Hepatitis: Cooper C

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.

Barry M, Cooper C. · University of Ottawa, The Ottawa Hospital, Division of Infectious Diseases, Room G12-501 Smyth Road, Ottawa, K1H 8L6, ON, Canada. · Expert Opin Biol Ther. · Pubmed #17961095 No free full text.

Abstract: Existing hepatitis B virus (HBV) vaccines produce seroprotective titers in > 90% of healthy adult recipients following 3 doses administered over 6 months. The durability of this response is variable. Vaccine efficacy is greatly diminished in immune compromised patients. Given the high worldwide prevalence and burden of disease produced by chronic HBV infection, vaccines capable of producing high rates of durable seroprotective HBV surface antibody titers are required. Immunostimulatory sequences (ISS) containing repeating sequences of cytosine phosphoguanosine (CpG) dinucleotide motifs have emerged as useful tools for modulating immune responses. Dynavax Technologies produced a synthetic oligodexynucleotide (ODN) containing these motifs, resulting in an unmethylated cytosine and phosphoguanosine ODN called 1018 ISS. Dynavax's hepatitis B virus vaccine HEPLISAV is comprised of 1018 ISS mixed with recombinant hepatitis B surface antigen. Clinical trials, to date, have shown that HEPLISAV produces rapid, high titer, sustained seroprotection in healthy adults and vaccine hyporesponsive populations. Although additional supporting data are required, this represents a promising strategy to facilitate worldwide HBV prevention efforts.

Sherman M, Bain V, Villeneuve JP, Myers RP, Cooper C, Martin S, Lowe C. · University of Toronto, Toronto, Ontario, Canada. · Can J Gastroenterol. · Pubmed #15605136 links to  free full text

Abstract: Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care.

Powis J, Peltekian KM, Lee SS, Sherman M, Bain VG, Cooper C, Krajden M, Deschenes M, Balshaw RF, Heathcote EJ, Yoshida EM, Anonymous00028. · Department of Medicine, University of Toronto, Toronto, ON, Canada. · J Viral Hepat. · Pubmed #18088245 links to  free full text

Abstract: Chronic hepatitis C virus (HCV) infections with genotype 2 or 3 are associated with favourable sustained virologic response (SVR) rates. However, genotype 3 may respond less well. We reassessed all treatment-naive patients with genotype 2 and 3 participating in a large expanded-access, non-randomized, open-label trial, evaluating 180microg pegylated interferon (peg-IFN) alpha-2a (40kD) once weekly and 800 mg/day ribavirin for 24-48 weeks. Factors measured prior to initiation of antiviral therapy were considered in the multiple logistic regression model for predicting SVR. In total, 180 patients were analysed of which 72 (40%) were infected by genotype 2 and 108 (60%) genotype 3. The baseline characteristics between patients infected by genotype 2 or 3 were no different including the distribution of hepatic fibrosis stages by METAVIR score. Overall SVR was lower in those patients infected with genotype 3. The significant multivariate predictors of lack of SVR were hepatic fibrosis (P = 0.014) and genotype 3 (P = 0.030). The negative impact of cirrhosis (METAVIR score F4) on treatment response was more evident among subjects with genotype 3 than those with genotype 2 (P = 0.027). There is significant interaction between cirrhosis and genotype 3 leading to a poor antiviral response in such patients requiring an alternate management strategy. This finding should be confirmed in a larger population.

Cooper C, Lawitz EJ, Ghali P, Rodriguez-Torres M, Anderson FH, Lee SS, Bédard J, Chauret N, Thibert R, Boivin I, Nicolas O, Proulx L. · The Ottawa Hospital, Division of Infectious Disease, Ottawa, ON, Canada K1H 8L6. · J Hepatol. · Pubmed #19446909 No free full text.

Abstract: BACKGROUND/AIMS: VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC(50) values versus genotype 1a/1b replicons. METHODS: The antiviral activity, pharmacokinetics and tolerability of VCH-759 administered as monotherapy for 10 days with a 14 day follow-up period were evaluated in 31 treatment-nai ve genotype 1 participants. Three cohorts received: 400mg thrice (t.i.d.), 800 mg twice (b.i.d.), 800 mg t.i.d or placebo. RESULTS: VCH-759 was well tolerated with the most frequent adverse event being gastrointestinal upset in both the active and placebo groups attributable, in part, to the dosing vehicle. VCH-759 was rapidly absorbed and trough plasma levels were at or above the IC(90) (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log(10) (IU/mL) was 1.97, 2.30 and 2.46 for 400mg t.i.d., 800 mg b.i.d. and 800 mg t.i.d. doses. Viral polymerase genotypic sequencing revealed emergence of HCV variants in a majority of participants that coincided with on-treatment viral rebound. CONCLUSIONS: VCH-759 was well tolerated and achieved a> or =2 log(10) decline in HCV RNA with 800 mg b.i.d. and t.i.d doses. In a subset of participants, viral rebound was observed and associated with resistant variants. This data supports further evaluation of VCH-759 in combination with interferon-ribavirin treatment.

Giordano C, Cooper C. · University of Ottawa, The Ottawa Hospital, Division of Infectious Diseases, Ottawa, Canada. · Eur J Gastroenterol Hepatol. · Pubmed #19092675 No free full text.

Abstract: Race, ethnicity and language influence health care delivery and satisfaction with treatment in many disease states including chronic hepatitis C virus (HCV) infection. In this review, HCV epidemiology and current standard of care is reviewed. The influence of race, ethnicity and language on screening, work-up and initiation of HCV antiviral treatment is evaluated. Acknowledging that these factors do influence health care quality and taking steps to improve communication (e.g. translated written documents; use of reliable, trained translators in the clinic setting) will facilitate the delivery of an equivalent level of care to all patients living with HCV.

McLaren M, Garber G, Cooper C. · University of Ottawa, The Ottawa Hospital, Ottawa, Canada. · Can J Gastroenterol. · Pubmed #18299730 links to  free full text

Abstract: BACKGROUND: Despite demonstrated efficacy in HIV-hepatitis C virus (HCV) coinfection, not all patients initiate, complete or achieve success with HCV antiviral therapy. PATIENTS AND METHODS: All HIV-HCV coinfected patient consults received at The Ottawa Hospital Viral Hepatitis Clinic (Ottawa, Ontario) between June 2000 and September 2006 were identified using a clinical database. A descriptive analysis of primary and contributing factors accounting for why patients did not initiate HCV therapy, as well as the therapeutic outcomes of treated patients, was conducted. RESULTS: One hundred two consults were received. Sixty-seven per cent of patients did not initiate HCV therapy. The key primary reasons included: HIV therapy was more urgently needed (22%), loss to follow-up (12%), patients were deemed unlikely to progress to advanced liver disease (18%) and patient refusal (12%). Many patients had secondary factors contributing to the decision not to treat, including substance abuse (23%) and psychiatric illness (14%). Overall, 59% of untreated patients (40 of 68) were eventually lost to follow-up. Thirty-three per cent of referred patients started HCV therapy. Twenty-seven of 42 courses (64%) were interrupted prematurely for reasons such as virological nonresponse (48%), psychiatric complications (10%) and physical side effects (7%). Of all treatment recipients, 12 of 42 full courses of therapy were completed and three remained on HCV medication. Overall, eight of the 102 coinfected patients studied (8%) achieved a sustained virological response. DISCUSSION: Not all HIV-HCV coinfected patients who are deemed to be in need of HCV treatment are initiating therapy. Only a minority of patients who do receive treatment achieve success. Implementation of HIV treatment, patient retention, attention to substance abuse and mental health care should be the focus of efforts designed to increase HCV treatment uptake and success. This can be best achieved within a multidisciplinary model of health care delivery.

Klein MB, Cooper C, Brouillette MJ, Sheehan NL, Benkelfat C, Annable L, Weston F, Kraus D, Singer J, Anonymous00318. · Department of Medicine, Divisions of Infectious Diseases/Immunodeficiency, Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada. · Contemp Clin Trials. · Pubmed #18262853 No free full text.

Abstract: Hepatitis C (HCV)-related end stage liver disease is a primary cause of morbidity and mortality in people with HIV. Despite this, co-infected patients have low rates of HCV treatment initiation and completion. This is in large part due to the risk of pegylated-interferon alpha (PEG-IFN-alpha)-related neuropsychiatric complications. We describe the design of a multicentre randomized, placebo-controlled trial that evaluates whether antidepressant prophylaxis is superior to early detection and treatment of depression in increasing the successful completion of HCV therapy. Seventy-six HIV+ adults with chronic HCV infection requiring therapy and with no contraindications to PEG-IFN-alpha/ribavirin will be randomized in a 1:1 ratio to receive citalopram or placebo starting three weeks prior to HCV treatment. A novel aspect of the trial design is the built-in management of emergent depression while maintaining the blinded treatment assignment. This will permit the comparison of prophylactic versus therapeutic use of citalopram. The primary outcome is the average proportion of prescribed PEG-IFN-alpha and ribavirin doses taken per month at weeks 12 and 24, and will be compared between treatment arms. The study will also compare the development of moderate-to-severe depression between treatment arms. A unique feature of this trial will be the use of Telepsychiatry to standardize observer-administered neuropsychiatric evaluations. Assessments of anxiety, quality of life, and adherence to therapy, as well as pathogenetic studies of neuropsychiatric side effects, will be conducted. Intention-to-treat analyses using random regression modeling will be employed to analyze longitudinal data on prescribed PEG-IFN-alpha and ribavirin doses. Survival analyses will be used to compare the time to the development of depression between the two arms. Effective prevention of a broad range of neuropsychiatric symptoms by citalopram has the potential to diminish PEG-IFN-alpha associated morbidity and consequently, allow a greater number of patients to complete full therapy.

Sherman M, Bain V, Villeneuve JP, Myers RP, Cooper C, Martin S, Lowe C. · University of Toronto, Toronto, Ontario; · Can J Infect Dis Med Microbiol. · Pubmed #18159509 links to  free full text

Abstract: Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care.

Balfour L, Cooper C, Kowal J, Tasca GA, Silverman A, Kane M, Garber G. · The Ottawa Hospital Division of Infectious Diseases Viral Hepatitis Program, University of Ottawa, Ontario. · Can J Gastroenterol. · Pubmed #16482232 links to  free full text

Abstract: BACKGROUND: Many people living with chronic viral hepatitis C (HCV) report reduced health-related quality of life. The relative contribution of behavioural, psychosocial and HCV disease factors to reduction in HCV health-related quality of life is not well understood. The objectives of the present study were to compare standardized health-related quality of life scores between Canadian HCV patients and age-matched Canadian and American norms, and to examine the relative contribution of biopsychosocial variables (ie, cigarette smoking, alcohol intake and depression) to health-related quality of life scores among Canadian HCV patients. METHODS: HCV RNA-positive patients were recruited during their first visit to the Ottawa Hospital Viral Hepatitis Clinic (Ottawa, Ontario). A questionnaire assessing health behaviours, health-related quality of life and depressed mood was completed. Data on liver studies, liver biopsy findings and HIV serostatus were also collected. RESULTS: A total of 123 participants (71% men) ranging from 20 to 67 years of age were evaluated. All had compensated liver function. Patients reported significantly lower health-related quality of life compared with age-matched Canadian and American normative samples. In a series of hierarchical multiple regression models, depression and smoking were independently related to compromised health-related quality of life scores, even after controlling for sociodemographic variables and health behaviours. DISCUSSION: These results highlight the value of adopting a biopsychosocial model of HCV care. Depressed mood and smoking behaviour should be evaluated in HCV patients. Empirically validated psychological and pharmacological treatments for depression and smoking cessation may improve health-related quality of life in HCV infected patients.

Al-Mohri H, Cooper C, Murphy T, Klein MB. · Department of Medicine, Divisions of Infectious Diseases/Immunodeficiency, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada. · HIV Med. · Pubmed #16268817 No free full text.

Abstract: OBJECTIVES: Recently, several models incorporating laboratory measurements have been validated for use as surrogate markers for liver fibrosis in hepatitis C virus (HCV) mono-infection, the simplest of these being the aspartate aminotransferase (AST) to platelet ratio index (APRI). We evaluated how well the APRI predicts significant hepatic fibrosis in patients with HIV/HCV coinfection. METHODS: Forty-six HIV/HCV-coinfected patients who underwent liver biopsy and had concomitant laboratory measurements (+/-3 months) were included in the study. Significant fibrosis was defined as F2-F4 using Batt and Ludwig scoring (=3 Ishak). APRI=[(AST/upper limit of normal)/platelet count (10(9)/L)] x 100. We used sas proc logistic (SAS Institute, Cary, NC) to calculate the area under the receiver operating curve (ROC) (AUC). Sensitivities, specificities, positive predictive value (PPV) and negative predictive value (NPV) were compared using cut-offs previously identified in the literature. RESULTS: Thirty-three of 46 patients (72%) had significant fibrosis on biopsy. For significant fibrosis, the area under the ROC for the APRI was 0.847+/-0.057. APRI scores >1.5 (the higher cut-off) were 100% specific and 52% sensitive; PPV was 100% and NPV 45%. Scores <0.5 (the lower cut-off) were 82% sensitive and 46% specific in ruling out significant fibrosis (PPV 79%; NPV 50%). CONCLUSIONS: A simple model incorporating readily available laboratory data is highly predictive of significant fibrosis in HIV/HCV coinfection and could serve as a biopsy-sparing measure, thus making treatment more accessible for this population.

Balfour L, Cooper C, Tasca GA, Kane M, Kowal J, Garber G. · Viral Hepatitis Unit, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, Ontario. · Can J Public Health. · Pubmed #15362469 No free full text.

Abstract: OBJECTIVE: To define self-reported hepatitis C knowledge, health care needs, and patient satisfaction in a representative cohort of hepatitis C virus (HCV)-infected adults treated at a university hospital-based viral hepatitis clinic in Canada. METHODS: A questionnaire package evaluating HCV knowledge, health care needs, and patient satisfaction was administered to 111 consecutive consenting HCV patients during their first and 10-month follow-up HCV clinic visits. RESULTS: At their first HCV clinic visit, 52% of patients rated their current HCV knowledge as "fair" or "poor". Patients identified HCV education, quality medical care, medication coverage, and psychological counselling as important HCV health care needs. Health care satisfaction outcome data at 10-month follow-up indicated that patients felt significantly better informed, more satisfied, and more actively involved in their HCV health care. CONCLUSION: A bio-psychosocial framework in which medical, psychological, educational, and social issues are addressed is desirable for optimal HCV health care.

Aweis D, Brabin BJ, Beeching NJ, Bunn JE, Cooper C, Gardner K, Iriyagolle C, Hart CA. · Tropical Child Health Group, Tropical Medicine Division, Liverpool School of Tropical Medicine. · Commun Dis Public Health. · Pubmed #12109390 No free full text.

Abstract: The prevalence of hepatitis B core antibody (anti-HBc) and surface antigen (HBsAg) in the Somali population in Liverpool is described and groups who may benefit from vaccination are identified. A cross-sectional descriptive study was undertaken. A total of 439 subjects, aged between 10 months and 80 years, from 151 households, were screened for anti-HBc and HBsAg. One hundred ninety-four (44.2%) were children aged less than 15 years. Three hundred and nine (69%) of enrolled subjects were born in Somalia, 122 (27.2%) were born in the UK and 8 were born elsewhere. Of the study population, 5.7% were carriers of HBsAg, with the highest prevalence in adults aged 20 to 44 years (9.4%). A history of circumcision (RR 95% CI; 1.2, 1.1-1.5) was the most significant risk factor for HBsAg carriage, but was not significant on multivariate analysis. Prevalence of anti-HBc was 27.5%, and increased with age over the first four decades. Univariate analysis showed that a history of living in a refugee camp (RR 95% CI; 3.1, 1.7-5.7), receiving an injection in Somalia (2.1, 1.7-2.5), a history of circumcision or other surgical procedure in Somalia (1.4, 1.3-1.6) and being born in Somalia (1.3, 1.2-1.4) were significant risk factors for anti-HBc positivity. On multivariate analysis, only circumcision (OR 95% CI; 4.3, 1.8-10.3) and receiving an injection in Somalia (2.5, 1.5-4.4) remained significant. Seven of 80 (8.7%) children born in the UK and aged five years or less had evidence of exposure to hepatitis B, of whom only one had a close family member identified to be HBsAg seropositive. Previous infection with hepatitis B is common in this population. Horizontal transmission may be continuing at an early age within the UK, suggesting a population of at risk individuals who would benefit from surveillance and immunisation. Community circumcision is a risk factor for hepatitis B transmission and best practice should be followed when this procedure is undertaken.

Cooper C. · No affiliation provided · Can J Gastroenterol. · Pubmed #19096734 links to  free full text

Abstract: Curtis Cooper is an Associate Professor with the University of Ottawa, Infectious Diseases Consultant with the Ottawa Hospital Division of Infectious Diseases, and a researcher with the Ottawa Health Research Institute. His research interests are in the evaluation of the clinical, biochemical, virological, immunological, psychological and pharmacokinetic interactions among viral hepatitis, HIV and the medications used to treat these chronic infections.

Cooper C, MacPherson P, Angel JB. · No affiliation provided · Clin Infect Dis. · Pubmed #15791529 No free full text.

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Cooper C, Kilby D. · No affiliation provided · Clin Infect Dis. · Pubmed #15127355 No free full text.

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Brabin B, Beeching NJ, Bunn JE, Cooper C, Gardner K, Hart CA. · No affiliation provided · Arch Dis Child. · Pubmed #11806897 links to  free full text

This publication has no abstract.