Hepatitis C Virus Progression Research Articles

Hepatitis C virus infection and alcohol

An interaction between hepatitis C and the consumption of alcohol was suspected before the discovery of the hepatitis C virus (HCV) in 1989. Alcohol and HCV both cause liver injury. Although it is known that alcohol consumption is associated with apoptosis, oxidative stress, immune dysfunction (lower activities of cytotoxic T cells and helper T cells and decreased cytokine expression), increased HCV viral load, and greater numbers of HCV quasispecies, the mechanism of the interaction between alcohol and HCV is unknown. The progression of hepatitis C to liver cirrhosis varies from 4% in donors to 22% in liver clinics, after 20 years of evolution. Epidemiological studies carried out in the 90s showed that excessive alcohol consumption is one of the main determinants of the severity of HCV progression. The definition of excessive alcohol consumption and the minimum amount of alcohol required to induce liver damage in patients with HCV infection is an important issue. It should be borne in mind that low levels of alcohol ingestion are beneficial and are associated with decreased mortality in conditions other than hepatitis C. Several studies demonstrated an association between a high level of alcohol consumption and a high prevalence of fibrosis and cirrhosis. The existing association between low and moderate levels of alcohol consumption and the progression or severity of liver damage caused by hepatitis C is less clear, and some results are contradictory. Two recent studies showed a direct relationship between a high level of alcohol consumption and severe fibrosis. There is no doubt that a relationship exists between HCV and hepatocellular carcinoma and that alcohol, by promoting cirrhosis, is conducive to the development of hepatocellular carcinoma. Some studies have even found that alcohol would be a predictive factor independently of histological state and even a predictor of evolution after surgical resection. The effects of drinking alcohol on responses to treatment are not well characterized, and existing data are derived from studies with small numbers of patients. Abstinence from alcohol is considered mandatory for preventing poor adherence to treatment and an increased incidence of adverse side effects. None of the studies on alcohol consumption and HCV is a randomized or blinded trial, more biochemical responses have been evaluated than virological responses, and almost all studies have been done using interferon monotherapy. Decreased responses to treatment have been associated with alcohol consumption, but whether alcoholics are the worst responders to therapy is unknown. Based on the best available evidence to date, which has mainly been supported by case-control studies, evidence type is III, and recommendation Grade is C, for general applicability or in an individual case. The pathophysiology of interactions between alcohol and hepatitis C remain to be elucidated by further research. Patients with HCV should avoid excessive alcohol consumption, because it induces progression of fibrosis to cirrhosis and because moderate or low alcohol consumption seems to contribute to liver damage. There is a relationship between alcohol consumption by patients with hepatitis C and the development of hepatocellular carcinoma in association to the interaction of alcohol and cirrhosis, even if an independent association has not been proven. The incidence of sustained responses to antiviral treatment seems to be inversely proportional to the amount of alcohol consumed before and during the treatment.

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.

Role of Hepatitis C Virus (HCV) Viremia and HCV Genotype in the Immune Recovery from Highly Active Antiretroviral Therapy in a Cohort of Antiretroviral-Naive HIV-Infected Individuals

The roles of hepatitis C virus (HCV) viremia and HCV genotype in the immune response to highly active antiretroviral therapy (HAART) are poorly understood. Our aim was to assess the CD4+ cell count recovery after HAART in human immunodeficiency virus (HIV)-infected patients with HCV viremia and HIV-infected patients who tested negative for HCV antibody (HCV-Ab). We also aimed to assess whether the response to HAART in these patients varied according to HCV genotype. The analysis focused on 1219 HCV-Ab-negative patients and 284 HCV-viremic patients from a cohort of HIV-infected subjects that includes persons who were antiretroviral naive before initiating HAART after cohort enrollment. HCV RNA load and HCV genotype were determined in plasma specimens obtained and stored during the 6-month period preceding the initiation of HAART. The chance of achieving a CD4+ cell count increase of > or = 100 cells/microL from the pre-HAART level tended to be poorer in HCV-viremic patients than in patients who tested negative for HCV-Ab (adjusted relative hazard [RH], 0.82; 95% confidence interval [CI], 0.66-1.01; P = .06). In contrast, a comparison of patients who had a HCV RNA load >1 x 10(6) IU/mL with patients who had a HCV RNA load of 5-1 x 10(6) IU/mL revealed no significant association between HCV RNA load and achievement of an increased CD4+ cell count (adjusted RH, 0.97; 95% CI, 0.75-1.27; P = .83). There was no clear association between HCV genotype and the probability of achieving a CD4+ cell count increase. An association between the presence of HCV-Ab and immune reconstitution after HAART has been shown elsewhere. Results of our large, prospective study support a direct role of HCV viremia in the CD4+ cell count response to HAART. Moreover, our results underline the fact that, in individuals coinfected with HIV and HCV, the goal of treating HCV infection is to eradicate HCV, to both slow the rate of HCV progression and limit potential interference with the response to HAART.

Early HCV-associated stellate cell activation in aggressive recurrent HCV: What can liver allografts teach about HCV pathogenesis?

Early HCV-associated stellate cell activation in aggressive recurrent HCV: What can liver allografts teach about HCV pathogenesis?

HAART and the HCV-infected liver: friend or foe?

HAART and the HCV-infected liver: friend or foe?

Hepatitis C Virus/HIV Coinfection: A New Challenge for Nurses in AIDS Care

HIV-infected patients are living longer owing to effective treatment with highly active antiretroviral therapy (HAART). As a result, the extent and impact of hepatitis C virus (HCV) infection in this patient population are now becoming apparent. HIV infection accelerates the progression of HCV to cirrhosis, endstage liver disease, and death. The presence of each disease also influences treatment of the other, and appropriate management of side effects (e.g., anemia, neutropenia, depression) is crucial for treatment success. The HIV nurse is well positioned to treat, counsel, and support the HIV/HCV-coinfected patient by encouraging screening and providing education on the side effects of treatment, the means of managing side effects, and the resources available to assist in problems of substance abuse and depression.

The costs of not treating hepatitis C virus infection in injecting drug users in New Zealand.

This paper estimates future health service costs of the current practice in New Zealand of not funding treatment of hepatitis C virus (HCV) infections. Costs are estimated separately for Māori and non-Māori, male and female IDUs. Markov modelling is used to track the infection and progression of HCV to severe liver disease and death, and accumulated costs are estimated for the life of the cohort. Upper and lower estimates of costs are calculated based on different assumptions of the rate of progression of HCV to more severe liver disease. Costs are estimated at dollars 24.6 million per 1000 non-Māori men IDUs (discounted at 3%), under progression assumptions based on liver clinic studies, compared with dollars 10.3 million per 1000 using lower rates of progression based on community studies. Similarly, corresponding costs for non-Māori women are estimated at dollars 27.6 million and $11.2 million per 1000 IDUs. Costs for women are higher because their greater life expectancy is associated with more cases of liver cirrhosis (LC) at older ages. Future costs for Māori are lower than non-Māori, because Māori are more likely to die at younger ages and hence fewer progress to more advanced liver disease. The current situation in New Zealand of not treating HCV infections will result in considerable future costs as some people with HCV progress to more severe liver disease. Provisional estimates are that the accumulated costs of HCV-related liver disease for all IDUs currently infected will be between dollars 166 million at lower rates of disease progression (discounted at 3%) to dollars 400 million at upper rates. Some of the associated morbidity and mortality could have been avoided if the HCV infections had been treated.

Health-state utilities and quality of life in hepatitis C patients.

Health-state utilities are global measurements of quality of life on a scale from 0 (death) to 1 (full health). Utilities are used to evaluate health outcomes and are the preferred outcome measure for policy models that determine the cost-effectiveness of treatments. Currently, utilities for hepatitis C virus (HCV)-infected patients have been estimated using expert judgments. The purpose of this study was to elicit HCV utilities directly from patients. We assessed the utilities of 193 outpatients at various stages of chronic HCV progression by using a visual analog scale, the standard gamble technique, the Health Utilities Index Mark 3 survey, and the EuroQol Index survey. We also incorporated the nonutility-based Short Form-36v2 survey, which provides a detailed profile of health status. The mean standard gamble utilities were: 0.78 for patients without a recent liver biopsy and no signs of cirrhosis; 0.79 for mild to moderate chronic HCV infection; 0.80 for compensated cirrhosis; 0.60 for decompensated cirrhosis; 0.72 for hepatocellular carcinoma; 0.73 for transplant; and 0.86 for sustained virological responders to interferon +/- ribavirin treatment. The Health Utilities Index Mark 3 survey and the EuroQol Index survey utilities were lower than Canadian population norms (p < 0.001). Patient-elicited utilities were lower than previous expert estimates for mild/moderate chronic infection and sustained virological responders, but higher for decompensated cirrhosis and hepatocellular carcinoma. The Short Form-36v2 survey scores revealed several significant health impairments (p < 0.005) when compared with U.S. population norms. These findings 1) suggest that quality of life (QOL) differences across the HCV clinical spectrum are smaller than previously believed; 2) support other evidence suggesting that QOL is significantly diminished in HCV patients; and 3) provide utility values derived directly from HCV patients.

Health-state utilities and quality of life in hepatitis C patients

Objective Health-state utilities are global measurements of quality of life on a scale from 0 (death) to 1 (full health). Utilities are used to evaluate health outcomes and are the preferred outcome measure for policy models that determine the cost-effectiveness of treatments. Currently, utilities for hepatitis C virus (HCV)-infected patients have been estimated using expert judgments. The purpose of this study was to elicit HCV utilities directly from patients. Methods We assessed the utilities of 193 outpatients at various stages of chronic HCV progression by using a visual analog scale, the standard gamble technique, the Health Utilities Index Mark 3 survey, and the EuroQol Index survey. We also incorporated the nonutility-based Short Form-36v2 survey, which provides a detailed profile of health status. Results The mean standard gamble utilities were: 0.78 for patients without a recent liver biopsy and no signs of cirrhosis; 0.79 for mild to moderate chronic HCV infection; 0.80 for compensated cirrhosis; 0.60 for decompensated cirrhosis; 0.72 for hepatocellular carcinoma; 0.73 for transplant; and 0.86 for sustained virological responders to interferon ± ribavirin treatment. The Health Utilities Index Mark 3 survey and the EuroQol Index survey utilities were lower than Canadian population norms ( p < 0.001). Patient-elicited utilities were lower than previous expert estimates for mild/moderate chronic infection and sustained virological responders, but higher for decompensated cirrhosis and hepatocellular carcinoma. The Short Form-36v2 survey scores revealed several significant health impairments ( p < 0.005) when compared with U.S. population norms. Conclusions These findings 1) suggest that quality of life (QOL) differences across the HCV clinical spectrum are smaller than previously believed; 2) support other evidence suggesting that QOL is significantly diminished in HCV patients; and 3) provide utility values derived directly from HCV patients.

Hepatitis C virus infection and renal transplantation

With the success of organ transplantation, liver disease has emerged as an important cause of morbidity and mortality of renal transplant (RT) recipients. Numerous studies performed during the 1990s have shown that hepatitis C virus (HCV) infection is the leading cause of chronic liver disease among RT recipients. The transmission of HCV by renal transplantation of a kidney from an HCV-infected organ donor has been shown unequivocally. Liver biopsy is essential in the evaluation of liver disease of RT recipients, and histological studies have shown that HCV-related liver disease after renal transplantation is progressive. The outcome of HCV-related liver disease is probably more aggressive in RT recipients than immunocompetent individuals. Various factors can affect the progression of HCV in the RT population: coinfection with hepatitis B virus, time of HCV acquisition, type of immunosuppressive treatment, and concomitant alcohol abuse. The role of virological features of HCV remains unclear. The natural history of HCV infection after renal transplantation is under evaluation; however, recent surveys with long follow-ups have documented adverse effects of HCV infection on patient and graft survival in RT recipients. Use of renal grafts from HCV-infected donors in recipients with HCV infection does not appear to result in a greater burden of liver disease, at least for a short period. The association between HCV and de novo or recurrent glomerulonephritis after RT has been hypothesized and is an area of avid research. Reported studies do not support interferon (IFN) treatment for RT recipients with chronic hepatitis C because of the frequent occurrence of graft failure, and information on the use of other types of IFN or combined therapy (IFN plus ribavirin or amantadine) is not yet available in the RT population. © 2001 by the National Kidney Foundation, Inc.

Projecting severe sequelae of injection-related hepatitis C virus epidemic in the UK - Part 2

In Part 2, we illustrate how available data can be used to obtain preliminary estimates for Scotland of prevalent injection-related hepatitis C carriers and of maternally hepatitis C virus (HCV)-infected infants. Novel approaches to reducing uncertainty about the number of Scotland's HCV infected children of injector parents are discussed in brief. Three approaches, one direct and two indirect, to estimating the number of current and ever-injectors are presented for England and Wales. Diagnosed HCV infections in injectors and HCV test uptake by current injectors are combined with survey estimates for the ratio of ever-injectors to current injectors to estimate prevalent injection-related hepatitis C carriers. Household surveys give direct but potentially biased estimates of the number of current and ever-injectors. Indirect estimates make use of hepatitis C diagnoses in injectors, HCV prevalence and test-uptake by injectors, or exploit international comparisons. We comment on key reporting problems that inhibit synthesis of HCV progression studies; and suggest how to derive preliminary gender-and-age specific progression rates to liver cirrhosis for use in projections. Preliminary estimates for Scotland of prevalent injection-related hepatitis C carriers are: central estimate 39,000, inner uncertainty 16,000-59,000; of maternally hepatitis C virus (HCV)-infected infants central estimate 260, uncertainty 110-1100; and for England and Wales estimates of the number of prevalent ever-injectors are central estimate 360,000, uncertainty 240,000-835,000. Both hepatitis C prevalence in injectors and estimated numbers of current injectors are similar in Australia, and England and Wales (but not so for Scotland), Australian work on projections of severe HCV sequelae from hepatitis C infections may therefore be a suitable starting point for projections for England and Wales. Australia anticipates a doubling in the number of persons living with hepatitis C cirrhosis from 8500 in 1997 to over 17,000 in 2010. Australian projections of severe HCV sequelae used progression rates that, for simplicity, were independent of gender and of age at HCV infection. Faster HCV progression for males, and their higher injector prevalence, means that the impact of HCV infection on, for example, liver cancer may be evident to a greater extent and earlier in males.

A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia

Background & Aims: At least half of patients with chronic hepatitis C virus (HCV) fail to respond to interferon or interferon/ribavirin therapy. Histological improvement is observed in some nonresponders. We conducted a randomized, controlled trial to determine if maintenance interferon therapy could prevent histological progression in this subset of nonresponders. Methods: Fifty-three patients with chronic HCV were enrolled. All were HCV-RNA positive after 6 months of treatment with interferon alfa-2b but had a histological response. Twenty-seven of the patients were randomly assigned to continue interferon (3 MU 3 times weekly) for 24 months; 26 patients discontinued treatment and were observed prospectively. Alanine aminotransferase (ALT) level and HCV-RNA titer were monitored, and liver biopsy was repeated every 12 months. Results: Before interferon therapy, the 2 groups were well matched for all demographic factors, serum ALT (94.0 ± 15.6), log HCV-RNA titer (5.85 ± 0.15 copies/mL), histology score (9.5 ± 0.2), and percentage with cirrhosis (25%). After 6 months of treatment, significant reductions ( P < 0.05) in serum ALT level (62.6 ± 9.6), log HCV-RNA titer (4.79 ± 0.13 copies/mL), and hepatic inflammation (4.0 ± 0.2) were observed. These improvements were maintained in the patients randomized to continue interferon. Stopping treatment was associated with an increase in serum ALT, log HCV-RNA, and hepatic inflammation back to baseline. After 30 months of treatment, mean fibrosis score declined from 2.5 to 1.7 and 80% of patients had histological improvement ( P < 0.03). Discontinuation of interferon was associated with an increase in mean fibrosis score from 2.2 to 2.4 and worsening of hepatic histology in 30% of patients ( P < 0.01). Conclusions: These data support the hypothesis that maintenance interferon may prevent histological progression of chronic HCV in patients who remain viremic. GASTROENTEROLOGY 1999;117:1164-1172

Natural history of chronic hepatitis B and C.

Hepatitis B virus (HBV) affects more than 300 million individuals worldwide and in the United States approximately 1.25 million individuals are chronic carriers of HBV. The risk of becoming a chronic hepatitis B virus surface antigen carrier is dependent upon the mode of acquisition of infection as well as the age of the individual at the time of infection. For those individuals with high levels of viral replication, chronic active hepatitis with progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC) is common and liver transplantation is an excellent treatment option for patients with end-stage liver disease from HBV. Patients with chronic HBV infection should be screened periodically for hepatoma, although screening strategies have not been proven to prolong survival. Newer antiviral agents for the treatment of HBV are potent inhibitors of HBV-DNA and their long-term effect on the natural history of HBV is yet to be proven. The natural history of hepatitis C virus (HCV) infection is less well defined than that of chronic HBV. Certain patients who are chronic carriers of HCV may never develop extensive fibrosis, whereas others will progress to chronic active hepatitis with cirrhosis, HCC and end-stage liver disease. Factors that influence the progression of HCV are those related to the host, including the age at acquisition of infection, gender and immune status, and the disease process is accelerated in patients who consume regular amounts of alcohol. Hepatocellular carcinoma develops frequently in patients with HCV infection and its overall incidence is increasing due to this chronic viral disease. Patients with HCV cirrhosis should be screened regularly for hepatoma and liver transplantation is an effective treatment option for those with end-stage disease. The impact of antiviral therapy on the natural history of HCV is still to be determined and should be the focus of large clinical trials.

Hepatitis C virus and HIV coinfection.

The world-wide prevalence of hepatitis C virus (HCV) is approximately 1%. Being primarily a blood-borne virus, the major risk factors for HCV include the receipt of blood and blood products, as well as intravenous drug use. As a result, many individuals infected with HIV are also infected with HCV. Any effect of coinfection on progression of either HIV or HCV is likely to have a tremendous impact on the mortality and morbidity of these individuals and should be considered when managing coinfected individuals. This review will describe the epidemiology and clinical manifestations of HCV and will consider the evidence for an impact of coinfection on the progression of both viruses.

Does hepatitis C virus co-infection accelerate clinical and immunological evolution of HIV-infected patients?

To study the influence of hepatitis C virus (HCV) co-infection on clinical and immunological evolution of HIV-infected patients. A longitudinal study of HIV-infected individuals with or without HCV infection, identified at the Infectious Diseases Department of Dijon University Hospital and enrolled in a historical cohort, was performed. One hundred and nineteen HIV-infected people co-infected with HCV and 119 matched individuals infected with HIV alone were included in the cohort (median participation time 3 years; range, 2 months to 11.5 years). Clinical progression was defined as one or more of the following: a 30% decrease in the Karnofsky index; a 20% loss of body weight; an AIDS-defining illness (for non-AIDS patients); death (except by accident, suicide or overdose). Immunological progression was defined as a 50% decrease in the initial CD4 T-cell count (for patients with an initial count > 100 x 10(6) cells/l). Effects of HCV co-infection were evaluated using Kaplan-Meier survival analysis and significance was tested using univariate (log-rank and Peto's tests) and multivariate methods (Cox's model). In univariate analysis, immunological progression was not statistically different between the HCV-positive group and the HCV-negative group, whereas clinical progression was significantly faster in HCV-positive patients (P < 0.005, log-rank test). In a multivariate Cox model, clinical progression remained significantly associated with infection by HCV [hazard ratio (HR), 1.64; 95% confidence interval (CI), 1.06-2.55; P < 0.05]. Stratified multivariable analysis retained HCV as a significant prognostic factor of clinical progression (HR, 10.9; 95% CI, 1.09-109.3; P < 0.05) and immunological progression (HR, 2.31; 95% CI, 1.16-4.62; P < 0.02) for patients with an initial CD4 count above 600 x 10(6) cells/l. Clinical progression is more rapid in HIV-HCV co-infected patients than in HIV-seropositive patients are not infected by HCV. The prognostic value of HCV infection for both clinical and immunological progression is significant at early stages of HIV infection. These findings may argue for active management of hepatitis C infection in co-infected individuals, especially for asymptomatic patients whose CD4 count is above 600 x 10(6) cells/l, to predict and prevent accelerated progression of HCV and HIV diseases.

The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of hemophilic men.

Patients coinfected with both hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) have more rapid progression of HCV infection; however, little is known about the effect of coinfection with HCV on the progression of HIV disease. This study assessed the association between infection with different HCV genotypes on progression to AIDS and death in a cohort of men with hemophilia. Patients infected with HCV type 1 experienced a more rapid progression to both AIDS (P = .009) and death (P = .007) than did those infected with other types. This effect was largely independent of age at seroconversion, hemophilia diagnosis, and changes in CD4 cell count over the follow-up period. These results suggest an association between HCV genotype and progression of HIV disease, which, if confirmed, could have important implications for the treatment and care of patients coinfected with both HIV and HCV.

Patterns of progression: unpredictability and risk of decompensated cirrhosis.

Hepatitis C virus (HCV) infection appears to have a slow but progressive evolution to chronic hepatitis and cirrhosis in a significant percentage of patients. Chronic hepatitis develops in 60-80% of patients. Worldwide prospective studies have shown that a further 20-30% of patients with chronic active hepatitis will develop cirrhosis regardless of the possible source of HCV infection. The percentage of cirrhotics is generally believed to increase progressively as the length of follow-up increases. In patients with chronic HCV, there also is high risk for the development of hepatocellular carcinoma. Factors influencing the rate of progression from chronic hepatitis to cirrhosis appear to include age at time of exposure, duration of infection, degree of liver damage at initial biopsy, immunological status, and possibly HCV genotype. The mean intervals between the time of initial infection and the diagnosis of chronic hepatitis, cirrhosis, and hepatocellular carcinoma have been estimated to be 10, 20, and 30 years, respectively. The progression of disease is variable and is not always orderly and sequential. Patients can progress from chronic persistent hepatitis or chronic active hepatitis directly to hepatocellular carcinoma without first developing cirrhosis, especially those with genotype 1b. In addition, cirrhosis does not appear to lead to clinically apparent hepatic failure in all patients. Because of the variability in the clinical presentation and clinical progression of chronic HCV, long-term follow-up studies may be necessary to fully assess the sequelae of chronic HCV infection. Most patients with chronic HCV have abnormal liver histology but can present as otherwise healthy individuals. In contrast, patients with chronic HCV who have normal hepatic chemistries can have substantial hepatocellular damage. Consequently, treatment at diagnosis offers the greatest likelihood of eliminating the virus and preventing progression to more severe liver disease.