, IFN dosage and amino acid substitutions) revealed that the mutation in NS5A-ISDR (>/= 4 vs < 4) was the only independent variable of treatment outcome. Our study showed that NS5A-ISDR mutations were correlated with the SVR to combination therapy in chronic HCV-1b patients in Taiwan.
TL;DR: Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory, and in spite of a lower initial response PEG‐IFN‐α‐2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness.
Abstract: Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory. The initial viral response to IFN identifies patients infected with IFN resistant viruses not responding to standard IFN/ribavirin therapy. The impact of primary IFN unresponsiveness for PEG-IFN-alpha-2a/ribavirin therapy is unknown. Viral load was measured in 22 chronic hepatitis C (genotype 1) patients before and 24 h after 9 MU IFN-alpha-2a (days 0 and 1), and before and during weekly 180 microg PEG-IFN-alpha-2a (days 7, 8, 11, 14 and 21) administration. Thereafter, ribavirin (800 mg/d) was added for 6 months. Virological responders continued treatment for a further 6 months. Twenty-eight patients treated with standard IFN/ribavirin therapy in a previous study using an analogous protocol served as historic controls. After 6 months 15 (68.2%) patients were (HCV-RNA) negative, eight of whom (36.4%) had a sustained response. The decrease in viral load 24 h after 9 MU IFN-alpha-2a was greater in virological responders (1.05 log [0.25-1.67]) than in nonresponders (NR) (0.34 [0.14-0.65]; P=0.003). In contrast, viral decline was not different between responders and NRs during the first 2 weeks on PEG-IFN-alpha-2a. All patients with an initial decline > 1.4 log became sustained responders. Five of 12 patients with a log change < 0.8 became end of treatment responders, two had a sustained response. Antiviral response to PEG-IFN-alpha-2a is different to that on standard IFN. In spite of a lower initial response PEG-IFN-alpha-2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness.
TL;DR: Spread of intravenous drug use determined HCV infection by genotypes other than 1b, and the risk of fibrosis progression was influenced more by age at viral acquisition and alcohol consumption than by the infecting genotype.
Abstract: The objective of this study was to assess the influence of age and date of acquisition of hepatitis C virus (HCV) infection on the distribution of genotypes and the progression of fibrosis in HCV-infected patients who were born in Spain and had their habitual place of residence in this country. Genotypic analysis was performed in 375 patients in whom it was possible to establish the year of HCV infection because the mode of transmission was known (transfusion, injection drug use, blood donor, or epidemic outbreak). In 298 patients with liver biopsy, fibrosis stage was related to age at infection, duration of infection, alcohol consumption, and HCV genotype. HCV subtype 1b was almost exclusively detected among transfusion recipients, but the onset of intravenous drug addiction was associated with the introduction of HCV genotypes other than 1b among injecting users with subsequent spread to other exposure risk groups. Fibrosis progression was influenced by alcohol consumption, increased duration of infection, and older age at infection. In summary, spread of intravenous drug use determined HCV infection by genotypes other than 1b. The risk of fibrosis progression was influenced more by age at viral acquisition and alcohol consumption than by the infecting genotype.
TL;DR: To study the correlation between total Hepatitis C virus (HCV) Core antigen (Ag) and HCV‐RNA, and to assess the proficiency of HCV Core Ag testing in monitoring and predicting virologic response during and after pegylated interferon (PEG‐IFN) and ribavirin combination therapy.
Abstract: Summary. To study the correlation between total Hepatitis C virus (HCV) Core antigen (Ag) and HCV-RNA, and to assess the proficiency of HCV Core Ag testing in monitoring and predicting virologic response during and after pegylated interferon (PEG-IFN) and ribavirin combination therapy.
A total of 307 samples from treated and untreated patients were used to assess the correlation between the total HCV Core Ag test and quantitative HCV-RNA assays (Superquant, and Quantiplex branched DNA 2.0 assay). Twenty-four patients received combination therapy for 48 weeks. Blood samples were collected at day 0, and week 2, 4, 12, 24, 48 and 72 for virologic evaluation.
A linear relation exists between total HCV Core Ag and HCV-RNA levels. At 3 months the positive predictive value (PPV) of response to therapy was 100% with either HCV Core Ag or HCV-RNA. For HCV Core Ag the negative predictive value (NPV) was 100% whereas for HCV-RNA the NPV was 80% (P > 0.05). At month 1, the PPV was 95% and 100% when determined by HCV Core Ag and HCV-RNA, respectively. The NPV value was 100% for HCV Core Ag and 33% for HCV-RNA (P = 0.005).
HCV Core Ag quantification could be useful in clinical practice to predict a sustained virological response early during therapy (4 weeks), reaching an optimal performance at month 3. The determination of total HCV Core Ag levels in serum, constitutes an accurate and reliable alternative to HCV-RNA for monitoring and predicting treatment outcome in patients receiving PEG-IFN/Ribavirin combination therapy.
TL;DR: Findings suggest that rck/p54 protein is possibly involved in the replication of HCV genomes in hepatocytes and in tumourigenesis of hepatocellular carcinomas.
Abstract: Summary. Hepatitis C virus (HCV) infection is the most common cause of chronic hepatitis, which frequently progresses to hepatocellular carcinoma. The pathogenesis of its persistent infection and tumour progression has not been fully characterized yet. The RCK gene was previously cloned at the breakpoint of the t(11;14)(q23;q32) chromosome translocation observed in human B-cell lymphoma cell line RC-K8. The RCK protein, rck/p54, which is a 54-kDa cytoplasmic protein belonging to the DEAD box/RNA helicase family, is considered to facilitate the translation of mRNA(s) of genes for cell proliferation and malignant transformation not only in B-cell lymphomas having the t(11;14) translocation but also in other solid tumours. The aim of this work was to examine the involvement of rck/p54 in carcinogenesis of hepatocellular carcinoma from HCV-related chronic hepatitis. We examined the expression of rck/p54 in 29 cases of HCV-related chronic hepatitis and eight cases of hepatocellular carcinoma by immunohistochemistry and Western blot analysis. Twenty-six of 29 cases with HCV-related chronic hepatitis and all cases with hepatocellular carcinoma tested overexpressed rck/p54 protein. The expression of rck/p54 was lowered by treatment with IFN-α in two cases who showed the decrease in HCV RNA levels. These findings suggest that rck/p54 protein is possibly involved in the replication of HCV genomes in hepatocytes and in tumourigenesis of hepatocellular carcinomas.
TL;DR: In conclusion, chronic or fulminant hepatitis B was not associated with pre‐C or BCP mutants and switching over to Pre‐C mutant was beneficial for the infected individual in maintaining disease free status for extended periods.
Abstract: To determine the association of precore (Pre-C)/basal core promoter (BCP) mutants with clinical outcome of hepatitis B in Western India, 192 hepatitis B virus (HBV) infected individuals were investigated. HBV-DNA PCR positivity among asymptomatic hepatitis B surface antigen (HBsAg) positive carriers (61/100) was lower (P < 0.0001) than chronic hepatitis B (CHB), acute (P = 0.0001), and fulminant hepatitis B patients (P = 0.047). Pre-C status was based on restriction fragment length polymorphism (RFLP, n = 153) and sequencing (n = 118). Prevalence of Pre-C mutants was higher among carriers (23/61) than CHB (10/62, P = 0.0071) or acute (3/22; P = 0.037) patients. Children from carrier and CHB categories showed significantly higher circulation of Pre-C-wild than mutant HBV. Clinical manifestations were independent of BCP mutations (1762/64-T/A). Hepatitis B e antigen (HBeAg) negative CHB patients [62.5% (15/24)] were circulating wild HBV. Higher HBV-DNA levels were associated with chronic hepatitis and HBeAg positivity, whilst Pre-C mutant positives had lower levels. BCP mutations did not affect HBV-DNA levels. Multivariate regression analysis identified HBeAg (OR = 4.3) and Pre-C mutants (OR = 3.1) to be associated with chronic hepatitis and carriers respectively. In a separate sub-set analysis (n = 59), HBV-DNA level was identified as the only variable. In conclusion, chronic or fulminant hepatitis B was not associated with Pre-C or BCP mutants and switching over to Pre-C mutant was beneficial for the infected individual in maintaining disease free status for extended periods.
TL;DR: It is concluded that a three‐dose hepatitis B vaccination regimen is generally effective in protecting newborns of hepatitis B carrier mothers from infection and chronic carriage and booster is not needed even after 16 years of monitoring.
Abstract: summary. The long-term efficacy of a childhood hepatitis B vaccination programme was evaluated. A total of 112 newborn babies of hepatitis B carrier mothers were given hepatitis B immune globulin (HBIG) and a 10-μg three-dose regimen of plasma-derived vaccine administered at a conventional (0, 1, 6 months), delayed (2, 3, 8 months) or accelerated (0, 1, 2 months) schedule. The vaccinees were followed up to determine their anti-HBs status over a 16-year period. Upon completion of the vaccination schedules, 92.6% developed antibody against surface antigen (anti-HBs) seroconverion, the rate of which fell to 33.3% at year 16. The three schedules were equally effective in preventing chronic infection, with a protective efficacy of 88.9% from hepatitis B surface antigen (HBsAg) carriage, compared with historical control. Vaccinees on the delayed schedule had a slightly higher seroconversion rate over years, and were better able to maintain an anti-HBs level of ≥ 100 iu/L. Overall, a quarter demonstrated evidence of exposure to the virus, being positive for antibody against core antigen or HBsAg, or mounting a rise in anti-HBs during the follow-up period. We conclude that a three-dose hepatitis B vaccination regimen is generally effective in protecting newborns of hepatitis B carrier mothers from infection and chronic carriage. Booster is not needed even after 16 years of monitoring.
TL;DR: To explain the p53‐independent regulation of p21 by Core, a Core‐responsive element between positions −74 and −83 of the p21 promoter, exactly overlapped with a tumour growth factor β (TGF‐β)/butyrate responsive element is identified.
Abstract: Summary. Transcription of p21 was activated in hepatitis C virus (HCV) Core-expressing HepG2 cells where its upstream p53 was stabilized. However, this effect was not absolutely required for the activation of p21 by Core, as demonstrated in Hep3B cells. In addition, an opposite effect on the transcription of p21 was observed in NIH3T3 and primary hepatocytes, where p53 was not decreased by Core. To explain the p53-independent regulation of p21 by Core, we identified a Core-responsive element between positions −74 and −83 of the p21 promoter, exactly overlapped with a tumour growth factor β (TGF-β)/butyrate responsive element. Furthermore, we demonstrated that Core could activate the p21 through the element by stimulating a butyrate pathway, whereas this was inhibited through a TGF-β pathway. The opposing effects of Core protein on the transcription of p21 might be important in understanding the progression of hepatic disease in HCV-positive patients.
TL;DR: Most patients with HBeAg‐negative chronic hepatitis B Chinese patients had biochemical relapse within 12’months after lamivudine treatment regardless of HBV genotype, suggesting a high pretreatment viral load is the determinant for early biochemical relapse.
Abstract: The efficacy of lamivudine for HBeAg-negative chronic hepatitis B (CHB) Chinese patients has not been fully investigated. The role of the Hepatitis B virus (HBV) genotype on the treatment effect of lamivudine is controversial. Thirty-two consecutive patients with HBeAg-negative CHB were enrolled. All patients were treated with lamivudine 100 mg once daily of 7–12 months duration. The mean total period of follow-up since entry for all patients was 24 ± 3.5 months. HBV genotypes were classified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and verified by sequencing. Precore (G1896A) and basic core promoter (BCP A1762T & G1764A) mutations were determined by PCR and direct sequencing. Twenty-one (65.6%) patients were infected by genotype B and 11 (34.4%) by genotype C. G1896A was predominant in genotype B infected patients (95.2% vs 63.6% P = 0.037). At the end of treatment 31 (96.8%) and 14 (43.8%) patients achieved biochemical and virological responses respectively. The biochemical and virological response rates were 40.6 and 0% at 12 months after treatment. Eighteen (56.3%) patients had biochemical relapse within 12 months after withdrawal of lamivudine. By multivariate analysis the pretreatment serum level of HBV DNA >/= 12 Meq/mL was the only factor associated with early biochemical relapse (Odds ratio = 9.333 95% CI = 1.497 ~ 58.197 P = 0.017). In conclusion the virological effect of lamivudine for HBeAg-negative CHB is transient. Most patients had biochemical relapse within 12 months after lamivudine treatment regardless of HBV genotype. A high pretreatment viral load is the determinant for early biochemical relapse. (authors)
TL;DR: Because of its speed, simplicity and flexibility, the rapid test is ideally suited for HBsAg and HBeAg screening in population‐based epidemiological studies and in low risk populations, particularly in regions of the world where hepatitis B is endemic.
Abstract: Simple, rapid and accurate assays for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) are helpful for clinical diagnosis and field epidemiological surveys. A commercially developed, rapid immunochromatographic test for simultaneous detection of HBsAg and HBeAg was evaluated using a total of 2463 selected samples (827 frozen sera, 1011 fresh sera, and 625 whole blood samples). Results of the rapid test were compared with standard enzyme immunoassay (EIA) methods for HBsAg and HBeAg detection. The accuracy of the rapid test was excellent and was similar for frozen sera, fresh sera and whole blood. The overall sensitivity and specificity for the detection of HBsAg were 95 and 100%, and the corresponding positive and negative predictive values were 100 and 99.7%, respectively. The sensitivity and specificity for the detection of HBeAg were slightly less than that for HBsAg, and were 80 and 98%, with positive and negative predictive values of 91 and 94%, respectively. Thus, compared with the EIA method, the rapid test was highly sensitive and accurate for the detection of HBsAg although somewhat less sensitive and specific for detection of HBeAg. Because of its speed, simplicity and flexibility, the rapid test is ideally suited for HBsAg and HBeAg screening in population-based epidemiological studies and in low risk populations, particularly in regions of the world where hepatitis B is endemic.
TL;DR: This work thoroughly investigated three patients with mixed cryoglobulinaemia who lack evidence of HCV infection to determine the aetiology of this disorder.
Abstract: Summary. Mixed cryoglobulinaemia, when not secondary to other well-defined immunological disorders, is commonly associated with hepatitis C virus (HCV) infection. However, a minority of cases lack evidence of HCV infection and are, therefore, defined as ‘true essential’ mixed cryoglobulinaemias. We thoroughly investigated three such patients to determine the aetiology of this disorder.
Antibodies to HCV (anti-HCV) and HCV RNA, detected by sensitive enzyme-linked immunosorbent and polymerase chain reaction assays in serum and in concentrated cryoglobulins, were repeatedly negative in the three patients. Despite the lack of evidence for HCV infection, two of them were still treated with interferon α-2a assuming unrecognized viral infection. Both patients demonstrated excellent clinical and laboratory responses, but cryoglobulinaemia relapsed after the withdrawal of therapy. At the time of relapse, HCV RNA genomic sequences were detected for the first time in the cryoprecipitates of both patients. In the third case, HCV RNA was demonstrated for the first time during a flare of cryoglobulinaemia coincident with varicella infection. In all three patients anti-HCV antibodies remained negative throughout follow-up.
We conclude that some apparently ‘essential’ forms of mixed cryoglobulinaemia can be caused by occult HCV infection. Interferon therapy can be taken into consideration in such HCV-negative cases.
TL;DR: The first case of IFN/R therapy associated with Vogt‐Koyanagi‐Harada disease is reported, a T‐cell‐mediated autoimmune response to melanocytes that elicits a systemic prodrome that may mimic side‐effect profile and delay ofIFN or mask its recognition.
Abstract: The complex immunological effects of interferon and ribavirin therapy (IFN/R) in hepatitis C virus (HCV) may also exacerbate or trigger the de novo development of autoimmunity. We report the first case of IFN/R therapy associated with Vogt-Koyanagi-Harada disease, a T-cell-mediated autoimmune response to melanocytes. This condition, which has characteristic ocular, neurological and integumentary findings, elicits a systemic prodrome that may mimic side-effect profile and delay of IFN or mask its recognition. We discuss this disease in the context of the known immunomodulatory effects of IFN-alpha and ribavirin and suggest potential mechanistic explanations for the association.