Biomedical subjects

D R Gretch

Publications and source records attributed to D R Gretch.

At least 37 records · Page 2Linked to original sources

PubMed1999

Evidence for sequence selection within the non-structural 5A gene of hepatitis C virus type 1b during unsuccessful treatment with interferon-alpha.

Resistance of the hepatitis C virus (HCV) to interferon-alpha (IFN-alpha) therapy in patients with hepatitis C may be genetically controlled by an IFN sensitivity-determining region (ISDR) within the non-structural 5A (NS5A) gene. To assess whether HCV 1b strains carrying a 'resistant' type of ISDR are selected during unsuccessful IFN therapy, we analysed the evolution of the NS5A quasispecies, as detected by the clonal frequency analysis technique, and of the ISDR sequence by nucleotide sequence determination, in 11 patients showing no virological response during two consecutive cycles of IFN-alpha therapy. IFN-resistant patients had a homogeneous ISDR quasispecies with sequences identical to those described as 'resistant-' or 'intermediate-' type ISDR. After retreatment with IFN, further selection towards a homogeneous viral population was observed and 10 out of 11 patients had only one variant of HCV with no or just one single amino acid mutation within the ISDR sequence. Treatment and retreatment with IFN was associated in our non-responder patients with evolution of the ISDR quasispecies towards a rather homogeneous viral population carrying a conserved or minimally mutated ISDR motif, supporting the idea that this motif may be relevant for IFN resistance in HCV 1b-infected individuals.

Adult↗

PubMed1999

Relationship between iron concentration and hepatitis C virus RNA level in liver tissue.

Patients with chronic hepatitis C virus (HCV) infection frequently have increased hepatic iron stores. The role of hepatitis C in hepatic iron deposition is unknown. The authors examined whether there is a relation between hepatitis C virus level in liver tissue and hepatic iron concentration. Forty-two paired samples obtained from the liver explants of five patients who underwent transplantation for liver disease due to hepatitis C were studied. Hepatitis C virus levels were measured at multiple sites within each liver by a branched deoxyribonucleic assay. Measurements of hepatic iron concentration were made at adjacent sites by a colorimetric assay. Random effects modeling showed wide intrahepatic variation in hepatic HCV ribonucleic acid (RNA) concentration (variance = 1.2 x 10(4) [mEq/g]2) and hepatic iron concentration (variance = 1.3 x 10(6) [microg/g]2). There was, however, a trend toward an association between the mean HCV level and the mean hepatic iron concentration for each liver (r = 0.30, p = 0.05). In conclusion, HCV level and iron concentration varied within and between cirrhotic livers. Variability in intrahepatic iron concentration was not related to variability in intrahepatic HCV RNA concentration. More studies are needed to determine the cause of variability in hepatic iron and HCV RNA concentration within and between livers in patients with chronic hepatitis C.

Hepacivirus↗

PubMed1999

Molecular epidemiology of hepatitis C infection in U.S. veteran liver transplant recipients: evidence for decreasing relative prevalence of genotype 1B.

OBJECTIVE: The U.S. Veteran population represents a unique patient group to study different HCV genotypes because of geographically diverse exposures. The aim of this study was to characterize the distribution of HCV genotypes in U.S. veterans undergoing liver transplantation (OLT), trace genotypes to modes of acquisition (risk behavior and location), and evaluate the relative prevalence of HCV genotypes according to the time of acquisition. METHODS: Between 10/88 and 12/95, 110 primary OLTs were performed in U.S. Veterans at our center. Forty-nine (45%) patients had detectable HCV-RNA by PCR at the time of OLT. Determination of HCV genotypes was performed by restriction fragment length polymorphism of the 5' noncoding region and classified according to Simmonds et al. RESULTS: Twenty-three of 49 (47%) veterans had 1a, 17 (35%) 1b, two (4%) 2a, three (6%) 2b, two (4%) 3a, two (4%) mixed (1a/2a, 1b/2a). This distribution of HCV genotypes was comparable to the genotypic distribution of a contemporary cohort of nonveteran OLT recipients at the University of Washington. There was a statistically significant association between illicit injection drug use (IDU) and 1a, with 63% of 1a patients having IDU whereas only 14% of 1b patients admitted to IDU (p = 0.03). All patients in whom the mode of acquisition was unknown had genotype 1b (p = 0.04). Intranasal cocaine use was strongly correlated with IDU (p = 0.002). Patients who had tattoos but no history of blood transfusion (BT) or recreational drug use had genotype 1 (2 had 1a, 2 had 1b; p = NS). Twenty-two (45%) patients had serological evidence of prior hepatitis B (HBV) infection. Patients who had genotype 2a, 2b, 3a, or mixed were much more likely to have had HBV (seven of nine, 78%) than patients with genotype 1a or 1b (15 of 40, 37.5%) (p = 0.03). There was no significant correlation between BT, dates, or military branch of service, high risk behavior in Southeast Asia, level of education, ethnicity, and particular genotype(s). Whereas the proportion of 1b accounting for HCV infection in patients with a first exposure before 1968 was 50%, all patients with a first exposure post-1975 were non-1b (p = 0.04), suggesting a change in the epidemiology of HCV in our cohort. CONCLUSIONS: In U.S. Veterans undergoing OLT: 1) 45% had PCR-confirmed HCV infection, 2) 1a was the predominant genotype and was associated with IDU, and 3) a significant decrease in the prevalence of genotype 1b from the pre-Vietnam era to post-1975 suggests a changing epidemiology of HCV genotypes.

Cocaine-Related Disorders↗

PubMed1999

Effect of retreatment with interferon alone or interferon plus ribavirin on hepatitis C virus quasispecies diversification in nonresponder patients with chronic hepatitis C.

Alpha interferon (IFN-alpha) treatment is effective on a long-term basis in only 15 to 25% of patients with chronic hepatitis C. The results of recent trials indicate that response rates can be significantly increased when IFN-alpha is given in combination with ribavirin. However, a large number of patients do not respond even to combination therapy. Nonresponsiveness to IFN is characterized by evolution of the hepatitis C virus (HCV) quasispecies. Little is known about the changes occurring within the HCV genomes when nonresponder patients are retreated with IFN or with IFN plus ribavirin. In the present study we have examined the genetic divergence of HCV quasispecies during unsuccessful retreatment with IFN or IFN plus ribavirin. Fifteen nonresponder patients with HCV-1 (4 patients with HCV-1a and 11 patients with HCV-1b) infection were studied while being retreated for 2 months (phase 1) with IFN-alpha (6 MU given three times a week), followed by IFN plus ribavirin or IFN alone for an additional 6 months (phase 2). HCV quasispecies diversification in the E2 hypervariable region-1 (HVR1) and in the putative NS5A IFN sensitivity determining region (ISDR) were analyzed for phase 1 and phase 2 by using the heteroduplex tracking assay and clonal frequency analysis techniques. A major finding of this study was the relatively rapid evolution of the HCV quasispecies observed in both treatment groups during the early phase 1 compared to the late phase 2 of treatment. The rate of quasispecies diversification in HVR1 was significantly higher during phase 1 versus phase 2 both in patients who received IFN plus ribavirin (P = 0.017) and in patients who received IFN alone (P = 0. 05). A trend toward higher rates of quasispecies evolution in the ISDR was also observed during phase 1 in both groups, although the results did not reach statistical significance. However, the NS5A quasispecies appeared to be rather homogeneous and stable in most nonresponder patients, suggesting the presence of a single well-fit major variant, resistant to antiviral treatment, in agreement with published data which have identified an IFN sensitivity determinant region within the NS5A. During the entire 8 months of retreatment, there was no difference in the rate of fixation of mutation between patients who received combination therapy and patients who were treated with IFN alone, suggesting that ribavirin had no major effects on the evolution of the HCV quasispecies after the initial 2 months of IFN therapy.

Adult↗

PubMed1998

Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.

To better understand the dynamics of hepatitis C virus and the antiviral effect of interferon-alpha-2b (IFN), viral decline in 23 patients during therapy was analyzed with a mathematical model. The analysis indicates that the major initial effect of IFN is to block virion production or release, with blocking efficacies of 81, 95, and 96% for daily doses of 5, 10, and 15 million international units, respectively. The estimated virion half-life (t1/2) was, on average, 2.7 hours, with pretreatment production and clearance of 10(12) virions per day. The estimated infected cell death rate exhibited large interpatient variation (corresponding t1/2 = 1.7 to 70 days), was inversely correlated with baseline viral load, and was positively correlated with alanine aminotransferase levels. Fast death rates were predictive of virus being undetectable by polymerase chain reaction at 3 months. These findings show that infection with hepatitis C virus is highly dynamic and that early monitoring of viral load can help guide therapy.

Alanine Transaminase↗

PubMed1998

Timing and severity of initial hepatitis C recurrence as predictors of long-term liver allograft injury.

BACKGROUND: The majority of patients infected with hepatitis C virus (HCV) undergoing liver transplantation develop evidence of histologic recurrence, and multiple mechanisms are likely poised to affect long-term allograft injury. The purpose of this analysis was to study the hypothesis that histologic and biochemical features at the onset of HCV recurrence predict the long-term evolution of allograft hepatitis. METHODS: We studied 34 consecutive liver transplant recipients with evidence of histologic HCV recurrence and with a minimal histologic follow-up of 1 year (up to 6.2 years; mean: 696+/-83.2 days). Two-hundred and seventy-eight serial allograft biopsies (mean: 6.85+/-0.62 per patient, range: 4-21) were analyzed. The hepatic activity index was utilized to quantitate piecemeal necrosis, intralobular degeneration, portal inflammation, and hepatic fibrosis. The presence of hepatocyte ballooning degeneration and cholestasis was also assessed. RESULTS: Although there was no significant difference with regard to initial hepatic activity index scores between patients who ultimately developed allograft cirrhosis (group 1; n=8) versus those with milder hepatitis (group 2; n=26), the finding of ballooning degeneration/cholestasis was more frequent in the former group (P=0.04). The distribution of HCV genotypes, the mean follow-up after orthotopic liver transplantation, the mean number of allograft biopsy specimens per patient, basal immunosuppression, and incidence of rejection were comparable in both groups. Patients who ultimately developed allograft cirrhosis had significantly higher initial total bilirubin at the onset of histologic recurrence and peak total bilirubin (pT. Bili, the highest value in the ensuing month). Actuarial rates of moderate-to-severe allograft hepatitis were significantly greater in patients with pT. Bili > or = 3.5 mg/dl (P=0.004). Multiple regression analysis identified pT. Bili as the only independent predictor of allograft cirrhosis. CONCLUSIONS: Features at the onset of histologic HCV recurrence predict the natural history of allograft injury; specifically, marked, transient hyperbilirubinemia is associated with the subsequent development of allograft cirrhosis.

Biopsy↗

PubMed1998

Donor-recipient sharing of HLA class II alleles predicts earlier recurrence and accelerated progression of hepatitis C following liver transplantation.

Both direct viral cytopathic effects and host immune responses appear to be important in the pathogenesis of hepatitis C virus (HCV) infection. Liver transplantation provides a means to explore the role of the immune system in the development of HCV-related liver damage through comparing the natural history of HCV in patients with different degrees of donor-recipient human leukocyte antigen (HLA) matching. We evaluated 36 patients with recurrent hepatitis C viremia following liver transplantation to determine whether hepatocellular injury or progression to bridging fibrosis occur more rapidly when donor and recipients share HLA alleles. HLA typing for the HLA-A and HLA-B loci was performed by serological techniques and PCR-based oligotyping was used to type alleles of the DRB1, DRB3, DQA1, and DQB1 loci. A median of eight liver biopsies, obtained during a median follow-up of 36 months, were reviewed per patient. Donor-recipient sharing of alleles of HLA-DQB1 or DRB1 was associated with more rapid development of recurrent hepatitis by univariate analysis (chi2=5.7, P=0.02 and chi2=5.54, P=0.02 respectively). However, only sharing of HLA-DRB1 alleles was identified as an independent predictor of reduced time to recurrent histologic injury by multivariate analysis (chi2 =5.74, P=0.02). Furthermore, sharing of HLA-DRB3 and histologic evidence of rejection were associated with more rapid progression to bridging fibrosis both by univariate methods (chi2=4.12, P=0.04 and chi2=4.66, P=0.03 respectively), and by multivariate analysis (chi2=13.01, P=0.001). These findings suggest that HLA class II-restricted immune responses may contribute to the pathogenesis of HCV-related liver injury in liver transplant recipients.

Adult↗

PubMed1998

Multigene tracking of hepatitis C virus quasispecies after liver transplantation: correlation of genetic diversification in the envelope region with asymptomatic or mild disease patterns.

To investigate the role of hepatitis C virus (HCV) quasispecies mutation in the pathogenesis of HCV infection, we analyzed changes in the genetic diversity of HCV genomes in 22 patients before and after liver transplantation by using heteroduplex mobility assay (HMA) technology. All patients were infected with HCV genotype 1 and developed high-titer posttransplant viremia. Each patient was classified according to the severity of posttransplant hepatitis, as assessed by standard biochemical and histological criteria. HCV quasispecies were characterized by HMA analysis of eight separate subgenomic regions of HCV, which collectively comprise 44% of the entire genome. The glycoprotein genes E1 and E2, as well as the nonstructural protein genes NS2 and NS3, had the greatest genetic divergence after liver transplantation (the change in the heteroduplex mobility ratio [HMR] ranged from 2.5 to 7.0%). In contrast, genes encoding the core, NS4, and NS5b proteins had the least amount of genetic divergence after liver transplantation (range, 0.3 to 1.2%). The E1/E2 region showed the greatest change in genetic diversity after liver transplantation, and the change in HMRs was 2.5- to 3.3-fold greater in patients with asymptomatic or moderate disease than in those with severe disease. The E1-5' region of HCV quasispecies isolated from patients in the asymptomatic group had a significantly greater degree of diversification after liver transplantation than the same regions of HCV quasispecies isolated from patients in the severe disease group (P = 0.05). While changes in the genetic diversity of some nonstructural genes were also greater in asymptomatic patients or in patients with mild disease than in patients with severe disease, the results were not significant. Data from this cohort demonstrate that greater rates of HCV quasispecies diversification are associated with mild or moderate liver disease activity in this immunosuppressed population.

Base Sequence↗

PubMed1998

Evolution of hepatitis C virus quasispecies in hypervariable region 1 and the putative interferon sensitivity-determining region during interferon therapy and natural infection.

To study hepatitis C virus (HCV) genetic mutation during interferon (IFN) therapy, the temporal changes in HCV quasispecies heterogeneity were compared before and after treatment for nine patients infected with HCV genotype 1, including four nonresponders, four responders who relapsed after therapy, and one responder who experienced a breakthrough of viremia during therapy. Nine untreated patients with an average time between specimens of 8.4 years served as controls. Sequences from the second envelope glycoprotein gene hypervariable region 1 (HVR1) and the putative IFN sensitivity-determining region (ISDR) of the nonstructural NS5A gene were analyzed by heteroduplex mobility assays and nucleotide sequencing. A strong positive correlation was found between the percent change in a heteroduplex mobility ratio (HMR) and percent change in nucleotide sequence (r = 0.941, P < 0.001). The rate of fixation of mutations in the HVR1 was significantly higher for IFN-treated patients than for controls (6.97 versus 1.31% change in HMR/year; P = 0.02). Similarly, a higher rate of fixation of mutations was observed in the ISDR for IFN-treated patients than for untreated controls, although the result was not significant (1.45 versus 0.15 amino acid changes/year; P = 0.12). On an individual patient basis, IFN therapy was associated with measurable HVR1 and ISDR mutation in nine of nine (100%) and two of nine (22.2%) patients, respectively. Evolution to IFN-resistant ISDR sequences was observed in only one of nine IFN-treated patients. These data suggest that IFN therapy frequently exerts pressure on the HCV envelope region, while pressure on the ISDR was evident in only a subset of patients. Thus, the selection pressures evoked on HCV genotype 1 quasispecies during IFN therapy appear to differ among different patients.

Amino Acid Sequence↗

PubMed1998

Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation.

The PKR protein kinase is a critical component of the cellular antiviral and antiproliferative responses induced by interferons. Recent evidence indicates that the nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) can repress PKR function in vivo, possibly allowing HCV to escape the antiviral effects of interferon. NS5A presents a unique tool by which to study the molecular mechanisms of PKR regulation in that mutations within a region of NS5A, termed the interferon sensitivity-determining region (ISDR), are associated with sensitivity of HCV to the antiviral effects of interferon. In this study, we investigated the mechanisms of NS5A-mediated PKR regulation and the effect of ISDR mutations on this regulatory process. We observed that the NS5A ISDR, though necessary, was not sufficient for PKR interactions; we found that an additional 26 amino acids (aa) carboxyl to the ISDR were required for NS5A-PKR complex formation. Conversely, we localized NS5A binding to within PKR aa 244 to 296, recently recognized as a PKR dimerization domain. Consistent with this observation, we found that NS5A from interferon-resistant HCV genotype 1b disrupted kinase dimerization in vivo. NS5A-mediated disruption of PKR dimerization resulted in repression of PKR function and inhibition of PKR-mediated eIF-2alpha phosphorylation. Introduction of multiple ISDR mutations abrogated the ability of NS5A to bind to PKR in mammalian cells and to inhibit PKR in a yeast functional assay. These results indicate that mutations within the PKR-binding region of NS5A, including those within the ISDR, can disrupt the NS5A-PKR interaction, possibly rendering HCV sensitive to the antiviral effects of interferon. We propose a model of PKR regulation by NS5A which may have implications for therapeutic strategies against HCV.

Animals↗

PubMed1998

Molecular tools for the treatment of hepatitis C.

The treatment of chronic hepatitis C is aimed at eliminating viral replication in order to prevent further evolution towards cirrhosis and hepatocellular carcinoma. Virological parameters include hepatitis C virus (HCV) genotype, qualitative viraemia, quantitative viral load and the characteristics of HCV quasi-species heterogeneity. These parameters can be used to predict and monitor the response to therapy, in order to help clinicians to tailor treatment of chronic hepatitis C and to better understand the molecular mechanisms underlying HCV resistance to antiviral drugs. Current knowledge on these various issues is reviewed in the present article.

Antiviral Agents↗

PubMed1997

Cytomegalovirus viremia: risk factor for allograft cirrhosis after liver transplantation for hepatitis C.

BACKGROUND: Despite recent advances in diagnosis and treatment, cytomegalovirus (CMV) infection continues to be a common cause of morbidity in liver transplant (LT) recipients. Because CMV infection suppresses cell-mediated immunity, which seems to be important in neutralizing hepatitis C virus (HCV) infection, we assessed the impact of CMV infection on histopathological HCV recurrence after LT. METHODS: The study group was comprised of 43 consecutive LT recipients with at least 6 months of histologic follow-up. Group 1 consisted of the 8 patients who developed CMV viremia after LT; group 2 comprised the 35 patients without CMV viremia. There was no significant difference with regard to age, initial immunosuppression, incidence of rejection, distribution of HCV genotypes, or mean follow-up between the groups. Semiquantitative histopathologic assessment of allograft hepatitis was performed using the Knodell's score. RESULTS: The mean total Knodell score of the final allograft biopsy was significantly greater in group 1 patients (P=0.016), with most of the difference due to periportal/bridging necrosis (P=0.009) and lobular activity subitem (P=0.01) scores. Half of the CMV viremic patients eventually developed allograft cirrhosis as compared with 11% of the CMV-negative patients (P=0.027). Accordingly, the cirrhosis-free actuarial survival by Kaplan-Meier estimates was significantly diminished in the CMV viremic patients. Glycoprotein B genotype analysis of CMV isolates revealed no significant differences between patients who did and those who did not develop allograft cirrhosis. CONCLUSIONS: After LT for chronic HCV, patients who develop CMV viremia incur a significantly greater risk of severe HCV recurrence.

Antiviral Agents↗

PubMed1997

Renal disease in hepatitis C-positive liver transplant recipients.

Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, renal dysfunction following transplantation is mainly attributed to cyclosporine toxicity. Membranoproliferative glomerulonephritis (MPGN) is seen in patients infected with hepatitis C virus (HCV), the virus responsible for 30% of the end-stage liver disease leading to liver transplantation. To determine the incidence of renal abnormalities in liver transplant recipients and the association with HCV, we undertook a longitudinal study in HCV-positive (n=91) and HCV-negative (n=106) liver transplant recipients. Mean creatinine clearance before transplantation was 94 ml/min/1.73 m2 in HCV+ patients and 88 ml/min/1.73 m2 in HCV- patients. By 3 months after transplantation, the mean creatinine clearance decreased by approximately one third in both groups. A greater proportion of HCV+ patients excreted >2 g protein/day after transplantation (P=0.05) and had renal biopsies showing MPGN than did HCV- recipients (4/10 HCV+ patients vs. 0/7 HCV- patients; P=0.1). In the HCV+ group, proteinuria was not associated with recurrent HCV hepatitis, DQ matching, posttransplant diabetes, or hypertension. Treatment of HCV-related MPGN with interferon-alpha2b appeared to stabilize proteinuria and renal function but did not reverse renal dysfunction nor cause liver allograft rejection. After transplantation, HCV+ patients had similar renal function over 3 years after transplantation, compared with HCV- patients, but they had an increased risk of proteinuria and occurrence of MPGN that was only partially responsive to interferon.

Adult↗

PubMed1997

Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein.

Hepatitis C virus (HCV) is the major cause of non-A non-B hepatitis and a leading cause of liver dysfunction worldwide. While the current therapy for chronic HCV infection is parenteral administration of type 1 interferon (IFN), only a fraction of HCV-infected individuals completely respond to treatment. Previous studies have correlated the IFN sensitivity of strain HCV-1b with mutations within a discrete region of the viral nonstructural 5A protein (NS5A), termed the interferon sensitivity determining region (ISDR), suggesting that NS5A may contribute to the IFN-resistant phenotype of HCV. To determine the importance of HCV NS5A and the NS5A ISDR in mediating HCV IFN resistance, we tested whether the NS5A protein could regulate the IFN-induced protein kinase, PKR, a mediator of IFN-induced antiviral resistance and a target of viral and cellular inhibitors. Using multiple approaches, including biochemical, transfection, and yeast genetics analyses, we can now report that NS5A represses PKR through a direct interaction with the protein kinase catalytic domain and that both PKR repression and interaction requires the ISDR. Thus, inactivation of PKR may be one mechanism by which HCV avoids the antiviral effects of IFN. Finally the inhibition of the PKR protein kinase, by NS5A is the first described function for this HCV protein.

Antiviral Agents↗

PubMed1997

Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1a or 1b.

Previous studies from Japan have described an association between a conserved sequence within the hepatitis C virus (HCV) genome and resistance to interferon (IFN) therapy for patients infected with HCV genotype 1b [Enomoto et al. (1995): Journal of Clinical Investigation 96: 224-230; Enomoto et al. (1996): New England Journal of Medicine 334:77-81]. The present study examines amino acid sequences surrounding the putative Interferon Sensitivity Determining Region (ISDR) of the NS5A gene of HCV in 21 North American patients with genotype 1a or 1b infection receiving recombinant IFN therapy. The ISDR consensus or intermediate pattern was observed in 13 of 14 NS5A clones from North American patients infected with genotype 1b. However, we found no evidence of the consensus ISDR sequence in any NS5A clones isolated from 15 patients with genotype 1a infection. In select cases, gel shift analysis showed no significant changes in the clonal frequency of the putative ISDR domain of HCV genotype 1a or 1b infected patients who were either nonresponsive to IFN therapy, or relapsed following withdrawal of IFN therapy. These results suggest that a conserved ISDR domain is neither associated with, nor responsible for, IFN resistance in North American patients infected with HCV genotype 1a, and demonstrate a need for further investigation into the reported association between ISDR consensus sequences and IFN resistance in genotype 1b clones.

Amino Acid Sequence↗

PubMed1997

Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa.

To determine if the clearance of hepatitis C genotype 1 virus (HCV) is dependent on the dose of interferon alfa-2b (IFN-alpha2b), the acute clearance of HCV after a single dose of either 3, 5, or 10 mIU of IFN-alpha was compared in patients with chronic hepatitis C. HCV-RNA levels following IFN-alpha administration were measured. At 24 hours, mean percentage serum viral reduction was 41.4%, 63.7%, and 85.5% for 3, 5, and 10 mIU, respectively (P < .001). At 48 hours, the mean viral reduction was consistently less than the reduction at 24 hours, averaging 22.9%, 61.9%, and 74.3%, respectively (P < .001), indicating that the drug effect diminishes before 48 hours. Regression analysis showed a positive correlation between dose and percent reduction of HCV-RNA levels (r = .6; P < .001). A mathematical model showed that such dose dependence is expected if IFN-alpha partially blocks viral production. Minimum clearance and production rates of HCV were estimated from measurements of HCV-RNA levels after the 10-mIU dose. HCV decay followed an exponential decline with a minimum estimate of the viral clearance rate constant of 2.8 per day, corresponding to a virion half-life of 0.3 days or less. A minimal estimate of the daily HCV production and clearance is 3.7 x 10(11) virions per day, indicating a high rate of replication and turnover. These results indicate that there is a dose-dependent effect of IFN-alpha in clearance of HCV genotype 1. Because the virion production rate is very rapid and because the current recommended dose of IFN-alpha (3 mIU) is often ineffective, larger doses should be considered to treat genotype 1-infected patients.

Adult↗

PubMed1997

Hepatitis G virus co-infection does not alter the course of recurrent hepatitis C virus infection in liver transplantation recipients.

Although hepatitis G virus infection (HGV) is usually asymptomatic, it has been associated with mild hepatic injury. Whether hepatitis G co-infection alters the natural history of other viral hepatitis infections remains to be determined. In the present study, we investigated whether hepatitis G impacts on the time to recurrent hepatitis or on the time to progression to fibrosis in hepatitis C-infected patients who undergo liver transplantation. Forty-five liver transplantation recipients with persistent hepatitis C viremia by polymerase chain reaction (PCR) were evaluated. Stored sera obtained before and after liver transplantation was tested for HGV RNA by reverse transcriptase (RT)-PCR using primers to the 5' region of the HGV genome. A median of eight serial liver biopsy specimens were reviewed per patient. The prevalence of HGV co-infection was 21% before transplantation and 22% following transplantation. During a median follow-up of 29 months, 78% (35/45) of patients with hepatitis C viremia developed histological features of recurrent hepatitis. Fifty-one percent (23/45) progressed to fibrous portal expansion and 16% (7/45) developed bridging fibrosis. Comparisons of patients with and without hepatitis G co-infection following transplantation showed no significant difference in time to recurrent hepatitis, fibrous portal expansion, bridging fibrosis, or of allograft or patient survival. In conclusion, hepatitis G co-infection does not seem to impact on the time to recurrent hepatitis C or progression of hepatitis C-related histological injury after liver transplantation.

Flaviviridae↗

PubMed1997

Histological and clinical outcome after liver transplantation for hepatitis C.

Hepatitis frequently recurs after liver transplantation for hepatitis C. However, the histological progression of disease, predictors of recurrence and disease severity, and patient survival remain uncertain. Fifty-five patients with cirrhosis caused by chronic hepatitis C underwent liver transplantation between January 1990 and December 1993. Hepatitis C genotype was determined, and liver biopsies were performed at frequent intervals posttransplantation. The median follow-up time was 40.4 months. The cumulative rate of survival was no different in liver transplant recipients for hepatitis C than in liver transplant recipients for other chronic liver diseases (P = .62). Histological recurrent hepatitis C developed in 33 of 50 patients assessable for disease recurrence; the median recurrence-free survival time was 13.4 months. Histological activity and stage were mild in most cases. Only 2 patients developed cirrhosis, and no patient required a second transplantation for recurrent disease. Patients with acute cellular rejection had a shorter recurrence-free survival (P = .0141). In patients with recurrent hepatitis, rejection also was correlated with increased histological grade 2 years after transplantation (P = .0061). Recurrence-free survival was decreased in patients infected with genotype 1 (1a and 1b combined) compared with genotypes 2 and 3 combined (P = .02), whereas there was no difference between genotypes 1a and 1b (P > .80). Only patients infected with genotype 1a or 1b developed bridging fibrosis or cirrhosis. In addition, patients who had an early recurrence had a greater risk of progressing to bridging fibrosis or cirrhosis (hazard ratio, 5.1; P = .0473). In our experience, recurrent hepatitiS C after liver transplantation in most cases is mild and survival is unaffected. Both acute cellular rejection and infection with genotype 1 are independent risk factors for reduced recurrence-free survival, and early recurrence is associated with a higher risk of disease progression.

Adolescent↗