Uhanova J: Chronic hepatitis B infection in Canada

Recent developments in the treatment and prevention of hepatitis B virus (HBV) infections warrant revisiting important epidemiological questions, such as how prevalent is chronic HBV infection in Canada, in which Canadian subpopulations are HBV prevalence rates the highest, in what percentage of infected individuals is the virus actively replicating, and how many infected Canadians are candidates for antiviral therapy? Currently available data suggest the overall prevalence of HBVinfected individuals in the general population is approximately 2%, with 5% to 10% having serological evidence of previous HBV infection. In high risk groups, such as street-connected individuals, Aboriginals and immigrants from endemic areas, these rates of viral prevalence and serological evidence of previous HBV infection are approximately two to 10 and five to 10 times higher, respectively, than in the general population. Candidates for antiviral therapy range from less than 1% of infected Aboriginals to 15% to 30% of Asians with chronic HBV. From these data, it is clear that chronic HBV remains an important public health problem in this country. Hence, resources must be identified to enhance Canadians' awareness of HBV infection, maintain, if not expand, efforts to identify and implement safe and effective antiviral therapy for HBV-infected individuals, and continue programs for universal vaccination to prevent new HBV infections. Key Words: Canada; Epidemiology; Hepatitis; Hepatitis B; Hepatitis B virus; Liver; Liver disease L'hépatite B chronique au Canada RÉSUMÉ : Compte tenu de récents progrès réalisés aux chapitres du traitement et de la prévention de l'hépatite B, il semble justifié de revoir les grandes questions épidémiologiques, par exemple, quelle est la prévalence de l'hépatite B chronique au Canada, dans quelle sous-population du Canada les taux de prévalence du HBV sont-ils les plus élevés, dans quel pourcentage des sujets infectés le virus se multiplie-t-il activement et combien de Canadiens infectés sont des candidats au traitement antiviral? Selon les données actuellement disponibles, la prévalence globale de l'infection au HBV dans la population générale s'élèverait à environ 2 %, de 5 à 10 % présentant des signes sérologiques d'infection au HBV. Dans les groupes à risque, par exemple chez les sans-abris, les Autochtones et certaines populations immigrantes provenant de régions endémiques du globe, ces taux de prévalence globale et de signes sérologiques d'infection au HBV sont de 2 à 10 et de 5 à 10 fois plus élevés respectivement que dans la population en général. Les pourcentages de candidats au traitement antiviral varient de moins de 1 % chez les Autochtones infectés à 15 ou 30 % chez les Asiatiques porteurs d'une infection chronique par le HBV. À partir de ces données, il est clair que le HBV reste un important problème de santé publique dans ce pays. Des ressources doivent donc être trouvées pour sensibiliser davantage les Canadiens au HBV, pour maintenir sinon élargir les efforts déployés pour découvrir et administrer un traitement antiviral sûr et efficace aux sujets infectés par le HBV et pour maintenir en place les programmes de vaccination universelle de façon à prévenir de nouvelles infections par le HBV. H epatitis B virus (HBV) infections are the ninth most common cause of death by disease in the world today (1). The majority of deaths due to HBV infection occur as a result of complications of cirrhosis and/or hepatocellular carcinoma (2). Recently, new developments in the treatment of chronic HBV infections (defined as serological evidence of HBV infection beyond six months duration) provide promise that the course of the disease may be favourably altered (3,4). Moreover, effective immunoprophylaxis raises the distinct possibility that HBV may eventually be eradicated from the world's population (5). In light of these encouraging therapeutic and preventive developments, it is timely to review the prevalence of chronic HBV infections in the general population of Canada and in certain high risk Canadian populations. HBV IN THE GENERAL POPULATION OF CANADA Numerous studies have attempted to document the prevalence of HBV carriers (for the purpose of this review 'carriers' are defined as individuals with a positive hepatitis B surface antigen (HBsAg) result for more than six months, regardless of viral or disease activity) in the general population of Canada (6-10). The results are prevalence figures that vary from 0.1% in pregnant women attending prenatal clinics in the Maritimes to 2.1% in unselected patients admitted to urban hospital centres Relatively few studies have documented the percentage of HBV carriers in Canada who have serological evidence of active (hepatitis B early antigen (HBeAg)-positive or HBeAgnegative with a positive HBV-DNA test by a non-polymerase chain reaction [PCR] assay) viral replication. One exception is a study by Richer et al (14, Relevant to the issue of antiviral therapy is the proportion of patients with active viral replication who have biochemical evidence of hepatic inflammation. In a study by Villeneuve et al Hepatitis D virus (HDV or delta agent) only infects individuals who are coinfected or have underlying chronic HBV infections. To date, three studies have reported the prevalence of HDV infection (anti-HDV-positive) in predominantly non-Aboriginal, non-Asian Canadian populations. In a study by Cheng et al (19) consisting of 245 HBsAg-positive western Canadians, only four (1.5%) were anti-HDV positive. A slightly higher figure (4%) was described by Hannan et al (20) in 123 HBsAg-positive carriers residing in Manitoba. The lowest HDV infection rates were reported by Villeneuve et al HBV and hepatitis C virus (HCV) coinfections were described in less than 1% of 218 HBsAg-positive carriers studied by Villeneuve et al It is difficult to ascertain the histological extent of disease in HBsAg-positive Canadians because the data are largely limited to patients who have been referred to secondary or tertiary care centres, and among those, only patients with more active disease tend to be biopsied. Nonetheless, in studies where such data are available, active histological disease was identified in 15% to 50% and cirrhosis in under 20% of biopsied cases There has been only one study reported to date documenting the incidence of hepatocellular carcinoma arising in HBsAg-positive Canadians who were not born in areas of the world where HBV is endemic (18). In the study, 317 subjects were followed for more than 16 years (5135 carrier years of follow-up), and no cases of hepatocellular carcinoma were identified. Based on incidence rates reported from general population studies in Alaska and Southeast Asia, 17 cases would have been predicted Annual spontaneous seroconversion rates from active, replicative disease (HBeAg-positive) to inactive, nonreplicative states (loss of HBeAg and appearance of anti-HBe) have been reported by Kim et al In summary, with respect to the general population, approximately 2% of the population of Canada is likely to be HBsAg positive and 5% to 10% have serological markers of previous HBV exposure HIGH RISK POPULATIONS Non-Aboriginal/non-Asian high risk groups: Sexual promiscuity and intravenous drug use are the two most common routes of HBV transmission in low endemic areas (26). In Canada, Yuan and Robinson (27) identified 0.9% of homosexual and bisexual individuals as being HBsAg-positive and 18% as having serological evidence of previous HBV exposure. Increased prevalences of HBV exposure have also been documented in individuals attending sexually transmitted disease clinics in this country (28,29). The highest prevalence figures for HBV exposure have been described in urban street youths, where nine of 43 prostitutes (21%) were found to be anti-HBc and/or anti-HBs seropositive (30). A somewhat lower figure (9.2%) was reported by Roy et al (31) in their study of 437 street youths in Montreal. The same study identified age older than 18 years, history of injection drug use and a sexual partner with unspecified hepatitis as independent factors associated with HBV in this population. Finally, a 2.5% HBsAg carrier rate and 5% prevalence of exposure was documented in institutionalized, mentally handicapped individuals (32). Aboriginal population: As of 1996, the total registered Aboriginal population of Canada was 799,010 people (33). Together with the nonregistered population, it has been estimated that in excess of 1,000,000 Inuit and First Nations peoples reside in Canada. The largest percent (23%) are in the province of Ontario. The first study documenting the prevalence of HBV infection in an Aboriginal population was performed by Minuk et al (34) in 1980, when 720 of 817 inhabitants (88%) of the community of Baker Lake, Northwest Territories were studied. In excess of 90% of this study population were Inuit, with an equal representation of males and females. All ages from three months to 86 years were included. The results of serological testing revealed that 4% were HBsAg positive and 27% had evidence of previous HBV exposure. Males were twice as likely to be HBsAg-positive than females. None of the 49 Caucasians in this community were HBsAg positive, and serological evidence of previous HBV exposure was present in only 5%. Serotyping of the HBV revealed serotype adw in all cases. The age at which Inuit in the community became infected is unclear. HBsAg persistence rates reflect the age of HBV exposure and are calculated by dividing the number of HBsAg-positive individuals by the number of individuals with any positive HBV marker. In this community, the persistence rate was 15%, suggesting these individuals tended to be infected at birth or during early childhood. However, agespecific prevalence rates revealed no carriers under the age of 20 years and relatively low rates of HBV exposure until early adulthood and beyond. Also in keeping with limited neonatal and childhood exposure were the results of HBeAg and antiHBe testing, wherein high HBeAg-positive rates are predicted in populations where infection occurs early in life. In the 36 HBsAg-positive carriers identified in Baker Lake, none were HBeAg positive and 34 were anti-HBe positive (35). In addition to the unusual serological pattern, biochemical evidence of active liver disease was surprisingly rare. Indeed, no HBV carrier had elevated liver enzymes or abnormal liver function tests. Alpha-fetoprotein levels, which are elevated in 60% to 80% of patients with hepatocellular carcinoma, were within the normal range in all cases. Recently, 38 HBsAg-positive carriers from the region were further studied for evidence of viral mutations (36). A large percentage (80%) were positive for the precore mutation, the highest reported prevalence to date. and higher than in Caucasians residing in the region (0.3% and 8.5%, respectively). Of note, Larke and colleagues To date, serological evidence of HDV infection has not been detected in Aboriginals infected with HBV (40). HCV coinfection is also rare, at least in the Inuit population (41), but appears to be more common in urban Aboriginals belonging to high risk groups (8% with serological evidence of both HBV and HCV infections) (unpublished data). In the most extensive study reported to date, hepatocellular carcinoma was less common in the Canadian Inuit than in Eskimos residing in Alaska and Greenland (42). Asian population: Statistics Canada has reported the Asian population in Canada to be slightly in excess of 3,000,000 individuals, with two-thirds of those residing in the provinces of Ontario and British Columbia (33). The largest seroepidemological survey of HBV infection in Canada's Asian population was carried out by Chaudhary et al (43) in 1981, wherein 14,347 first-generation immigrants to Canada were tested for serological evidence of HBV infection. The results revealed that 11.6% were HBsAg positive and 48% had serological evidence of previous HBV exposure. As reported elsewhere, carrier rates were higher in men (14%) than in women (9%), despite a similar rate of HBV exposure (51% and 47%, respectively). Of interest, HBeAg positivity was clearly more common than was described in the general and Aboriginal carrier populations, in that 55% of Asian HBsAg carriers were HBeAg-positive and 39% anti-HBe-positive. Subtyping of the HBsAg was different from the Inuit results, with the largest percentage of Asians (42%) being serotype ayw, 35% adr and 23% adw. Follow-up in this population revealed that within five years, 22% lost HBsAg, and evidence of HBV infection appeared in 18% of those who had been previously seronegative (44). Further characterization of HBV infections in the Asian population was carried out by Wong and Minuk (45) in 1994, when 140 Chinese and Vietnamese HBsAg-positive carriers residing in Winnipeg were described. In that study, the majority (61%) were male, with a mean age of 33.5 years. As described by Chaudhary et al The only prospective study of hepatocellular carcinoma developing in Asian immigrants to Canada reported to date was that by Sherman et al (46) in 1995. Here, 1069 HBsAgpositive carriers, with a mean age of 39 years, were followed for 2340 person years. The prevalence of hepatocellular carcinoma at the outset of the study was 281/100,000, and the subsequent incidence rate was 470/100,000, in keeping with the rates reported in areas of the world where HBV is endemi

Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial

Background: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke or other cardiovascular events. We compared the selective thromboxane-prostaglandin receptor antagonist terutroban with aspirin in the prevention of cerebral and cardiovascular ischaemic events in patients with a recent non-cardioembolic cerebral ischaemic event. <p/>Methods: This randomised, double-blind, parallel-group trial was undertaken in 802 centres in 46 countries. Patients who had an ischaemic stroke in the previous 3 months or a TIA in the previous 8 days were randomly allocated with a central interactive response system to 30 mg per day terutroban or 100 mg per day aspirin. Patients and investigators were masked to treatment allocation. The primary efficacy endpoint was a composite of fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (excluding haemorrhagic death). We planned a sequential statistical analysis of non-inferiority (margin 1·05) followed by analysis of superiority. Analysis was by intention to treat. The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee. This study is registered, number ISRCTN66157730. <p/>Findings: 9562 patients were assigned to terutroban (9556 analysed) and 9558 to aspirin (9544 analysed); mean follow-up was 28·3 months (SD 7·7). The primary endpoint occurred in 1091 (11%) patients receiving terutroban and 1062 (11%) receiving aspirin (hazard ratio [HR] 1·02, 95% CI 0·94–1·12). There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints. We recorded some increase in minor bleedings with terutroban compared with aspirin (1147 [12%] vs 1045 [11%]; HR 1·11, 95% CI 1·02–1·21), but no significant differences in other safety endpoints. <p/>Interpretation: The trial did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban. In a worldwide perspective, aspirin remains the gold standard antiplatelet drug for secondary stroke prevention in view of its efficacy, tolerance, and cost

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.Journal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event