Natural History Of Hepatitis Research Articles

The natural history of hepatitis C with severe hepatic fibrosis

To examine the morbidity and mortality of patients with severe fibrosis secondary to HCV infection, within a population unbiased by tertiary referral. One hundred and fifty HCV infected patients were identified from the Trent HCV study with a liver biopsy taken before 2002 demonstrating severe fibrosis (Ishak stage > or =4). Follow-up data were extracted from the database and hospital records. Median follow-up was 51 months. Of the 131 patients with no prior history of decompensation, 33 (25%) died (n=25) or were transplanted (n=8), after a median interval of 42 months. The probability of survival without liver transplantation was 97%, 88%, and 78% at 1, 3, and 5 years, respectively. Hepatocellular carcinoma and/or decompensation was diagnosed in 33 (25%), after a median interval of 41 months. In multivariate analysis, combination antiviral therapy was associated with improved survival. Prognosis was not affected by the Ishak stage at index biopsy. There was a worse prognosis for the 19 patients with previous decompensation; 17 (89%) having either died (n=15) or been transplanted (n=2). This study demonstrates that severe liver fibrosis (Ishak stage > or = 4) secondary to hepatitis C is associated with a poor prognosis, that may be improved following combination antiviral treatment.

The management of HIV and hepatitis B coinfection

Coinfection with HIV and hepatitis B virus has a significant impact on the natural history of hepatitis B disease with faster rates of progression to cirrhosis and end stage liver disease. An increasing number of hepatitis B virus active drugs are now available, many of which have dual anti-HIV activity. This review highlights the most important recent developments in the management of HIV and hepatitis B virus coinfection. Natural history studies continue to confirm the increased rate of liver-related mortality in coinfected individuals and the importance of hepatocellular carcinoma in this population. The most recent studies of adefovir and tenofovir in open label use in coinfected individuals are discussed and new data on the activity of emtricitabine, entecavir and pegylated interferon are presented. Strategies for use of these new options for anti-hepatitis B virus therapy in coinfected individuals are discussed. Prevention of end stage liver disease and hepatocellular carcinoma in the coinfected population is vital and the increasing availability of drugs with potent anti-hepatitis B activity is encouraging. Appropriate diagnosis and monitoring of hepatitis B, coupled with better understanding of the mechanisms of drug resistance, will enable clinicians to manage coinfection more effectively.

The Role of the Hepatology Nurse in the Difficult-To-Treat Hepatitis C Population

The Role of the Hepatology Nurse in the Difficult-To-Treat Hepatitis C Population

Hepatitis B in children

We read with interest the special article by Shneider et al.1, which was published in November 2006, but related to a conference held in March 2006. As regards hepatitis B, Shneider et al. state: “Unfortunately at present there are inadequate numbers of patients with sufficiently long follow-up to give an accurate assessment of the lifelong risk and/or predictors of serious morbidity and mortality in children with chronic hepatitis B”, and “it is nearly impossible to assess an accurate risk of development of HCC before the age of 20 years in children with HBV infection acquired early in life.” We believe that our 29-year longitudinal study of chronic hepatitis B in 99 otherwise healthy children, published in March 2006,2 and commented on in Hepatology Highlights of April 2006,3 can give some answers with regard to the prognosis of chronic hepatitis in children infected postnatally early in life. Pediatric HBV infection is often identified with the Chinese model of vertical transmission and tolerance to the virus. However, in many areas of the world, including Southern Europe before compulsive HBV vaccination and Eastern Europe, children are preferably infected postnatally and do not develop tolerance. In this latter model of infection, the outcome within the first 20 years of life is benign (inactive hepatitis B surface antigen carrier state) in the vast majority of cases, although 2 patients in our cohort developed HCC and are long-term survivors after surgery. It is certainly true that life-long risks remain undefined, and environmental factors can change the prognosis at any time, but 3 decades of follow-up have covered at least the gap between the natural history of hepatitis B in children and in young adults in our endemic area. Flavia Bortolotti M.D.*, Maria Guido M.D. , * Department of Clinical and Experimental Medicine, University of Padua, Padova, Italy, Department of Pathology, University of Padua, Padova, Italy.

Acute Hepatitis C in Patients Receiving Hemodialysis

Hepatitis C virus (HCV) infection is frequent in patients with end-stage renal disease treated by chronic dialysis, with a prevalence varying from 10–65% according to the geographical data. The prevalence is significantly associated with the duration of dialysis and the number of transfused blood products and has dramatically declined with efficient blood screening. We studied patients with acute HCV infection in a dialysis unit. The diagnosis was based on both anti-HCV detection and HCV-RNA detection. Other virological tools including HCV genotype determination was also used to tailor treatment to the individual patient and determine its efficacy for a one-year follow-up period. Seventeen patients (7 male and 10 female, mean age: 63.7 ± 11.6 SD) with acute hepatitis C were enrolled to our study. All of them were followed up for a period of one year after the diagnosis was established. Phylogenetic analysis distinguished two separate HCV subtypes 1b, which were both responsible for this acute infection (see ). These types did not differ in their behavior on the clinical situation of our patients, as confirmed by the fact that in both groups of patients, there was only one patient who presented with acute illness. Six patients of our study group, three months after the acute infection, received pegylated interferon (Peg-IFNa2a) 135 μg for a six-month period. Four of them responded very well to therapy and at the first determination HCV RNA was below the cutoff point. One of our patients with very high HCV levels (HCV RNA > 50,000,000 IU/mL), despite receiving the same therapy, did not respond well and developed cirrhosis. In conclusion, it is clear from our experience that better information is needed about the current incidence, prevalence, and risk factors for HCV infection in dialysis patients. Algorithms for the diagnosis and management of hepatitis C should be developed by academic societies. Routine screening for hepatitis C also would allow for better definition of the natural history of hepatitis C in patients with end stage renal disease.Figure 1. NS 5B gene phylogenetic tree analysis of the acute hepatitis C epidemic.

Hépatite C et transplantation hépatique: Histoire naturelle et traitement ou comment améliorer la prise en charge ?

Hepatitis C virus-related end-stage liver disease, alone or in combination with alcohol, has become the leading indication for liver transplantation in most transplant programs accounting for approximately half of transplants performed in European centers. Hepatitis C virus infection recurs virtually in every post-transplant patient. The natural history of hepatitis C after liver transplantation is variable. Progression of chronic hepatitis C virus is more aggressive after liver transplantation with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. Approximately 10% of the patients with recurrent disease will die or require re-transplantation within 5 years post-transplantation. Several factors, including those related to the virus, the host, the environment and the donor, are probably implicated in the outcome. The immune status represents the main significant variable in influencing disease severity in hepatitis C virus-infected patients; with higher HCV viral load and the significant association described between the degree of immunosuppression and disease severity. Interventions to prevent, improve, or halt the recurrence of hepatitis C virus infection have been evaluated by multiple small studies worldwide with similar overall rates of virological clearance of approximately 9-30%. Current consensus recommends combination therapy with pegylated interferon and ribavirin for those patients with histological recurrence of hepatitis C virus infection and fibrosis. Therapy is adjusted to tolerance and rescued with granulocyte colony-stimulating factor and erythropoietin for bone marrow suppression. In this article we present a comprehensive review of post-transplant hepatitis C virus infection; in particular fibrosis progression and the major challenges according to treatment.

Genetic Polymorphism of Interferon-γ, Interferon-γ Receptor, and Interferon Regulatory Factor-1 Genes in Patients with Hepatitis B Virus Infection

The natural history of hepatitis B virus (HBV) infection is probably related to host immune factors. Interferon-gamma (IFN-gamma) plays significant roles in immune defense. This study was undertaken to investigate the association between HBV infection and single nucleotide polymorphisms (SNPs) of IFN-gamma, IFN-gamma receptor (IFNGR)-1 and 2, and interferon regulatory factor (IRF)-1 genes. Between March 2002 and December 2002, 614 Korean patients were enrolled in two different groups: an HBV clearance group (n = 201), who were hepatitis B surface antigen (HBsAg) negative with antibodies to HBsAg and hepatitis B core antigen, and an HBV persistence group (n = 413), who were repeatedly HBsAg positive. We assessed polymorphisms in the IFN-gamma gene at position +874, in the IFNGR-1 gene at positions -56 and +95, in the IFNGR-2 gene at the second position of codon 64 (Gln64Arg), and in the IRF-1 gene promoter (-410, -388), and the genotype distributions of the HBV clearance and persistence groups were compared. On the basis of unconditional logistic regression analysis with adjustment for age and sex, no statistically significant association with susceptibility to persistent HBV infection was observed with the IFN-gamma, IFNGR-1 and 2, and IRF-1 gene polymorphisms under the codominant, dominant, and recessive models.

Does the clinical outcome of hepatitis C infection vary with the infecting hepatitis C virus type?

Whether differences in the natural history of hepatitis C virus (HCV) can be explained by differences in the infecting HCV type is unknown. The aim of this study was to investigate whether the HCV type might influence the clinical outcome of infection. Study serum samples were assembled from 749 individuals enrolled into the UK HCV National Register from which data on clinical outcomes were extracted. HCV-RNA-positive specimens were genotyped and HCV-RNA-negative specimens serotyped. Logistic regression analysis was used to investigate the independent effect of HCV type on viral clearance by comparing patients who were HCV RNA negative (n = 86) with those who were HCV RNA positive (n = 508). The same method was used to investigate whether HCV type was associated with histological stage of liver disease. The prevalence of HCV type 1 among those who cleared infection was 69% and among those who remained HCV RNA positive was 51%: Type 1 infections were more likely to be HCV RNA negative than non-1 types (OR 0.47, 95% CI 0.29-0.78, P = 0.003). Type 1 infections were also more likely to be associated with histological stage scores above the median when compared with non-1 types (OR 2.03, 95% CI 1.07-3.83, P = 0.03). In conclusion, HCV type 1 infection was more often HCV RNA negative, suggesting that spontaneous clearance may occur more commonly with this type. Among the RNA-positive infections, type 1 infection may be more aggressive than types 2/3.

Viral hepatitis B and C in children

Viral hepatitis B and C are the cause of significant disease worldwide. Acute infection is more common with hepatitis B than C in childhood; but chronic asymptomatic infection leading to chronic liver disease and hepatocellular carcinoma is a considerable concern. The natural history of hepatitis B is well established in adults but the long-term outcome for children is still under debate. Following an acute infection, 90% will recover spontaneously; but approximately 1% of patients develop acute fulminant hepatitis requiring liver transplantation. The main source of infection in childhood is perinatal transmission, which is effectively prevented using vaccination, antenatal screening and screening of blood products and organ donors. The vaccine is effective in 97% of newborn infants and lasts for 10-15 years. All children with chronic hepatitis B infection should be annually monitored and those with persistent infection should be considered for anti-viral therapy. Treatment options include Interferon (5 M units per m2 subcutaneously ×3 weekly for 6 months) or Lamivudine (3 mg/kg for 12-24 months), but neither therapy is completely effective. Interferon clears viral infection in 20%-40% and is most effective in children with elevated transaminases or horizontal transmission. Only 23% seroconvert after lamivudine, 26% of whom may develop resistance with YMDD mutant variants of the hapatitis B virus. A number of other drugs, such as Adefovir Dipivoxil, Famciclovir, Entecavair and Pegylated Interferon, are under evaluation. Liver transplantation is an effective treatment for children with acute or chronic liver failure, but recurrence is high without prophylaxis. The main route of transmission for hepatitis C was originally through infected blood products or organs; but now the most common source is vertical transmission which ranges from 2%-12% depending on maternal infectivity. Breast feeding is safe in mothers with low titres of hepatitis C RNA. The natural spontaneous clearance rate for hepatitis C is between 20% and 40% and is higher in children who have been parenterally infected compared to perinatal infection. It is a mild disease in children, but the indication for treatment is based on the future risk of cirrhosis and hepatocellular cancer. Children with persistent infection (hepatitis C RNA positive for 6 months) and evidence of histological disease should be considered for combination treatment with Pegylated Interferon (3 M units/m2 subcutaneously × 1 weekly) and oral Ribavirin (15 mg/kg) which has a sustained response rate of 80%-100% for genotypes 2 and 3, and 50% for genotype 1. Liver transplantation for hepatitis C in children is rarely required, but 100% recurrence can be expected without prophylaxis. Emerging new therapies include viral enzyme inhibitors, cytokines, antisense oligonucleosides which are at an early stage of development.

P52: Natural history of hepatitis C following gastric bypass surgery

P52: Natural history of hepatitis C following gastric bypass surgery

Hepatitis B e Antigen-Positive Chronic Hepatitis B: Natural History and Treatment

The natural history of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is very heterogeneous. Age at acquisition is a major factor in determining the natural history of chronic infection. The vigor of the host immune response to the virus, viral factors (genotype, core promoter mutations, and duration of viral replication) as well as exogenous factors (alcohol, immune suppression) all influence the severity of disease. The goal of antiviral therapy is HBeAg seroconversion, and preferably HB surface Ag seroconversion as this latter end-point is associated with sustained immune control and the halting of disease progression. Although peginterferon is now considered as the first line of therapy for HBeAg-positive chronic hepatitis B, in most cases there are circumstances where nucleos(t)ide analogues are indicated (e.g., decompensated liver disease) for those requiring cancer chemotherapy/other immunosuppressive agents and for those with contraindications to interferon. The major challenge for the clinician using these agents is the emergence of antiviral drug resistance. Long-term immune control of viral replication is key to improving patient outcome.

The natural history of hepatitis C virus in pediatric liver transplant recipients

Although rare in the pediatric population, the natural history of hepatitis C virus (HCV) recurrence in pediatric patients undergoing orthotopic liver transplantation (OLT) for end-stage liver disease secondary to HCV has not been well described. We performed an analysis of all 67 pediatric patients (< 17 years old) who have undergone OLT for HCV in the United States between 1/1988 and 6/2005. The 67 pediatric patients received a total of 83 OLTs for HCV. Following initial OLTs performed for HCV, the patient and allograft survival rates were 71.6% and 55.0%, respectively, at 5 years. Following retransplantation these rates decreased to 55.0% and 33.8%, respectively, following retransplantation. Recipients were listed for retransplantation after 31.3% of all OLTs, and overall recipients were retransplanted after 19.3% of OLTs. The overwhelming majority of retransplants were performed for HCV recurrence. A mean of 1.2 OLTs were performed per patient for HCV. The median time between OLTs for HCV was 290 days. In conclusion, the risk of HCV recurrence in pediatric OLT recipients is high and is associated with a high rate of retransplantation. Still, OLT represents the only treatment option that may achieve long-term survival in pediatric patients with end-stage liver disease secondary to HCV that is recalcitrant to medical management.

Natural History of Hepatitis B and C in Renal Allograft Recipients

Natural History of Hepatitis B and C in Renal Allograft Recipients

Histopathology of chronic hepatitis C in relation to virus genotype

The natural history of hepatitis C virus (HCV) infection is variable and the factors determining the course of the illness are unclear. There are geographical variations in the distribution of different HCV genotypes, and some of them are related to the specific infection routes. Regarding our country, the dominant genotype is genotype 1b. It is unclear and still remains a question whether the distinct histopathological manifestations are related to the particular genotypes of HCV. Thus, the aim of this study was to determine whether the distinct histopathological manifestations of HCV infection might be in relation to the individual virus genotype. In this study we examined 126 patients with chronic HCV infection regarding the histopathological features, demographic data, and virus genotype. The observed groups of patients were predominantly infected with HCV genotypes 1b and 3a. In this study we found that the patients infected with HCV genotype 1b had more frequently moderate or severe necroinflammatory activity of the disease, significantly higher grading score as compared with other genotypes (p < 0.0001). A higher degree of fibrosis was, also, more common in the patients infected with genotype 1b of HCV as compared with other genotypes (p < 0.05). There were no significant correlations between the necroinflammatory activity of the disease and the stage of fibrosis in 1b, 4 and mixed genotypes. The present data support the hypothesis that distinct genotypes of HCV are associated with the particular histopathological manifestation of the disease.

Cost-effectiveness of hematologic growth factors for anemia occurring during hepatitis C combination therapy

In hepatitis C virus (HCV)-infected patients who develop anemia during combination therapy, erythropoietic growth factors maintain higher drug treatment levels compared to ribavirin dose reduction, which may lead to an increase in treatment response rates. This study estimated the cost-effectiveness of growth factor therapy in maintaining anemic HCV-infected patients on target drug levels during combination therapy. A decision analysis using a Markov model was developed with 7 health states: Sustained viral response, chronic HCV, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Data sources included population-based studies of growth factor therapy, previously published estimates of costs and natural history of hepatitis C, and recent prospective studies. Our reference case was a 45-year-old Caucasian man with HCV infection (genotype 1, 2, or 3) who developed anemia while undergoing combination therapy with ribavirin and pegylated interferon. We compared growth factor injections (darbepoetin alpha or epoetin alpha) during combination therapy with standard ribavirin dose reduction. Compared to a ribavirin dose reduction strategy, the cost of darbepoetin per additional quality-adjusted life-year was 34,793 dollars for genotype 1 and 33,832 dollars for genotypes 2 or 3 versus 60,600 dollars and 64,311 dollars for epoetin. For all genotypes, the results were sensitive to changes in the cure rates of HCV therapy, the utility of chronic HCV, the costs of growth factors, and the age at which therapy is begun. In conclusion, use of erythropoietic growth factors, specifically darbepoetin, for patients with anemia occurring during HCV combination therapy appears to be cost-effective for genotypes 1, 2, or 3.

HBsAg Seropositive Status and Survival After Renal Transplantation: Meta‐Analysis of Observational Studies

The natural history of hepatitis B virus (HBV) infection after renal transplantation (RT) remains unclear. We conducted a systematic review of the published medical literature on the impact of HBV surface antigen (HBsAg) seropositivity on survival of RT recipients. We used the random effects model of DerSimonian and Laird to generate a summary estimate of the relative risk for mortality and graft loss in HBsAg positive RT recipients across the published studies. We identified six observational studies (6050 unique patients); all of them being cohort, retrospective studies. Pooling of study results demonstrated that HBsAg in serum was an independent and significant risk factor for death after RT; the summary estimate for relative risk was 2.49 with a 95% confidence interval (95% CI) of 1.64-3.78. A test for homogeneity of the relative risk across the studies gave a p-value of <0.0001. HBsAg seropositivity was an independent and significant risk factor for graft failure after RT; the summary estimate was 1.44 with a 95% CI of 1.02-2.04 (homogeneity test, p <0.0001). This meta-analysis shows that HBsAg positive RT recipients have an increased risk for mortality and graft failure compared to seronegative patients.

Natural history of chronic hepatitis B in co-infected patients

HIV co-infection influences the course and natural history of hepatitis B virus (HBV) infection by impairing the quantity and quality of the innate and adaptive immune response. The rates of spontaneous resolution after acute infection and spontaneous anti-HBe and anti-HBs seroconversions are decreased, and levels of HBV replication are increased in HIV-infected patients. A more rapid progression of liver fibrosis and a higher rate of cirrhosis decompensation (but not hepatocellular carcinoma) have been demonstrated in co-infected patients. The risk of HBV-associated end-stage liver disease and liver-related mortality may be increased by HIV co-infection. Antiretroviral therapy may trigger spontaneous anti-HBe and anti-HBs seroconversion and/or a better immune control of HBV replication by restoring adaptive immunity, but can also increase hepatitis flares. Reactivation of chronic hepatitis B has been observed after suspension of anti-retrovirals with anti-HBV activity or after occurrence of HBV resistance to lamivudine. Future research should focus on: the impact of HIV-induced changes in innate and adaptive immune response and modifications induced by anti-retroviral therapy that may impact on progression of advanced chronic hepatitis B; the association between HBV genotype and clinical course of disease; and the role of occult HBV infection as a co-factor with other causes of liver injury.

Quality of life and cost-effectiveness of anti-HCV therapy in HIV-infected patients

Quality of life studies in chronic hepatitis C using specific questionnaires have been performed in mono-infected patients; however, these studies have just begun in HIV-HCV co-infected patients. The questionnaires used in mono-infected patients are not well adapted for co-infected patients and need to be redesigned. Typically, co-infected patients have multiple symptoms that may be attributable to HIV, to HCV, to a combination of both diseases or even to side effects related to drug therapy. These patients usually need substitutive therapy to manage side effects related to HCV therapy, particularly anaemia, leukopenia and depression. There are no cost-effectiveness studies published on the current HCV standard therapy with pegylated interferon and ribavirin. However, there is some research on the old standard interferon and ribavirin, which shows that HCV therapy is cost-effective. Cost-effectiveness studies in co-infected patients will have to take into account variables that do not affect mono-infected patients, such as the different levels of CD4, the increase in the fibrosis progression rate and the use of other expensive drugs for the management of side effects. Currently, the literature does not provide adequate information on the effect of HCV infection on the quality of life of HIV-HCV co-infected patients or the most cost-effective HCV therapy.

Hepatitis C Virus Antibody Status and Survival After Renal Transplantation: Meta-Analysis of Observational Studies

The natural history of hepatitis C virus (HCV) among patients after renal transplantation (RT) remains incompletely defined. We conducted a systematic review of the published medical literature on the impact of hepatitis C antibody status on survival of patients who received RT. We used the random effects model of DerSimonian and Laird to generate a summary estimate of the relative risk (RR) for mortality and graft loss with HCV seropositivity across the published studies. We identified eight clinical trials (6365 unique patients); six (75%) were cohort studies and two (2/8 = 25%) controlled trials, respectively. Pooling of study results demonstrated that presence of anti-HCV antibody was an independent and significant risk factor for death and graft failure after RT; the summary estimate for RR was 1.79 (95% CI, 1.57-2.03; homogeneity test, p = 0.0427) and 1.56 (95% CI, 1.35-1.80; homogeneity test, p = 0.0192), respectively. As a cause of death, hepatocellular carcinoma (HCC) and liver cirrhosis were significantly more frequent among anti-HCV positive than anti-HCV negative RT patients. This meta-analysis demonstrates that RT recipients with anti-HCV antibody have an increased risk of mortality and graft failure compared with HCV antibody negative patients.

Natural History of Hepatitis B and C in Renal Allograft Recipients

In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available. In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation. At enrollment in 1989 (5.5+/-4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk [RR], 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival. In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.