Hepatitis: Canada

Small D. · Department of Medicine, University of British Columbia, Vancouver, Canada. · Harm Reduct J. · Pubmed #18957091 links to  free full text

Abstract: ABSTRACT: The art in law, like medicine, is in its humanity. Nowhere is the humanity in law more poignant than in BC Supreme Court Justice Ian Pitfield's recent judgment in the legal case aimed at protecting North America's only supervised injection facility (SIF) as a healthcare program: PHS Community Services Society versus the Attorney General of Canada. In order to protect the SIF from politicization, the PHS Community Services Society, the community organization that established and operates the program, along with two people living with addiction and three lawyers working for free, pro bono publico, took the federal government of Canada to court. The courtroom struggle that ensued was akin to a battle between David and Goliath. The judge in the case, Justice Pitfield, ruled in favour of the PHS and gave the Government of Canada one year to bring the Controlled Drugs and Substances Act (CDSA) into compliance with the country's Charter of Rights and Freedoms. If parliament fails to do so, then the CDSA will evaporate from enforceability and law in June of 2009. Despite the fact that there are roughly twelve million intravenous drug addiction users in the world today, politics andprejudice oards harm reduction are still a barrier to the widespread application of the "best medicine" available for serious addicts. Nowhere is this clearer than in the opposition by conservative Prime Minister Stephen Harper and his faithful servant, federal health minister Tony Clement, towards Vancouver's SIF ("Insite"). The continued angry politicization of addiction will only lead to the tragic loss of life, as addicts are condemned to death from infectious diseases (HIV & hepatitis) and preventable overdoses. In light of the established facts in science, medicine and now law, political opposition to life-saving population health programs (including SIFs) to address the effects of addiction is a kind of implicit capital punishment for the addicted. This commentary examines the socio-political context of the legal case and the major figures that contributed to it. It reviews Justice Pitfield's ruling, a judgment that has brought Canada one step closer to putting a stop to addiction's death row where intravenous drug users are needlessly, for political and ideological reasons alone, forced to face increased risks of death due to AIDS, hepatitis and overdose.

Power C, Boissé L, Rourke S, Gill MJ. · Department of Medicine (Neurology), 6-11 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. · Can J Neurol Sci. · Pubmed #19534327 No free full text.

Abstract: Over 60,000 Canadians are infected with human immunodeficiency virus (HIV). Greater than 50% of these individuals will develop a neurological disorder despite the availability of highly active antiretroviral therapy. HIV causes nervous system disease at all stages of infection with adverse effects on quality of life, adherence to medications, employment and survival. These disorders include opportunistic infections in addition to distinct HIV-associated neurological syndromes and undesirable treatment-related effects. The latter two groups of disorders are often undiagnosed and untreated in both adolescents and adults. Direct HIV infection of central nervous system causes HIV-associated dementia, which is a progressive subcortical dementia. HIV infection of the peripheral nervous system produces a painful sensory neuropathy termed distal sensory polyneuropathy, which may be exacerbated by several antiretroviral drugs. Other important HIV-induced neurological disorders include vacuolar myelopathy and an increased risk of seizures. Future issues that will confound the presentation and treatment of HIV-induced nervous system disorders include the increasing prevalence of drug-resistant HIV strains, increasing age of HIV-infected patients, hepatitis C virus co-infection and the Immune Reconstitution Inflammatory Syndrome. Herein, we review the clinical presentations, underlying pathogenesis and treatments of this burgeoning group of neurological disorders.

Oreopoulos DG, Ossareh S, Thodis E. · Peritoneal Dialysis Program, Toronto Western Hospital, University Health Network and University of Toronto, Toronto, Ontario, Canada. · Iran J Kidney Dis. · Pubmed #19377234 links to  free full text

Abstract: Approximately, 10% to 15% of patients with end-stage renal disease are on peritoneal dialysis (PD) worldwide, with a dramatic difference in the use of PD among various countries. Recent data show a survival benefit of PD over hemodialysis which is maintained up to the 3rd year. The quality of life studied by various models is as good as, if not better than, that in patients on hemodialysis, for at least the first 2 years. In most countries that locally manufacture PD solutions, PD is significantly cheaper than hemodialysis. Several studies have found a better immediate graft function, lower rate of delayed graft function, and lower use of immunosuppressive medication after kidney transplantation in patients previously on PD compared to those on hemodialysis. There is a significantly lower rate of hepatitis C and hepatitis B infections in patients on PD compared to those on hemodialysis. Longer maintenance of residual renal function in PD compared to hemodialysis adds to the lower morbidity and the survival benefit of PD mentioned above. Many developments in the prevention of the causes of technique failure, including measures to prevent serious peritonitis episodes and new biocompatible PD solutions, together with the possible advantages of some types of catheters and implantation techniques, encourage us to believe that we can offer successful long-term PD in the near future. Overall, the new insight into the pathogenesis of peritoneal membrane changes, the response of the industry to this knowledge by producing new biocompatible PD solutions, the decrease in the peritonitis rate and the introduction of assisted PD at home encourages us to believe that the future of PD is indeed bright.

Nouvion AL, Beauchemin N. · Centre de cancérologie McGill, Département de biochimie, Université McGill, 3655 Promenade Sir-William-Osler, Montréal, Québec, H3G 1Y6, Canada. · Med Sci (Paris). · Pubmed #19361387 No free full text.

Abstract: CEACAM1 (carcinoembryonic antigen cell adhesion molecule 1), a member of the immunoglobulin (Ig) superfamily, is a heavily glycosylated protein. This glycoprotein exhibits an intracytoplasmic region that can be either long (71-73 amino acids) with two inhibitory tyrosine-phosphorylated motifs and several phosphorylated serine residues, or short (10 amino acid). CEACAM1 is a multifunctional protein that plays a role in intercellular adhesion, as an inhibitor of tumor development, as a bacterial adhesin, and as a receptor for the mouse hepatitis virus. Moreover, CEACAM1 is an active regulator of cell signaling, modulating the insulin or EGF receptor pathways in epithelial cells or the Zap-70 pathway in hematopoietic cells. The recent development of genetically modified mouse models altering the Ceacam1 gene corroborates most of these data, but also highlights CEACAM1's functional complexity. Thus, in addition to the functions identified previously, CEACAM1 is an important regulator of lipid metabolism, of tumor progression as a regulator of the Wnt signaling pathway, of normal and tumor neo-angiogenesis and of immunity.

Coffin CS, Lee SS. · Liver Unit, University of Calgary, Calgary, AB, Canada. · Liver Int. · Pubmed #19207974 No free full text.

Abstract: The two main goals of hepatitis B therapy are durable viral suppression and avoidance of antiviral resistance. Recent treatment guidelines now recognize the importance of these treatment endpoints in the prevention of end-stage liver disease and hepatocellular carcinoma rather then other surrogate markers such as HBeAg seroconversion and serum alanine aminotransferase normalization, especially in patients who acquired hepatitis B virus infection early in life. A variety of therapeutic options are now available for the treatment of chronic hepatitis B infection, including four nucleos/tide analogues (i.e lamivudine, adefovir, entecavir and telbivudine), along with standard and pegylated interferon. Newer oral nucleos/tide analogues that include tenofovir, emtricitabine and clevudine are soon likely to be approved worldwide. Given the wide array of choices and the complex nature of chronic hepatitis B infection, selection of the appropriate therapeutic agent can be challenging for clinicians. Effective treatment decisions require an understanding of the natural history of hepatitis B and knowledge of its life cycle and molecular biology. This review includes the range of treatment options and criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients positive for the HBeAg.

Heathcote J. · University of Toronto, Toronto, ON, Canada. · Liver Int. · Pubmed #19207966 No free full text.

Abstract: All but about 10% of patients with chronic hepatitis C (CHC) (predominantly those infected with genotype 1) can respond to some degree to 'combination' therapy with interferon (IFN) and ribavirin. The slower the virological response to treatment, the less likely sustained viral clearance will take place. Many factors influence response to antiviral therapy; most cannot be reversed (e.g. sex, age, cirrhosis, genotype and viral load). A sustained viral clearance is considerably facilitated by compliance with full-dose therapy for the prescribed time. The potential cause(s) for non-response need(s) to be ascertained before attempting retreatment. The 10% of patients who are true 'null' responders may respond to the new specifically targeted antiviral therapies but whether the response can be sustained off-therapy is unclear. Adjunctive therapies may facilitate response to retreatment if intolerance to treatment leading to diminished or absent doses was problematic in the past. Retreatment with a long-acting IFN and an adequate ribavirin dose (15 mg/kg), but given for 72 weeks in prior relapsers following 48 weeks of treatment, will enhance sustained virological response (SVR) rates. No benefit is gained from changing one pegylated IFNalpha (PEG IFNalpha) to another unless the treatment duration is extended. Only alpha-interferons are effective. For those individuals who still fail to achieve SVR, recruitment to trials of new treatments should be encouraged particularly for those with advanced liver disease. Lifestyle modification may be appropriate in attempt to reduce the chance of complications of liver disease, namely hepatocellular carcinoma, by smoking cessation, eliminating obesity and increasing coffee consumption.

Mackie CO, Buxton JA, Tadwalkar S, Patrick DM. · Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario. · CMAJ. · Pubmed #19153395 links to  free full text

This publication has no abstract.

Ouellet G, Tremblay L, Marleau D. · Department of Medicine, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. · South Med J. · Pubmed #19077780 No free full text.

Abstract: Anticonvulsant hypersensitivity syndrome (AHS) is a potentially life-threatening adverse drug reaction presenting with fever, skin eruptions, and internal organ involvement. We describe a case of AHS with fulminant hepatitis that occurred two weeks after introduction of lamotrigine in a 40-year-old female patient with a recently diagnosed bipolar disorder, no pre-existent systemic organ involvement, and no other medication. Lamotrigine was introduced at a dosage of 25 mg daily and increased to 50 mg daily 12 days later. The patient had favorable evolution with cessation of lamotrigine and supportive treatment. This report suggests that AHS with fulminant hepatitis may occur idiosyncratically, independent of dosage, titration and comedication with other potentially hepatotoxic drugs.

Wainberg MA. · McGill University AIDS Centre, Jewish General Hospital, Montreal, Canada. · Antiviral Res. · Pubmed #18948140 No free full text.

Abstract: The 21st International Conference on Antiviral Research provided novel insights and approaches to drug discovery across a wide array of virologic fields. Topics ranged from the chemical synthesis of new compounds against the human immunodeficiency virus (HIV) to the long-term use of established drugs against influenza. A session on novel targets for HIV therapy focused on the importance of Apobec3G, LEDGF/p75 and other cellular factors as innovative ways to control infection. New targets for hepatitis B and C viruses were surveyed. There were also discussions as to how the development of new antiviral compounds might lead to novel mechanisms of drug resistance by HIV, herpesviruses and hepatitis viruses. These covered such issues as transmission dynamics, viral fitness, the acquisition of differential resistance patterns depending on viral subtype, and clinical outcomes. Drug efficacy, toxicity, patient adherence, treatment interruption and the importance of generic drugs in resource-poor settings were also extensively discussed. These topics will all play a pivotal role in drug development and the management of viral infections in the years to come.

Montano-Loza AJ, Lalor E, Mason AL. · Division of Gastroenterology and Liver Unit, Zeidler Ledcor Centre, University of Alberta Hospital, Edmonton, Alberta. · Can J Gastroenterol. · Pubmed #18925309 No free full text.

Abstract: The first description of autoimmune pancreatitis and elevated serum immunoglobulin-G4 (IgG4) in 2001 heralded further reports of several related autoimmune diseases with raised IgG4 levels. It is now recognized that a spectrum of overlap syndromes associated with increased IgG4 and biopsy evidence of IgG4-producing plasma cells, which has now been convincingly linked with cholangitis, autoimmune hepatitis, Sjögren's syndrome, nephritis and retroperitoneal fibrosis. Collectively, this disease cluster is referred to as IgG4-related systemic disease. The importance of making the correct diagnosis is underscored by the management of individuals with IgG4-related systemic disease. In the first instance, patients generally have a dramatic response to immunosuppressive therapy, whereas patients with other forms of cholangitis and pancreatitis do not. Also, surgical management of pancreatic malignancy can be avoided once the correct diagnosis of IgG4-related disease has been made. In the present review, an overview of the current information regarding the role of IgG4 and IgG4-positive cells affecting the biliary system, pancreas and liver is provided.

Thein HH, Yi Q, Dore GJ, Krahn MD. · University Health Network, Division of Clinical Decision-Making and Healthcare Research, Toronto, Canada. · AIDS. · Pubmed #18784461 No free full text.

Abstract: OBJECTIVES: To estimate stage-specific transition probabilities in individuals coinfected with HIV and hepatitis C virus (HCV), to examine the effect of covariates on these rates, and to investigate the effect of HIV on HCV-related cirrhosis in the era of highly active antiretroviral therapy (HAART). DESIGN: Systematic review of natural history studies among HCV-infected individuals. METHODS: Markov maximum likelihood estimation method was used to estimate stage-specific transition probabilities. A meta-analysis was performed to obtain pooled transition probabilities, and a meta-regression to investigate the impact of covariates on these rates. Risk of cirrhosis between individuals monoinfected with HCV and coinfected with HIV/HCV were compared by HAART status. RESULTS: The estimated mean (95% confidence intervals) annual transition probabilities of 3567 individuals coinfected with HIV/HCV (n = 17 studies) were as follows: fibrosis stage (F) F0 --> F1 0.122 (0.098-0.153); F1 --> F2 0.115 (0.095-0.140); F2 --> F3 0.124 (0.097-0.159); and F3 --> F4 0.115 (0.098-0.135) units/year. The prevalence of cirrhosis after 20 and 30 years of HCV infection was 21% (16-28%) and 49% (40-59%), respectively. Longer duration of HCV infection was significantly associated with slower rate of fibrosis progression. The overall rate ratio of cirrhosis between individuals coinfected with HIV/HCV and monoinfected with HCV (n = 27 studies) was 2.1 (1.5-3.0), 2.5 (1.8-3.4) in the non-HAART group, and 1.7 (1.1-2.8) in the HAART group. CONCLUSION: The rate of fibrosis progression among individuals coinfected with HIV/HCV appears constant. Our results confirm that chronic hepatitis C outcomes are worse among coinfected individuals. Over the period studied, HAART did not appear to fully correct the adverse effect of HIV infection on HCV prognosis.

Patten SB. · Department of Community Health Sciences and Psychiatry, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. · Curr Drug Saf. · Pubmed #18690925 No free full text.

Abstract: BACKGROUND: Interferons are employed in the management of multiple sclerosis, hepatitis C and certain malignancies. Neuropsychiatric toxicity can interfere with the successful use of these drugs. METHODS: This review was based on Medline literature searches, supplemented by bibliographical citations in identified papers. Information uncovered in the literature review was interpreted in light of related pharmacoepidemiological and psychiatric literature. RESULTS: Interferon-associated neurotoxicity does not adhere closely to standard psychiatric syndromal and diagnostic definitions. Delirium, depression, non-specific symptoms related to sickness behavior and, rarely, manic and psychotic syndromes are all potential adverse events during interferon treatment. For depression, the evidence of increased risk is stronger for interferon alpha than for interferon beta. The availability of preventive and treatment interventions suggest that neuropsychiatric toxicity can often be managed without needing to discontinue the treatment. CONCLUSIONS: Safety can be maximized by organization of health services in ways that enhance detection and management of neuropsychiatric problems, and which support access to basic and specialized mental health services.

Cooper CL. · University of Ottawa Hospital, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, Canada. · J Addict Dis. · Pubmed #18681192 No free full text.

Abstract: Hepatitis C (HCV) infection in substance addicted patients is common and represents a therapeutically challenging co-morbidity. Alcohol and perhaps other substances of abuse directly influence the natural progression of HCV disease. Concurrent mental health illness, poor socioeconomic status, and unstructured life styles are often incompatible with safe and successful delivery of HCV treatment. These issues and their effect on treatment suitability and outcome are considered in this review. Funding for HCV-addiction research and strong political backing for interventions proven to benefit those struggling with addiction are paramount to increasing access to and uptake of HCV treatment. These interventions include substance cessation programs, safe injection settings to reduce HCV incidence and multidisciplinary teams to facilitate HCV treatment provision.

Grebely J, deVlaming S, Duncan F, Viljoen M, Conway B. · Vancouver Coastal Health, Vancouver, British Columbia, Canada. · J Addict Dis. · Pubmed #18681189 No free full text.

Abstract: Injection drug use (IDU) accounts for 75% of incident cases of hepatitis C virus (HCV) infection in the developed world. Of those infected with HCV, up to 80% will go on to develop chronic disease. Intervention with effective treatment in eligible subjects will limit the impact of the long-term consequences of infection. The use of combination therapy with pegylated interferon and ribavirin may lead to a cure in up to 80% of treated individuals who carry genotype 2 or 3 isolates. Such individuals account for up to 45% of certain cohorts, such as in the inner city of Vancouver. Historically, many IDUs have not received treatment for HCV infection even if it were medically indicated. Recent data (including our own) suggest that, in the right context, response rates similar to those reported in clinical trials of HCV therapy can be achieved in IDUs, even with ongoing drug use. This is all the more important given that prior infection may protect against re-infection even in the presence of ongoing risk behaviors for HCV transmission. The keys to a successful program appear to be appropriate patient selection as well as the delivery of care within an appropriate setting, preferably with a multidisciplinary team in a way that addresses the issue of addiction and other conditions simultaneously. The development of such programs may be quite complex, but the ultimate benefit (for the treated population and for society as a whole) is certainly worth the effort.

Babatin M, Lee SS, Pollak PT. · Department of Medicine, University of Calgary, Calgary, Alberta, Canada. · Curr Vasc Pharmacol. · Pubmed #18673162 No free full text.

Abstract: Potential hepatotoxicity related to amiodarone therapy is often a concern when deciding whether to initiate or continue treatment with this medication. While mostly associated with long-term oral administration of the drug, toxicity has also been reported early during intravenous administration and months after discontinuation of therapy. In the majority of patients, it is discovered incidentally during routine testing of liver biochemistry and rarely do the hepatic effects develop into symptomatic liver injury or failure. Despite the widespread use of amiodarone, prospective clinical studies have been sparse and there has been little consensus among experts in the field regarding optimum monitoring for adverse effects in patients receiving this drug. In order to examine the current state of knowledge surrounding the incidence, pathogenesis and mechanism of liver effects associated with amiodarone, the existing literature was reviewed, with particular emphasis on clinical recommendations for monitoring.

Barton M, Finkelstein Y, Opavsky MA, Ito S, Ho T, Ford-Jones LE, Taylor G, Benson L, Gold R. · Division of Infectious Diseases, the Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada. · Pediatr Infect Dis J. · Pubmed #18664932 No free full text.

Abstract: We report the first cases of tissue-proven eosinophilic myocarditis after single vaccine administration of conjugate meningococcal C and hepatitis B vaccine, respectively. The nature of histopathologic findings strongly supports hypersensitivity reaction and negates viral etiology, which is typically characterized by a lymphocytic infiltrate. Both episodes resolved with corticosteroid therapy.To enhance discussion of our cases, we performed a systematic review of the literature on postimmunization myocarditis or pericarditis, and identified 37 publications, reporting 269 cases during the search period (1966-2007). Time of onset of cardiac symptoms in all patients ranged from 1 to 30 days postimmunization.

Roy J, Carrier S. · McGill University, Montreal, Canada. · J Sex Med. · Pubmed #18624965 No free full text.

Abstract: INTRODUCTION: Potassium para-aminobenzoate is an agent used in the treatment of sclerotic diseases including Peyronie's disease of the penis. It has been reported that this medication may have been responsible for cases of acute liver injury. AIM: To inform clinicians of the possibility of an adverse drug event associated with the oral intake of potassium para-aminobenzoate by reporting an additional case and compiling information from previous reports. METHODS: The affected patient's medical records were diligently reviewed; all available and relevant information pertaining to this adverse event is reported. Similar case reports were analyzed and compared, and relevant information was compiled in this report. RESULTS: The patient enjoyed a full biochemical recovery from his hepatitis 4 months after discontinuation of potassium para-aminobenzoate. CONCLUSION: To date, the oral use of potassium para-aminobenzoate has been reported to be linked to acute liver injury in six individuals. Appropriate management of this adverse drug event is the immediate discontinuation of the offending drug and general patient support measures.

Thein HH, Yi Q, Dore GJ, Krahn MD. · University Health Network, Division of Clinical Decision-Making and Health Care Research, Toronto, Ontario, Canada. · Hepatology. · Pubmed #18563841 No free full text.

Abstract: Published estimates of liver fibrosis progression in individuals with chronic hepatitis C virus (HCV) infection are heterogeneous. We aimed to estimate stage-specific fibrosis progression rates and their determinants in these individuals. A systematic review of published prognostic studies was undertaken. Study inclusion criteria were as follows: (1) presence of HCV infection determined by serological assays; (2) available information about age at assessment of liver disease or HCV acquisition; (3) duration of HCV infection; and (4) histological and/or clinical diagnosis of cirrhosis. Annual stage-specific transition probabilities (F0-->F1, ... , F3-->F4) were derived using the Markov maximum likelihood estimation method and a meta-analysis was performed. The impact of potential covariates was evaluated using meta-regression. A total of 111 studies of individuals with chronic HCV infection (n = 33,121) were included. Based on the random effects model, the estimated annual mean (95% confidence interval) stage-specific transition probabilities were: F0-->F1 0.117 (0.104-0.130); F1-->F2 0.085 (0.075-0.096); F2-->F3 0.120 (0.109-0.133); and F3-->F4 0.116 (0.104-0.129). The estimated prevalence of cirrhosis at 20 years after the infection was 16% (14%-19%) for all studies, 18% (15%-21%) for cross-sectional/retrospective studies, 7% (4%-14%) for retrospective-prospective studies, 18% (16%-21%) for studies conducted in clinical settings, and 7% (4%-12%) for studies conducted in nonclinical settings. Duration of infection was the most consistent factor significantly associated with progression of fibrosis. CONCLUSION: Our large systematic review provides increased precision in estimating fibrosis progression in chronic HCV infection and supports nonlinear disease progression. Estimates of progression to cirrhosis from studies conducted in clinical settings were lower than previous estimates.

Butt G. · BC Hepatitis Services, BC Centre for Disease Control, Vancouver, British Columbia, Canada. · J Adv Nurs. · Pubmed #18503656 No free full text.

Abstract: AIM: This paper is a report of a concept analysis of stigma in the context of hepatitis C. BACKGROUND: Stigma is a complex and powerful social phenomenon that influences the course of illness and marginalizes populations. Knowledge of hepatitis C stigma is central to assisting people with hepatitis C self-manage their illness and reduce the disease burden. DATA SOURCES: Thirty studies from 1995 to 2007 located in health and social sciences databases constituted the data for an evolutionary concept analysis and ecological theory guide the review. FINDINGS: Stigma is a subjective and variable, perceived and/or experienced phenomenon, most frequently but not exclusively viewed as negative, that has interrelated intrapersonal, interpersonal and structural or institutional dimensions. The antecedents of hepatitis C stigma are help-seeking situations most frequently occurring in healthcare settings. Attributes include the association of hepatitis C with illicit drug use, fear of transmission of a contagious and life-threatening infection, acceptable level of risk, and the power to impose restrictions on the part of healthcare practitioners, family and friendship networks and society. Stigma consequences are mainly, but not exclusively, negative. CONCLUSION: A central and distinctive feature of hepatitis C stigma in the Western world is its association with illicit drug use. Further research is required to understand the complexities associated with the sociocultural, situational and structural features that influence the stigma experience as well as the trajectory of the disease to understand the concept better and inform nursing practice.

Missiha SB, Ostrowski M, Heathcote EJ. · Division of Gastroenterology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Gastroenterology. · Pubmed #18471548 No free full text.

Abstract: The hepatic complications of chronic hepatitis C (CHC) usually occur only after progression to cirrhosis has taken place. Progression to cirrhosis, however, is extremely variable and depends on a broad set of host and viral factors that modify the rate at which fibrosis develops in a given individual. Despite their inherent limitations, studies of the natural history of CHC have identified several nonmodifiable factors associated with disease progression. These include age at acquisition of infection, sex, and race. More recent reports suggest important roles for host genetic polymorphisms and viral factors. Of greater immediate relevance to patients and their clinicians are the potentially modifiable factors, which include excessive alcohol consumption; smoking (tobacco and marijuana); insulin resistance; and coinfection with hepatitis B virus, human immunodeficiency virus type 1, or schistosomiasis. Unfortunately, to date, there are no reliable predictive models that can accurately estimate the risk of CHC disease progression.

Gupta K, Cooper C. · Division of Infectious Diseases, University of Ottawa, Ottawa, Ontario, Canada. · Drugs R D. · Pubmed #18457466 No free full text.

Abstract: This article reviews the biology of Toll-like receptors, the current understanding of the mechanism by which CpG oligodeoxynucleotides (ODNs) perturb immune function and the published literature describing their evaluation in the development of vaccines in humans. The role of these molecules as immune modulators in HCV treatment is also considered. There has been considerable research evaluating the role of CpG ODNs as an adjuvant and immune modulator in hepatitis B, hepatitis C and influenza. The safety and immunogenicity of the 1018 ISS compound in combination with Engerix-B was assessed in 99 healthy, adult seronegative volunteers. One month following the first immunization dose, 78.7% in the rHBsAg plus 1018 ISS group versus 11.8% in the Engerix-B group achieved protective titres. One hundred percent of rHBsAg plus 1018 ISS and 18.0% of hepatitis B vaccine-alone recipients were seroprotected 1 week following the second dose of study vaccine. After all doses of vaccine had been administered, seroprotection rates were 100% and 64%, respectively (p < 0.001). CPG 7909 was co-administered with Engerix-B in 56 healthy adults. After the second injection (week 6 time point), seroprotection was achieved in 100% of CPG 7909 recipients (0.5 mg 13/13; 1.0 mg 12/12; 0.125 mg 12/12) compared with 55% (6/11) of control participants (p = 0.0003). Twelve months post prime, all subjects who had received the full course of vaccination maintained seroprotective anti-HBs titres. The safety and immunogenicity of Engerix B plus CPG 7909 was assessed in HIV seropositive patients. All CPG 7909 recipients (n = 19) and 17/19 (89%) control subjects achieved seroprotection by 2 weeks after the third and final injection (10 weeks). Seroprotective titres remained in all CPG 7909 recipients at 48 weeks (100%) versus 12/19 (63%) for controls (p = 0.008). This cohort of HIV-infected patients was followed at 6-month intervals for up to 60 months after enrolment. The difference in seroprotection (> or =10 mIU/L) and GMT between study arms remained significant (p < 0.05) at all time points from month 24 to month 60. There is great potential for CpG ODN as vaccine adjuvants and as therapeutic immune modulators. The use of these molecules as a hepatitis B vaccine adjuvant is most promising.

Lee SS, Ferenci P. · Liver Unit, University of Calgary, Calgary, Alberta, Canada. · Antivir Ther. · Pubmed #18432158 No free full text.

Abstract: Currently, many decisions for the treatment of hepatitis C virus (HCV) are based on genotype, which is the most significant baseline predictor of response to therapy; however, it has become increasingly apparent that fixed treatment durations might not be appropriate for all patients. The use of on-treatment predictors such as rapid virological response (RVR) at week 4 and early virological response (EVR) at week 12 can be used to predict the likelihood of achieving a sustained virological response (SVR), helping to tailor treatment to the individual. Until now, EVR has been defined as achieving either undetectable HCV RNA (< 50 IU/ml) or a > 2 log drop in HCV RNA, but still detectable, at week 12. However, rates of SVR in patients achieving an EVR are heterogeneous. It has recently been suggested that by subdividing EVR into RVR (< 50 IU/ml at week 4), complete EVR (HCV RNA < 50 IU/ml at week 12) or partial EVR (HCV RNA > 2 log drop in HCV RNA but still detectable [> 50 IU/ml] at week 12), it might be possible to further improve the prediction of patients likely to achieve an SVR and may allow for tailoring of treatment duration. Genotype 1 and 4 patients achieving an RVR have high rates of SVR and may be candidates for shorter treatment duration. Patients with a complete EVR achieve high SVR rates with the current treatment duration of 48 weeks, whereas patients achieving a partial EVR have lower rates of SVR and could benefit from treatment intensification to 72 weeks. Here, we discuss the importance of baseline predictors of response and the emerging concept of response-guided therapy in genotype 1 and 4 patients.

El-Far M, Halwani R, Said E, Trautmann L, Doroudchi M, Janbazian L, Fonseca S, van Grevenynghe J, Yassine-Diab B, Sékaly RP, Haddad EK. · Centre de Recherche du CHUM, Hôpital Saint-Luc, 264, René-Lévesque est, Bureau 1317, Montréal, Québec, H2X 1P1, Canada. · Curr HIV/AIDS Rep. · Pubmed #18417030 No free full text.

Abstract: Generation of memory T cells, which mediate immunity against microbes and cancers, relies, for optimal activity, on the interactions of multiple cell types that are highly regulated through the expression of soluble factors and negative and positive receptors. Their disruption will lead to aberrant immune responses, which can result in the invasion of the host by foreign pathogens. In chronic viral infections including HIV and hepatitis C virus, persistence of antigen and lack of CD4 help (HIV) disrupt memory T-cell function and induce defects in memory T-cell responses, which have been defined as T-cell exhaustion. In this review, we examine the molecular mechanisms involved in such T-cell dysfunction. Better understanding of these mechanisms will assist in the development of novel therapies to prevent the immune damage mediated by HIV infection.

Swain MG. · Liver Unit, Division of Gastroenterology, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada. · Clin Sci (Lond). · Pubmed #18302533 No free full text.

Abstract: The innate immune system represents a critical first line of host response to infectious, injurious and inflammatory insults. NKT cells (natural killer T-cells) are an important, but relatively poorly understood, component of the innate immune response. Moreover, NKT cells are enriched within the liver, suggesting that within the hepatic compartment NKT cells probably fulfil important roles in the modulation of the immune response to infection or injury. NKT cells are characterized by their rapid activation and secretion of large amounts of numerous types of cytokines, including those within the Th1-type, Th2-type and Th17-type groups, which in turn can interact with a multitude of other cell types within the liver. In addition, NKT cells are capable of participating in a wide array of effector functions with regards to other cell types via NKT cell-surface-molecule expression [e.g. FASL (FAS ligand) and CD40L (CD40 ligand)] and the release of mediators (e.g. perforin and granzyme) contained in cellular granules, which in turn can activate or destroy other cells (i.e. immune or parenchymal cells) within the liver. Given the huge scope of potential actions that can be mediated by NKT cells, it has become increasingly apparent that NKT cells may fulfil both beneficial (e.g. clearance of virally infected cells) and harmful (e.g. induction of autoimmunity) roles in the setting of liver disease. This review will outline the possible roles which may be played by NKT cells in the setting of specific liver diseases or conditions, and will discuss the NKT cell in the context of its role as either a 'friend' or a 'foe' with respect to the outcome of these liver disorders.

Kovacs CS. · Faculty of Medicine - Endocrinology, Health Sciences Centre, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, Newfoundland, Canada A1B 3V6. · Transfus Apher Sci. · Pubmed #18255340 No free full text.

Abstract: A recent case series from Australia suggested that children with hemophilia may be more likely to have low bone density or osteopenia than healthy controls. This finding has led to uncertainty among patients and their physicians as to whether treatment with bisphosphonates is indicated to treat osteopenia and prevent osteoporosis in children or young adults with hemophilia. In fact, several studies confirmed that selected patients with hemophilia were shorter, weighed less, had reduced physical activity, and had other factors (hepatitis C and HIV seropositivity) which predict lower peak bone mass. Some of these factors may accelerate loss of bone mass between ages 20 and 50 when bone mass should otherwise be stable, but no study has yet confirmed if this is the case for patients with hemophilia. Treatment with weight-bearing physical activity, physiotherapy and surgery to remobilize diseased joints, and calcium and vitamin D supplementation, can be recommended for anyone at any age. Treatment with an antiresorptive medication (usually a bisphosphonate) is not indicated for low peak bone mass that will otherwise be maintained by the patient between ages 20 and 50. On the other hand, on an individualized basis, treatment with an antiresorptive may be indicated for patients in whom rapid loss of bone mass has been confirmed by sequential BMD measurements, or who have already suffered fragility fractures, or who have reached an age and BMD value that places them into a high-risk category for estimated 10-year fracture risk.