Hepatitis: Heathcote J

Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Büschenfelde KH, Zeniya M. · Institute of Liver Studies, King's College Hospital, London, UK. · J Hepatol. · Pubmed #10580593 No free full text.

This publication has no abstract.

Hirschfield GM, Heathcote J. · No affiliation provided · Liver Int. · Pubmed #18251975 No free full text.

This publication has no abstract.

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.

Heathcote J. · University of Toronto, Toronto, Canada. · Am J Gastroenterol. · Pubmed #17177867 No free full text.

This publication has no abstract.

Fischer B, Reimer J, Firestone M, Kalousek K, Rehm J, Heathcote J. · Centre for Addictions Research of British Columbia (CAR-BC), University of Victoria, Victoria, Canada. · Eur J Gastroenterol Hepatol. · Pubmed #16957507 No free full text.

Abstract: Illicit drug users are the primary risk group for HCV transmission, and will form the largest HCV treatment population for years to come. Sylvestre et al.'s study suggests that cannabis use may benefit treatment retention and outcomes in illicit drug users undergoing HCV treatment. In fact, there is substantial evidence that cannabis use may help address key challenges faced by drug users in HCV treatment (e.g., nausea, depression), especially when such treatment occurs in the context of methadone maintenance treatment which may amplify these consequences. While further research is required on the biological and clinical aspects of the benefits of cannabis use for HCV treatment, and the effectiveness of cannabis use for HCV treatment needs to be explored in larger study populations, we advocate that in the interim existing barriers to cannabis use are removed for drug users undergoing HCV treatment until the conclusive empirical basis for evidence-based guidance is available.

Sherman M, Cohen L, Cooper MA, Elkashab M, Feinman V, Fletcher D, Girgrah N, Heathcote J, Levstik M, McNaull WB, Wong D, Wong F, Yim C. · Toronto General Hospital, University of Toronto, Toronto, Canada. · Can J Gastroenterol. · Pubmed #16858501 links to  free full text

Abstract: Today, combination antiviral therapy with pegylated interferon-alpha and ribavirin (RBV) allows many patients infected with hepatitis C virus (HCV) to achieve a sustained virological response, which is equivalent to cure. Data also support the clinical benefit of combination antiviral therapy in patients coinfected with HCV and HIV, and in patients who have received a liver transplant. Antiviral therapy with pegylated interferon-alpha and RBV is, however, associated with a high incidence and significant magnitude of anemia. This anemia may have several mechanisms, including bone marrow suppression and hemolysis. In addition, patients coinfected with HIV may have both pre-existing and RBV-associated anemia. Management of anemia in patients with HCV through RBV dose reduction or treatment discontinuation may compromise the effectiveness of treatment, because studies have demonstrated that treatment adherence or maintenance of antiviral therapy dose is an important predictor of sustained virological response. Anemia associated with combination antiviral therapy in patients with HCV is frequently associated with an inadequate or blunted endogenous erythropoietin response. Accumulating evidence now supports the use of recombinant human erythropoietin (rHuEpo) to manage anemia in these patients, with the objective of maintaining the RBV dose, but clinical standards are lacking. The present article reviews the data relevant to the use of rHuEpo in this patient population and proposes a set of clinical practice standards to assist clinicians in selecting patients for rHuEpo and in implementing rHuEpo therapy effectively.

Heathcote J, Main J. · University of Toronto, Ontario, Canada. · J Viral Hepat. · Pubmed #15850462 No free full text.

Abstract: The combination of pegylated interferon alpha and ribavirin has improved treatment success rates in patients with hepatitis C with sustained response rates of just over 50% overall and more than 70% for those with genotypes 2 and 3. This article reviews the use of combination therapy, contraindications, factors influencing response and describes approaches to specific patient groups.

Locarnini S, Hatzakis A, Heathcote J, Keeffe EB, Liang TJ, Mutimer D, Pawlotsky JM, Zoulim F. · Victorian Infectious Diseases Reference Laboratory, North Melbourne, Vic., Australia. · Antivir Ther. · Pubmed #15535405 No free full text.

Abstract: A meeting of physicians and scientists involved in the management of chronic hepatitis B (CHB) was held to review current scientific data regarding antiviral resistance in hepatitis B virus (HBV) infection. The goals of the meeting were to describe current treatments for CHB, discuss emerging issues in HBV drug resistance and to delineate patient monitoring, including markers for resistance, during administration of antiviral therapy. The aim of this review article is to provide treating physicians with a framework for the management of CHB in the context of antiviral resistance. Definitions of primary and secondary antiviral treatment failure can be used to aid monitoring and early diagnosis of drug resistance before disease progression occurs as a consequence of viral breakthrough. Primary antiviral treatment failure is defined as failure of a drug to reduce HBV DNA levels by > or = 1 x log10 IU/ml within 3 months following initiation of therapy, and secondary antiviral treatment failure as a rebound of HBV replication of > or = 1 x log10 IU/ml from nadir in patients with an initial antiviral treatment effect (> or = 1 x log10 IU/ml decrease in serum HBV DNA). Confirmation of antiviral drug failure can be established by sequencing the HBV DNA polymerase and identifying specific genetic markers of antiviral drug resistance. In addition to virological assays, HBV resistance can be assessed from a clinical perspective including increased serum alanine aminotransferase levels and the development of systemic symptoms or signs of liver failure. Potential strategies to prevent the emergence of resistance and how to manage drug-resistant HBV once it emerges are discussed.

Heathcote J, Zeuzem S. · Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. · Semin Liver Dis. · Pubmed #15346245 No free full text.

Abstract: Interferon (IFN) alpha-2a has been attached to a branched 40-kD PEG molecule and IFN alpha-2b to a linear 12-kD PEG molecule leading to elimination half-lives of approximately 75 and approximately 30 hours, respectively. In one pivotal trial, 531 patients with chronic hepatitis C were assigned to receive either 180 microg of pegylated IFN alpha-2a once weekly for 48 weeks or 3 x 6 mIU standard IFN for 12 weeks, followed by 3 x 3 mIU for 36 weeks. Sustained virological response rates were 39 and 19% for pegylated and standard IFN alpha-2a, respectively. In a second trial in patients with hepatitis C virus (HCV)-associated cirrhosis and bridging fibrosis, sustained virological response rates were 8% (3 x 3 mIU IFN three times a week), 15% (90 microg PEG-IFN alpha-2a four times a week), and 30% (180 microg PEG-IFNalpha-2a four times a week). In a third trial, 1219 patients with chronic hepatitis C were randomly assigned to receive either standard IFN alpha-2b (3 x 3 mIU) or once weekly pegylated IFN alpha-2b (0.5, 1.0, or 1.5 microg/kg). Sustained virological response rates were highest in the 1.0 microg/kg dose and achieved 25% compared with 12% in the standard IFN group. In conclusion, each regimen of pegylated IFN given once weekly is more effective than a regimen of standard IFN given three times weekly.

Heathcote J, Ramji A. · Department of Medicine, Toronto Western Hospital, University Health Network/University of Toronto, 399 Bathurst Street, Fell Pavilion, 6th floor, Room 170, Toronto, ON M5T 2S8, Canada. · Curr Gastroenterol Rep. · Pubmed #15245691 No free full text.

This publication has no abstract.

Heathcote J. · Toronto Western Hospital, University of Toronto, University Health Network 6B Fell Room 170, 399 Bathurst Street, Toronto, Ont. M5T 2S8, Canada. · J Hepatol. · Pubmed #14708687 No free full text.

This publication has no abstract.

Heathcote J. · University of Toronto, Toronto Western Hospital, Ontario, Canada. · Semin Liver Dis. · Pubmed #12616452 No free full text.

Abstract: Spontaneous loss of hepatitis B e antigen (HBeAg) followed by seroconversion to anti-HBe usually coincides with normalization of serum alanine aminotransferase (ALT) levels, reduction in HBV DNA in serum (< 1 x 10(6) copies/mL), and a marked reduction in hepatic inflammation. Licensed antiviral therapies are the interferon (IFN) alphas and the nucleoside analogue lamivudine. Both drugs enhance the rate at which HBeAg seroconversion takes place and thus reduce progression of disease. These therapeutic agents are ineffective if given when there is no ongoing hepatitis (i.e., normal ALT), and their efficacy is greatest in individuals with the most active disease. The effectiveness of these two classes of drugs is similar, and it is possible that the two therapies combined are more effective than monotherapy with either drug. A high side-effect profile and the high risk of further morbidity when given to patients with decompensated disease limit the use of IFN-alpha. When prescribing lamivudine, drug resistance that increases with duration of therapy and the potential risk of a severe flare of hepatitis with sudden cessation of therapy, probably greatest in patients with cirrhosis, are realistic concerns. Both patient and physician need to recognize the need for close monitoring both during and after cessation of any antiviral therapy for hepatitis B.

Heathcote J. · University Health Network, Toronto Western Hospital, 399 Bathurst Street, 6B #170 Fell Pavilion, Toronto, Ontario M5T 2S8, Canada. · Clin Liver Dis. · Pubmed #12362574 No free full text.

Abstract: The diagnostic criteria for each of the three major autoimmune liver diseases must be codified and the boundaries between diseases established. There will always be syndromes with mixed or atypical features because classically defined disorders represent only the outer ends of the diagnostic spectrum. It is only after boundaries have been decided by consensus that the true variants of autoimmune liver disease can be appreciated. Until then, both the diagnosis and treatment of these syndromes will be arbitrary and unclear.

Heathcote J. · University of Toronto, Toronto Hospital Western Division, Suite 1070, 6B Fell, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. · Curr Gastroenterol Rep. · Pubmed #11177696 No free full text.

Abstract: The diagnosis of primary biliary cirrhosis (PBC) is made via a composite of clinical, laboratory, serologic, and histologic assessments, but within each parameter there exists a wide spectrum, so that the features of PBC are not always uniform. PBC is just one of several liver diseases thought to have an autoimmune basis. Therefore, it is not surprising, given the complexity of the immune response, that some patients thought to have PBC may have features of autoimmune hepatitis (AIH). Whether such patients have PBC with features of AIH, or antimitochondrial antibody-negative PBC, or another disease altogether, remains unclear.

Heathcote J. · University of Toronto, University Health Network, Ontario, Canada. · Semin Liver Dis. · Pubmed #10946423 No free full text.

Abstract: Several large, randomized, controlled treatment trials in persons with hepatitis C and ongoing hepatitis have been reported recently. These have shown that, in patients without other comorbid conditions, treatment for from 6 to 12 months with a combination of interferon-alpha 2b, 3 MU three times a week (ttw), plus ribavirin, 1,000-1,200 mg daily, results in a higher incidence of sustained virologic response than does treatment with interferon-alpha 2b monotherapy, 3 MU ttw, given for similar durations. Patients who have relapsed after interferon monotherapy may achieve a sustained virologic response when retreated with interferon plus ribavirin for 6 months or when given a higher dose of interferon for a longer duration than the initial treatment. By contrast, patients who had no virologic response to prior interferon monotherapy have only a small chance of achieving a sustained response when similarly retreated. Although the efficacy of treatment for hepatitis C has improved steadily over the last decade, current interferon-based therapies still achieve a sustained virologic response in fewer than half of patients who initiate therapy, are associated with appreciable side effects, and are expensive. Furthermore, the natural history of chronic hepatitis C suggests that even in the absence of therapy, most patients with chronic hepatitis C infection may experience little morbidity or mortality for decades. Finally, published therapeutic trials stem largely from tertiary referral centers, where an especially high level of commitment is expected from both the patients and the team in charge of therapy. Typically, such trials have also excluded patients with comorbid diseases, thus reducing their "generalizability." This review focuses on two fundamental questions about the currently available treatments for this disease: Who should be treated with them? And when should they be treated? Critical analysis suggests that the answers to these questions are not as clear as they may superficially appear.

Cooper CL, Davis HL, Morris ML, Efler SM, Adhami MA, Krieg AM, Cameron DW, Heathcote J. · Division of Infectious Diseases, University of Ottawa at The Ottawa Hospital and Ottawa Health Research Institute, Ottawa, Canada. · J Clin Immunol. · Pubmed #15622454 No free full text.

Abstract: Oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN) act as potent Th1-like immune enhancers with many antigens in animal models. We have extended these observations to the first clinical evaluation of the safety, tolerability and immunogenicity of CPG 7909 when added to a commercial HBV vaccine. In a randomized, double-blind phase I dose escalation study, healthy volunteers aged 18-35 years were vaccinated at 0, 4 and 24 weeks by intramuscular injection with Engerix-B (GlaxoSmithKline). The regular adult dose of 20 microg recombinant hepatitis B surface antigen (HBsAg) adsorbed to alum was administered mixed with saline (control) or with CPG 7909 at one of three doses (0.125, 0.5 or 1.0 mg). HBsAg-specific antibody responses (anti-HBs) appeared significantly sooner and were significantly higher at all timepoints up to and including 24 weeks in CPG 7909 recipients compared to control subjects (p< or = 0.001). Strikingly, most CpG 7909-vaccinated subjects developed protective levels of anti-HBs IgG within just two weeks of the priming vaccine dose. A trend towards higher rates of positive cytotoxic T cell lymphocyte responses was noted in the two higher dose groups of CPG 7909 compared to controls. The most frequently reported adverse events were injection site reactions, flu-like symptoms and headache. While these were more frequent in CPG 7909 groups than in the control group (p<0.0001), most were reported to be of mild to moderate intensity regardless of group. In summary, CPG 7909 as an adjuvant to Engerix-B was well-tolerated and enhanced vaccine immunogenicity. CPG 7909 may allow the development of a two-dose prophylactic HBV vaccine.

Siegrist CA, Pihlgren M, Tougne C, Efler SM, Morris ML, AlAdhami MJ, Cameron DW, Cooper CL, Heathcote J, Davis HL, Lambert PH. · Department of Pediatrics, Center for Vaccinology and Neonatal Immunology, University of Geneva, C.M.U., 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. · Vaccine. · Pubmed #15542181 No free full text.

Abstract: We assessed the avidity maturation process elicited by human immunization with alum-adsorbed HBsAg alone or with a novel adjuvant containing CpG motifs (CpG 7909). Mean avidity indexes and distribution of low- and high-avidity anti-HBs indicated that avidity maturation essentially takes place late after priming. CpG 7909 markedly enhanced this affinity maturation process, increasing the pool of high-avidity antibodies. The influence of CpG 7909 was antigen-specific, isotype-specific and distinct from the influence on anti-HBs production, as avidity did not correlate with anti-HBs IgG titers. This is the first demonstration that a novel human adjuvant may induce antibodies with higher antigen-binding affinity.

Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, Dhillon A, Moorat A, Barber J, Gray DF. · Department of Hepatology and Gastroenterology, Erasmus University Hospital Rotterdam, Rotterdam, Netherlands. · Gut. · Pubmed #10716688 links to  free full text

Abstract: BACKGROUND, AIM, AND METHODS: Alpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside analogue which potently inhibits hepatitis B virus (HBV) DNA replication. To investigate the possibility of an additive effect of interferon-lamivudine combination therapy compared with interferon or lamivudine monotherapy, we conducted a randomised controlled trial in 230 predominantly Caucasian patients with hepatitis B e antigen (HBeAg) and HBV DNA positive chronic hepatitis B. Previously untreated patients were randomised to receive: combination therapy of lamivudine 100 mg daily with alpha interferon 10 million units three times weekly for 16 weeks after pretreatment with lamivudine for eight weeks (n=75); alpha interferon 10 million units three times weekly for 16 weeks (n=69); or lamivudine 100 mg daily for 52 weeks (n=82). The primary efficacy end point was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of antibodies to HBeAg and undetectable HBV DNA). RESULTS: The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for interferon monotherapy, and 18% for lamivudine monotherapy (p=0.12 and p=0.10, respectively, for comparison of the combination therapy with interferon or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for the combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis (36% (20/56) v 19% (13/70), respectively; p=0.02). The effect of combining lamivudine and interferon appeared to be most useful in patients with moderately elevated alanine aminotransferase levels at baseline. Adverse events with the combination therapy were similar to interferon monotherapy; patients receiving lamivudine monotherapy had significantly fewer adverse events. CONCLUSIONS: HBeAg seroconversion rates at one year were similar for lamivudine monotherapy (52 weeks) and standard alpha interferon therapy (16 weeks). The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels. The potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.

Hyman A, Yim C, Krajden M, Read S, Basinski AS, Wanless I, Levy G, Heathcote J. · Department of Medicine, University of Toronto, Canada. · J Viral Hepat. · Pubmed #10607248 No free full text.

Abstract: The cytoprotective effects of prostaglandins have been utilized in the prevention of hepatitis B virus reactivation after liver transplantation. This pilot study evaluated the effects of oral prostaglandin E2 (PGE2) in chronic viral hepatitis B and C. Twenty patients with chronic hepatitis B and 20 patients with chronic hepatitis C received 4mg day-1 PGE2 for 6 months. The lymphocyte antiviral enzyme 2',5'-oligoadenylate synthetase (2',5'-OAS) and peripheral blood monocyte procoagulant activity (PCA) were measured before, during and after the treatment. Three of 20 hepatitis B and five of 20 hepatitis C patients withdrew from the study. Eight of 17 hepatitis B patients responded: in seven of these eight patients, serum alanine aminotransferase (ALT) levels normalized; loss of viral replication was sustained in all eight patients; and seroconversion from hepatitis Be antigen (HBeAg) to hepatitis Be antibody (HBeAb) positivity occurred in seven patients over the 48-week duration of this study. In 14 of the 15 hepatitis C patients, hepatitis C virus (HCV) RNA remained detectable and the serum ALT levels remained elevated. 2',5'-OAS levels and PCA values did not correlate with other markers of response to PGE2 therapy in either chronic hepatitis B or C. In summary, PGE2 was associated with sustained loss of viral replication in 47% of chronic hepatitis B patients; no beneficial effects were apparent in chronic hepatitis C.

Tassopoulos NC, Volpes R, Pastore G, Heathcote J, Buti M, Goldin RD, Hawley S, Barber J, Condreay L, Gray DF. · Western Attica General Hospital, Athens, Greece. · Hepatology. · Pubmed #10051494 No free full text.

Abstract: This placebo controlled, double-blind study evaluated the efficacy and safety of lamivudine in patients with hepatitis B e antigen (HBeAg)-negative/hepatitis B virus (HBV) DNA-positive chronic hepatitis B. Patients were randomized to receive 100 mg lamivudine orally once daily for 52 weeks (n = 60) or placebo for 26 weeks (n = 65). Patients who were HBV DNA positive at week 24 were withdrawn at week 26. The primary efficacy endpoint was loss of serum HBV DNA plus normalization of alanine transaminase (ALT) at week 24. A significantly higher proportion of patients receiving lamivudine (63%) had a complete response at week 24 compared with patients receiving placebo (6%) (P <.001). Secondary efficacy parameters included histological response from baseline to week 52 in the lamivudine-treated patients. At week 52, 60% of lamivudine-treated patients with liver biopsy specimens available showed histological improvement (>/=2-point reduction in Knodell necro-inflammatory score), 29% showed no change, and 12% worsened. In a ranked assessment of pretreatment and post-treatment biopsy pairs 11% improved, 86% showed no change, and 2% worsened in fibrosis. At week 52, 27% of patients receiving lamivudine had YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. The incidence of adverse events and laboratory abnormalities was similar in both groups. In conclusion, lamivudine treatment results in a significant virological and biochemical improvement compared with placebo, induces an improvement or no change in histology in most patients, and is well tolerated. The response to lamivudine therapy in HBeAg-negative patients is similar to the response reported in previous studies of patients with HBeAg-positive chronic hepatitis B.

Wu H, Yim C, Chan A, Ho M, Heathcote J. · University of Toronto, Toronto, Ontario, Canada. · Can J Gastroenterol. · Pubmed #19172206 No free full text.

Abstract: BACKGROUND: Despite the availability of screening for chronic hepatitis B (CHB) infection and effective treatments now available, many at-risk individuals fail to seek appropriate medical attention. OBJECTIVE: To identify the barriers to care for CHB infection in a Chinese Canadian community. METHODS: A survey conducted in English or Chinese collected information from individuals with CHB infection that evaluated the level of understanding and identified the barriers that may prevent Chinese patients from undergoing monitoring, screening and/or treatment for CHB infection. RESULTS: Among the 204 patients enrolled, common misconceptions were that sharing food transmits hepatitis B and that patients with severe disease are always symptomatic. Patients with a better understanding of hepatitis B were better educated, younger and were being followed at a tertiary care centre (P<0.01 for all). Prominent barriers to health care were time, inconvenience and language difficulties. Patients under the care of family physicians who had extended office hours were less likely to cite time (P=0.06) and distance (P=0.05) as barriers. CONCLUSION: Patient misconceptions that severe liver disease due to hepatitis B infection is symptomatic may factor into the unwillingness to spare the time and undergo the inconvenience associated with regular medical follow-up. Implementation of programs that increase awareness of the silent progression of CHB infection and provide culturally responsive clinics, better able to work within patients' time constraints may improve Chinese patients' access to health care.

Kumagi T, Alswat K, Hirschfield GM, Heathcote J. · Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Hepatol Res. · Pubmed #18462376 No free full text.

Abstract: Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.

Missiha S, Heathcote J, Arenovich T, Khan K, Anonymous00213. · Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · Am J Gastroenterol. · Pubmed #17640318 No free full text.

Abstract: BACKGROUND: Prior investigation has identified factors associated with response to treatment in hepatitis C including viral genotype and titre, body weight, hepatic fibrosis, and adherence to therapy. The lower response rate of African-Americans relative to whites has been previously described, but studies of other racial or ethnic groups remain limited. OBJECTIVE: To determine whether Asian race is an independent marker for response to antiviral therapy in hepatitis C. METHODS: Data on treatment-naïve patients from a large multicenter study of combination therapy with peginterferon alfa-2a (180 mug SC each week) and ribavirin (800 mg daily) were analyzed retrospectively to identify factors associated with an SVR, defined as an undetectable serum HCV RNA at least 24 wk after completion of therapy. RESULTS: SVR occurred in 45% of 384 whites and 65% of 52 Asians (P= 0.0047) who were treatment naïve. In a multivariate logistic regression analysis that adjusted for all the aforementioned factors known to be associated with treatment response, Asian race was shown to be an independent predictor of achieving an SVR (OR 2.22, 95% CI 1.11-4.46). Other independent predictors of SVR include viral genotype, body mass index, degree of hepatic fibrosis, and adherence with ribavirin. CONCLUSIONS: Asians are more likely to achieve an SVR to treatment with peginterferon alfa-2a and ribavirin than whites with chronic hepatitis C, suggesting a genetic influence on the antiviral response.

Randall G, Chen L, Panis M, Fischer AK, Lindenbach BD, Sun J, Heathcote J, Rice CM, Edwards AM, McGilvray ID. · Center for the Study of Hepatitis C, Rockefeller University, New York, New York, USA. · Gastroenterology. · Pubmed #17101330 No free full text.

Abstract: BACKGROUND & AIMS: Modulation of the host innate immune response is an attractive means of inhibiting hepatitis C virus (HCV) replication. Having previously determined that expression of the interferon-sensitive gene (ISG)15 protease USP18 is increased in the liver biopsy specimens of patients who do not respond to interferon (IFN)-alfa therapy, we hypothesized that USP18 might hinder the ability of IFN to inhibit HCV replication. METHODS: The role of USP18 in IFN antiviral activity was examined using an in vitro model of HCV replication that reproduces the full viral life cycle. USP18 was silenced specifically using small inhibitory RNAs (siRNAs), and the dose response of HCV replication and infectious virus production to IFN-alfa was measured. RESULTS: The siRNA knockdown of USP18 in human cells consistently potentiated the ability of IFN to inhibit HCV-RNA replication and infectious virus particle production by a factor of 1-2 log(10). USP18 knockdown also resulted in a number of cellular changes consistent with increased sensitivity to IFN. Decreasing USP18 expression led to increased cellular protein ISGylation in response to exogenous IFN-alfa, prolonged tyrosine phosphorylation of signal transducer and activation of transcription (STAT1), and a general enhancement of IFN-stimulated gene expression. CONCLUSIONS: These data suggest that USP18 modulates the anti-HCV type I IFN response, and is a possible therapeutic target for the treatment of HCV infection.

Witkos M, Yi QL, Heathcote J, Kapral MK, Krahn MD. · Department of Health Policy, Management and Evaluation, University of Toronto, Toronto General Hospital, Ontario, Canada. · Can J Gastroenterol. · Pubmed #16482237 links to  free full text

Abstract: INTRODUCTION: In the past, antiviral therapy has been given to 15% to 30% of patients infected with hepatitis C virus (HCV). The efficacy of therapy has recently improved with the addition of ribavirin and pegylated interferon. The aim of the present study was to identify the clinical, socioeconomic and health-system predictors of antiviral treatment for HCV. METHODS: A retrospective analysis of compensation claims data of patients who acquired HCV through blood transfusions between 1986 and 1990 was performed. The patients consisted of 2456 Canadian HCV-positive individuals. The authors reviewed narrative comments from physicians, and constructed univariate and multivariate logistic regression models, using receipt of antiviral therapy with interferon or interferon/ribavirin as the primary outcome. RESULTS: Of the 2456 patients, approximately 30% appeared to be eligible, but only 16% received treatment. Univariate analyses suggested that the disease severity, age, HIV status and province of residence were associated with the likelihood of receiving treatment (P<0.01). The final, multivariable model indicated that in patients with HCV: intermediate disease severity (eg, fibrosis, P<0.0001); middle age (P<0.0001); HIV-negative status (P<0.0001); and province of residence (Quebec, P<0.0001; and Saskatchewan, P<0.0001) were independent predictors of treatment. Narrative comments of physicians emphasized the importance of age, HIV status and patient preferences in clinical decision-making. DISCUSSION: Given the efficacy and cost-effectiveness of current antiviral therapy, treatment rates of HCV patients may be suboptimal. Further work is required to understand barriers to treatment related to geography, organization of medical care, age, medical provider and patient preferences.