Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 17, 2008


Contents

Acute Hepatitis C: Epidemiology, Pathogenesis and Therapy
Executive Editor: Paolo Fabris



Editorial: Pp. 1644-1645


Epidemiology of HCV Infection Pp. 1646-1654
V. Baldo, T. Baldovin, R. Trivello and A. Floreani
[Abstract]


HCV Screening to Enable Early Treatment of Hepatitis C: A Mathematical Model to Analyse Costs and Outcomes in Two Populations Pp. 1655-1660
A. Tramarin, N. Gennaro, F.A. Compostella, C. Gallo, L.J. Wendelaar Bonga and M.J. Postma
[Abstract]


Acute Hepatitis C: Clinical Aspects, Diagnosis, and Outcome of Acute HCV Infection Pp. 1661-1665
P. Fabris, V.M. Fleming, M.T. Giordani and E. Barnes
[Abstract]


Cellular Immunity and Acute Hepatitis C Infection Pp. 1666-1677
K. Fitzmaurice and P. Klenerman
[Abstract]


HCV and Autoimmunity Pp. 1678-1685
S. Ferri, L. Muratori, M. Lenzi, A. Granito, F.B. Bianchi and D. Vergani
[Abstract]


Therapy of Acute Hepatitis C: A Review of Literature Pp. 1686-1689
T. Santantonio and M. Fasano
[Abstract]


Acute HCV in HIV-Positive Individuals – A Review Pp. 1690-1697
M. Danta and G.M. Dusheiko
[Abstract]


General Articles


Ligands and Therapeutic Perspectives of Adenosine A_2A Receptors Pp. 1698-1722
C. Diniz, F. Borges, L. Santana, E. Uriarte, J.M.A. Oliveira, J. Gonçalves and P. Fresco
[Abstract]


Clinical Drugs that Interact with St. John’s Wort and Implication in Drug Development Pp. 1723-1742
Y.M. Di, C.G. Li, C.C. Xue and S.-F. Zhou
[Abstract]




Abstracts


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Editorial: Acute Hepatitis C: Epidemiology, Pathogenesis and Therapy

HCV (Hepatitis C Virus) infection is a serious problem worldwide. It has been estimated that around 2% of population is HCV infected . Most importantly, chronic HCV infection accounts for 40% to 60% of end-stage liver disease (ESLD) cases and is the most frequent indication for orthotopic liver transplantation (OLT) either in the United States or in Europe. In the first chapter of this issue Baldo et al. [1] provides a complete overview of HCV epidemiology around the world. It emerges that the incidence of HCV infection has declined since the late 1980s. In 2005, as in previous years, the majority of such cases in North America and Northern Europe occurred among young adults and injected drug use was the most common risk factor. Less common modes of HCV acquisition remain occupational exposure to blood, high-risk sexual activity, tattooing, body piercing and other forms of skin penetration. Finally, the overall rate of mother-to-child transmission from HCV-infected, HIV-negative mothers has been estimated at around 5% (co-infection with HIV raises this figure to 19.4%). Tramarin et al. [2] evaluated using cost effectiveness analysis the impact of anti-HCV screening in two cohorts: Injecting Drug Users (IDUs) and Individuals With Surgery (IWSs), who represent people potentially exposed to HCV infection, using a Markov model of the natural history of HCV infection they derive costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness related to screening versus no-screening strategies. The main conclusion of this interesting study is that only in the setting of IDUs, the screening strategy can result in a substantial difference in premature deaths and dominates (less costs better outcomes) the no-screening one. The number of premature deaths prevented in the IWSs cohort is lower and there seems to be an unacceptable incremental cost per QALY gained, which may be unsustainable for society.

Although most acute HCV infections are asymptomatic, in a proportion of them the onset of the disease in accompanied by typical signs and symptoms of acute hepatitis while acute liver failure due to acute hepatitis C infection is rarely reported. From a clinical point of view, symptomatic infections recover more frequently than asymptomatic infections. The progression of acute hepatitis C virus (HCV) infection to chronic disease ranges from 50% to 84% of cases. The mechanisms related to clearance of HCV or persistence are still incompletely understood. Clinical aspects, diagnosis, and outcome of acute HCV infection are provided in a specific chapter [3] .In the same chapter the role of quasispecies and the relationship with the persistence of infection are deeply discussed. They include host and viral factors. HCV infection becomes chronic most frequently in immune-compromised patients, such us HIV infected people and in other conditions. T cells response play a key role during the acute phase, but other mechanism may be involved, including innate responses and antibodies. The extensive and elegant review by Fitzmaurice and Klenerman analyzed all aspects of cellular immunity during acute hepatitis C [5]. In particular, the key role of CD4+ T cells for priming CD8+ T cells in the clearance or persistence HCV infection is extensively explained. Persistent HCV infection is a leading cause of chronic liver diseases but it is also associated with a wide spectrum of extra-hepatic manifestations often symptomatic, due to autoimmune phenomena triggered by HCV. In fact, Hepatitis C virus infection is characterized by a number of autoreactive manifestations, such as autoantibody production, cryoglobulinemia and thyroid disorders. In the review by Ferri et al. the authors have highlighted potential mechanisms responsible for such manifestations: clinical and laboratory immunopathological manifestations have been reviewed within the setting of available experimental evidence describing, in turn, roles for molecular mimicry between self and HCV in promoting autoantibody production and in favouring clinical autoimmune manifestations such as thyroiditis; HCV lymphocyte infection as a possible step towards cryoglobulinemia and B cell lymphoma. These information provide further insights supporting the idea that HCV infection is a systemic disease affecting deeply the immune system. The goal of treatment for acute hepatitis C patients is to eradicate the virus in the early phase of infection, thus preventing progression to chronicity. According to the review by Santantonio, several studies have demonstrated that Interferon treatment, used during or just after the acute phase of hepatitis C infection, is able to obtain a favourable response (Sustained Virological Response) in over 80% of patients [6]. However, is not yet demonstrated whether Interferon plus ribavirin is more effective than Interferon used in mono-therapy. Delaying treatment for 3 months after disease onset does not appear to reduce treatment efficacy and allows the identification of subjects with spontaneous resolution. At present, there is no evidence that Peg-IFN/ribavirin combination therapy is more effective than Peg-IFN mono-therapy On the basis of published data, pegylated IFN mono-therapy seems to offer the best therapeutic option because it is as effective as standard IFN mono-therapy, but more convenient for the patient. In the last chapter by Danta and Dusheiko report clinical, immunological and therapeutic aspect of acute hepatitis C in HIV positive patients [7]. Acute HCV in HIV-positive individuals differs significantly from acute HCV mono-infection in its epidemiology, natural history, immunology and virology and is becoming an increasingly significant problem in the HIV community. An increasing rate of acute HCV infection in HIV positive people (mainly in men who have sex intercourses with men) has been reported both in USA and in Europe. Significantly, permucosal rather than percutaneous transmission is occurring, probably as a result of behavioural risks that have occurred following the introduction of HAART. Comparing with HIV negative people, the rate of chronic evolution is significantly higher and the course of the disease appears to be more rapid. Furthermore, basing on data available the rate of SVR in this setting is lower than in patient with HCV acute hepatitis but HIV negative.

References

[1] Baldo V, Baldovin T, Trivello R, Floreani A. Epidemoiology of HCV infection. Curr Pharm Des 2008; 14(17): 1646-1654.

[2] Tramarin A, Gennaro N, Compostella FA, Gallo C, Wendelaar Bonga LJ, Postma MJ. .HCV screening to enable early treatment of hepatitis C: A mathematical model to analyse costs and outcomes in two populations. Curr Pharm Des 2008; 14(17): 1655-1660.

[3] Fabris P, Fleming VM, Giordani MT, Barnes E. Acute hepatitis C: Clinical aspects, diagnosis, and outcome of acute HCV infection. Curr Pharm Des 2008; 14(17): 1661-1665.

[4] Fitzmaurice K, Klenerman P. Cellular immunity and acute hepatitis C infection. Curr Pharm Des 2008; 14(17): 1666-1677.

[5] Ferri S, Muratori L, Lenzi M, Granito A, Bianchi FB, Vergani D. HCV and autoimmunity. Curr Pharm Des 2008; 14(17): 1678-1685.

[6] Santantonio T, Fasano M. Therapy of acute hepatitis C: A review of literature. Curr Pharm Des 2008; 14(17): 1686-1689.

[7] Danta M, Dusheiko GM. Acute HCV in HIV-positive individuals – A review. Curr Pharm Des 2008; 14(17): 1690-1697.


Paolo Fabris
Department of Infectious Diseases
and Tropical Medicine
S. Bortolo Hospital
Vicenza,
Italyt


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Epidemiology of HCV Infection
V. Baldo, T. Baldovin, R. Trivello and A. Floreani

It is estimated that approximately 130-170 million people worldwide are infected with hepatitis C virus (HCV). According to data from WHO community and blood donor surveys, the African and Eastern Mediterranean countries report the highest prevalence rates (>10%). The rates of infection in the general population and the incidence of newly-acquired cases indicate an appreciable change in the epidemiology of the infection in recent years. Prior to the widespread screening of blood donations, infected blood and blood products represented a common source of infection. On the other hand, the high peak in HCV antibodies among the elderly in Italian epidemiological studies on the population at large reflects a cohort effect due to an epidemic of HCV infection occurring after the Second World War. According to data reported by the CDC Surveillance System, the incidence of acute hepatitis C has declined since the late 1980s. In 2005, as in previous years, the majority of such cases in North America and Northern Europe occurred among young adults and injected drug use was the most common risk factor. Other, less commonly reported modes of HCV acquisition are occupational exposure to blood, high-risk sexual activity, tattooing, body piercing and other forms of skin penetration. Finally, the overall rate of mother-to-child transmission from HCV-infected, HIV-negative mothers has been estimated at around 5% (coinfection with HIV raises this figure to 19.4%). HCV prevention relies on identifying and counseling uninfected persons at risk of contracting hepatitis C.


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HCV Screening to Enable Early Treatment of Hepatitis C: A Mathematical Model to Analyse Costs and Outcomes in Two Populations
A. Tramarin, N. Gennaro, F.A. Compostella, C. Gallo, L.J. Wendelaar Bonga and M.J. Postma

Early treatment of acute hepatitis C virus (HCV) infections reflects a new clinical paradigm and a significant option to reduce the socioeconomic burden of HCV. Therefore, this approach seems suitable as a new strategy to face HCV and prevent end stage liver diseases and premature deaths due to progressed chronic HCV-infections. The main limitation of this approach is that the majority of acute infections show an asymptomatic course and do thus not present to the health-care settings.

Screening for HCV has already been extensively studied in the literature. This paper offers further insights in screening for HCV using cost effectiveness analysis for the impact of screening in two cohorts: Injecting Drug Users (IDUs) and Individuals With Surgery (IWSs). The setting of the cost effectiveness simulation is the Veneto Region in the North-east of Italy. Using a Markov model of the natural history of HCV infection we derive costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness related to screening vs. no-screening strategies.

In the IDUs cohort, the screening strategy can result in a substantial difference in premature deaths and dominates (less costs better outcomes) the no-screening one. The overall outcomes of the screening strategy are mostly affected by the prevalence of HCV and of genotypes that are more relatively more difficult to treat (above 10% of prevalence for its cost effectiveness). The number of premature deaths prevented in the IWSs cohort is lower and there seems to be an unacceptable incremental cost per QALY gained, which may be unsustainable for society.


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Acute Hepatitis C: Clinical Aspects, Diagnosis, and Outcome of Acute HCV Infection
P. Fabris, V.M. Fleming, M.T. Giordani and E. Barnes

Acute hepatitis C virus (HCV) infection is often a clinically silent infection, and is therefore rarely detected. A high index of clinical suspicion in addition to careful serological and virological assessment is required to identify the disease, and to determine the eventual clinical outcome after primary infection; the minority of acutely infected individuals spontaneously control viremia in long term whilst the majority become persistently infected. Here, we describe the clinical presentation of acute HCV infection and the patterns of viremia and liver alanine transaminase levels (ALT) observed. We discuss the serological and virological assessment and potential pitfalls in accurately diagnosing acute HCV. Good prospective studies that identify host and virological factors that determine clinical symptoms and disease outcome are difficult to perform due to the asymptomatic nature of infection, but some progress has been made in this field. Host factors including gender, age at time of infection, prior resolution of infection, symptomatic infection and host immune responses, and viral factors such as the nature of the infecting quasispecies and more speculatively viral genotype, are some features that have been correlated with disease outcome. In spite of this, on an individual patient level, it is currently not possible to predict those that will resolve infection. Identifying, in detail therefore, those factors that are responsible for viral control remains an important research goal not only to aid clinical management but also to develop effective treatment and vaccination strategies.


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Cellular Immunity and Acute Hepatitis C Infection
K. Fitzmaurice and P. Klenerman

Hepatitis C virus (HCV) infects an estimated 170 million people globally and persistent infection within the liver is the usual outcome of infection. The resulting liver disease leads to substantial morbidity and to date no vaccine exists. Furthermore the treatments available are frequently ineffective. A minority of those exposed will however successfully control the virus and the factors that dictate this remain elusive. The events that occur in the immediate and early phase post exposure are thought to play a crucial role in determining the outcome and virus specific T cells have a confirmed role in directing the immune response towards a successful outcome. An understanding of the T cell responses and the strategies, which allow the virus to evade these responses in the majority, is an essential prerequisite both for vaccine design and the development of therapeutic agents. We review here the characteristics of the cellular immune responses in acute infection and how the virus manages to undermine these responses and establish chronicity.


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HCV and Autoimmunity
S. Ferri, L. Muratori, M. Lenzi, A. Granito, F.B. Bianchi and D. Vergani

Hepatitis C virus (HCV) infection is characterized by a number of autoreactive manifestations, such as autoantibody production, cryoglobulinemia and thyroid disorders. We will analyse critically the mechanisms invoked, and partially documented, to explain such manifestations arising in genetically predisposed individuals exposed to HCV. In particular we will examine the available evidence implicating the virus in lowering the B cell activation threshold, in directly infecting lymphocytes and in inducing self-reactivity through a mechanism of molecular mimicry. We will then move to the HCV related clinical immunopathological manifestations, with a specific attention to the effects of antiviral treatment.


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Therapy of Acute Hepatitis C: A Review of Literature
T. Santantonio and M. Fasano

The goal of treatment for acute hepatitis C patients is to eradicate the virus in the early phase of infection, thus preventing progression to chronicity. Early interferon (IFN) monotherapy has been shown to significantly reduce this risk, and therefore it has been recommended by international guidelines. To date, there is no standard treatment for the acute form of hepatitis C because available studies refer to small patient series receiving a variety of treatment regimens administered at varying time-points after onset of acute infection. Nevertheless, on the basis of published data, pegylated IFN monotherapy seems to offer the best therapeutic option because it is as effective as standard IFN monotherapy, and more convenient for the patient. Delaying treatment for 3 months after disease onset does not ap-pear to reduce treatment efficacy and allows the identification of subjects with spontaneous resolution. It remains to be defined if an immediate treatment is more effective in patients with asymptomatic disease or those with genotype 1b. The optimal duration of Peg-IFN monotherapy should be 6 months. The efficacy of a 3-month course is under evaluation, especially for patients with clearance of HCV viremia within the first 4 weeks of therapy. There is no evidence that Peg-IFN/ribavirin combination therapy is more effective than Peg-IFN monotherapy, thus combination therapy might represent an alternative for patients who do not respond to IFN monotherapy or for HIV/HCV co-infected patients. Ongoing randomized controlled clinical trials should focus on unresolved questions and definitely establish the optimal treatment for acute hepatitis C.


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Acute HCV in HIV-Positive Individuals – A Review
M. Danta and G.M. Dusheiko

HCV/HIV co-infection is a major public health problem with between 10-25% of HIV-positive individuals infected with HCV. Following the introduction of effective HIV therapies, HCV has become a leading cause of morbidity and mortality in the HIV population. Since the early 2000s, there has been a marked rise in the diagnosis of acute HCV in HIV-positive populations. Cohorts have been reported in Europe, USA and Australia. Molecular studies have revealed multiple HCV variants circulating within the HIV-positive men who have sex with men (MSM) population. There is also evidence of a large international transmission network, particularly in Europe. Significantly, permucosal rather than percutaneous risk factors related to high-risk traumatic sexual and drug factors have been associated with transmission. This has important implications for public health interventions aimed at mitigating the spread of HCV. HIV also impacts the early cell-mediated immunological responses to HCV, leading to higher rates of persistence. Data now exists supporting early treatment of these individuals with combination pegylated interferon and ribavirin. This epidemic has come about as a result of significant change in patient behavioural risk factors and these factors need to be the focus of a concerted effort on the part of public health specialist, clinicians and HIV-positive individuals themselves at a national and international level. Acute HCV in HIV-positive individuals differs significantly from acute HCV mono-infection in its epidemiology, natural history, immunology and virology and is becoming an increasingly significant problem in the HIV community. This will be the focus of this review article.


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Ligands and Therapeutic Perspectives of Adenosine A_2A Receptors
C. Diniz, F. Borges, L. Santana, E. Uriarte, J.M.A. Oliveira, J. Gonçalves and P. Fresco

Adenosine A_2A receptors are members of the G protein-coupled receptor family and mediate multiple physiological effects of adenosine, both at the central nervous system (CNS) and at peripheral tissues, by activating several pathways or interacting with other receptors or proteins. Increasing evidence relate A_2A receptors with pharmacological stress testing, neurodegenerative disorders (such as Parkinson’s disease) and inflammation, renewing the interest in these receptors, increasingly viewed as promising therapeutic targets.

Series of agonists and antagonists have been developed by medicinal chemistry artwork either by structure activity relationship (SAR) or quantitative structure activity relationship (QSAR) studies. These studies have allowed identification of the structural and electrostatic requirements for high affinity A_2A receptor binding and, therefore, contributing to the rational design of A_2A receptor ligands. Additional rational chemical modifications of the existing A_2A receptor ligands may further improve their affinity/selectivity.

The purpose of this review is to analize and summarize aspects related to the medicinal chemistry of A_2A receptor ligands, their present and potencial therapeutic applications by exploring the molecular structure and physiological and pathophysiological roles of A_2A receptors.


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Clinical Drugs that Interact with St. John’s Wort and Implication in Drug Development
Y.M. Di, C.G. Li, C.C. Xue and S.-F. Zhou

St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and the potential clinical impact.