Hoow Easy is It to Get a Cure for Hepititus C in Canada
Introduction
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Chronic hepatitis C virus (HCV) infection affects more than 250,000 people living in Canada and is regarded as a significant health challenge nationwide (1), as acknowledged by recent reports and statements by the Public Health Agency of Canada and the Canadian Institutes of Health Research. Nearly half of individuals infected with HCV are unaware of their infection status. The most likely mode of transmission is through receipt of contaminated blood products or needle puncture via a variety of means (2). Approximately 15%–20% of exposed individuals (acute HCV infection) will develop chronic HCV infection, with liver disease often not evident until 20–30 years after the acute infection. Severe manifestations of end-stage liver disease include advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC; liver cancer) (3). Liver disease progression is variable and complex, affected in part by alcohol consumption, co-infections, and age at time of acute infection. Much remains to be elucidated with regard to host–virus interactions and correlates of HCV-related liver disease.
The advent of highly effective interferon-free direct-acting antiviral (DAA) treatments for HCV infection has brought great excitement, with the ability to deliver a clinical cure to upward of 95% of infected individuals (4). Many Canadian provinces are improving HCV treatment access and subsidized pharma care programs that previously limited access to these expensive drugs to only those with advanced liver fibrosis (eg, > F2 Metavir score). Currently, the Public Health Agency of Canada advises against screening for HCV among those without recognized risk factors, and this has been supported by the Canadian Task Force on Preventive Health Care. This recommendation is part of a strategy that is deemed appropriate to focus screening efforts on individuals with elevated risk factors for HCV and to focus on related resources with proven benefit (5).
The Canadian Network on Hepatitis C (CanHepC) is at the forefront of this effort to conquer HCV infection through its collaborative work on the prevention and treatment of HCV infection and a view toward understanding HCV-related outcomes for Canadians. CanHepC is composed of more than 100 researchers, trainees, knowledge users (community members, community-based organizations), policy-makers, and decision makers working in the HCV field in Canada. Along with its international partnerships, this collaborative network seeks to translate knowledge through a broad circle of influence. To do so, CanHepC is organized around six cores: basic science discovery, behavioural and epidemiology research, clinical research, health system and policy research, knowledge translation and implementation, and training and mentorship.
In this article, we review the 6th Canadian Symposium on HCV, highlighting revised approaches to prevention; new knowledge on disease pathogenesis; treatment updates; cultural pressures; challenges for Indigenous populations; and important advocacy work led by scientists, clinicians, community members, policy-makers, and front-line workers in Canada. The conference chairs Drs Lorne Tyrell and Carla Coffin oversaw the theme "Delivering a Cure for Hepatitis C Infection: What Are the Remaining Gaps?" which was intended to cover topics ranging from host–virus interactions to advances in immunity, treatment challenges, and the effects of popular culture on health care. This one-day meeting was held in Banff, Alberta, and hosted more than 264 attendees in a highly dynamic and productive symposium. Speakers included trainees, as well as national and international leaders across the four pillars of the Canadian Institutes of Health Research: biomedical research; clinical research; health services research; and social, cultural, environmental, and population health research. A summary of the sessions held within this framework is provided, including for a highly relevant panel discussion that took place at the end of the symposium on issues related to the impact of HCV on Canada's Indigenous peoples. All presentations can be viewed by accessing the CanHepC YouTube channel (https://www.youtube.com/watch?v=_Zby3OETLh8&list=PLy0zwf7_pKrWrZPMd4JvuOlfaWtec0gL5).
Biomedical Sciences
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Oral DAAs can now effectively cure more than 95% of HCV-infected individuals receiving treatment, but a small yet significant cohort of patients continue to fail therapy. The study of host–virus interactions can provide essential knowledge for the development of new therapeutics and inform vaccine design. Dr Thomas Baumert (Université de Strasbourg, Strasbourg, France) presented data evaluating the clinical potential of therapies targeting claudin-1 (CLDN1), a tight junction protein essential for HCV viral entry. Baumert's team previously reported the robust anti-HCV activity of a rat anti-CLDN1 monoclonal antibody in human liver chimeric mice, mediated via neutralization of the E2–CD81–CLDN1 associations required for HCV entry (6). They described the successful humanization of this anti-CLDN1 antibody (H3L3) without loss of function. The group found that H3L3 exhibited pan-genotypic activity against HCV entry into primary human hepatocytes obtained from 12 donors, without the evidence of escape via other claudins that has been reported in some cell lines (7). Future work will assess efficacy and toxicity in animal models in preparation for clinical trials. Because CLDN1 has been described as having roles in the pathogenicity of many other human viruses, including Dengue and West Nile virus, this work will pave the way for further clinical developments of claudin-targeted antiviral therapies (8).
Additional work from Dr Baumert's laboratory was presented by Dr Che Colpitts, who investigated the role of sodium taurocholate co-transporting polypeptide (NTCP) in HCV infection. NTCP is a solute bile acid transporter recently identified as the obligate receptor for hepatitis B and hepatitis D virus entry into hepatocytes (9,10). Dr Colpitts then demonstrated that the effect of NTCP on HCV infection may be mediated by its bile acid transport activity because blocking the latter induced expression of interferon-stimulated genes, thereby restricting viral infection (11). Identification of NTCP as a regulator of innate antiviral immune responses against HCV is an important step in understanding host–virus interactions in the human liver and highlights it as a novel antiviral target for HCV infection
HCV-induced liver disease can also serve as a model to study the molecular events leading to advanced liver diseases and HCC. The analysis of T cell populations and cytokine profiling from liver biopsies was reported in a study conducted in Dr Naglaa Shoukry's laboratory (Centre de Recherche du Centre hospitalier de l'Université de Montréal, Montreal, Quebec). Dr Shoukry demonstrated a bias toward Th17/Th9 cytokine profile in fibrotic livers with viral hepatitis. Fibrotic livers exhibited a fivefold increase in interleukin (IL)-22 production, a pro-inflammatory cytokine associated with hepato-protective properties. Further validation using transgenic mouse models of liver fibrosis identified IL-22 as a factor in advanced liver fibrosis, acting through sensitization of hepatic stellate cells to transforming growth factor-β. Previous work showed a similar effect of IL-17A on hepatic stellate cells (12). Because activation of these cells is a key event in the initiation of liver fibrosis, these findings provide insight for the design of novel treatments for advanced liver fibrosis, not only those cases induced by chronic hepatitis C infection.
To further elucidate the pathogenesis of liver disease, Dr Paul Kubes (University of Calgary, Calgary, Alberta) examined the trafficking of immune cells through virally infected livers using intravital imaging. He described a Toll-like receptor 3– or 4–induced neutrophil–platelet interaction leading to the hyperactivation of the neutrophils, which release their content to form neutrophil extracellular traps. Neutrophil extracellular traps, composed of DNA, histones and proteases, and bind and sequester virions, prevent cell-to-cell spread (13). However, they can act as double-edged swords because they can also damage bystander cells (14).
Although research on HCV is moving away from the treatment of chronically infected individuals, investigators will next have to address the remaining gaps in delivering a cure by assessing how to treat patients with advanced liver diseases and HCC. Improving the current understanding of host–virus interactions and the liver's immune response to HCV infection represents a key step in this process.
Clinical Sciences
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The clinical sciences session focused on new treatment options for difficult-to-cure patients and on the barriers to achieving HCV treatment success. Although the cure rates with new oral DAAs are now more than 95%, a significant subset of patients do not respond to treatment and remain infected with HCV (15–17). In addition, access to curative treatment poses several hurdles, including the need for widespread and early detection of HCV infection in individuals.
Dr Jean-Michel Pawlotsky (University of Paris-Est, Paris, France) presented on treatment options for three difficult-to-cure patient populations: patients with advanced liver disease, including those with decompensated cirrhosis; patients with genotype 3 (G3) infection; and patients who have failed previous DAA-containing therapy and are likely to be infected with drug-resistant virus (15–19). He emphasized that the focus should be on strategies that maximize efficacy of currently available antiviral DAA regimens, such as the inclusion of the nucleoside analogue class of DAAs, use of ribavirin, and extended duration of DAA treatment. In clinical trials for treatment of HCV G3, involving the combinations of sofosbuvir and daclatasvir, the inclusion of ribavirin was shown to improve the outcome in patients with advanced liver disease, but a prolonged duration of therapy could have a lower impact on increasing cure rates or treatment efficacy (20–22). Similar results were obtained with sofosbuvir–velpatasvir–ribavirin in the treatment of patients with HCV G3 and decompensated cirrhosis (~85% with ribavirin vs 50% without) (23,24). Pawlotsky also noted that the recently approved pan-genotypic regimen of glecaprevir/pibrentasvir and sofosbuvir–velpatasvir–voxilaprevir showed promise in curing cirrhotic G3 patients without the need for ribavirin (25,26). This and other next-generation DAA regimens may allow G3 patients to be removed from the difficult-to-cure category.
Discussing treatment of patients with advanced liver disease, Dr Pawlotsky reiterated the recommendations of the European Association for the Study of the Liver, stating that patients with a model for end-stage liver disease (MELD) score of less than 18–20 are likely to benefit from HCV antiviral therapy before liver transplantation, whereas those with higher MELD scores may be better served by deferring treatment until after liver transplantation (27,28). With regard to retreating treatment-experienced patients, Dr Pawlotsky presented analyses demonstrating that those with a history of NS5A inhibitor exposure are the most difficult to salvage (29). Treatment-experienced patients with no previous exposure to NS5A can be successfully treated with a combination of DAA regimens, assuming that characteristics of prior regimens are considered. However, given limited efficacy data, patients should be carefully monitored if salvage therapy is pursued (23,30). Finally, another option is to defer treatment until next-generation DAA medications become available.
Along with improving treatment outcomes for difficult-to-cure patients, the identification of patients with chronic hepatitis C and prioritizing certain populations for treatment through a coordinated, effective nationwide strategy are key to reducing HCV incidence and prevalence in Canada. Current epidemiological studies have inherent limitations in predicting the true burden of HCV in Canada (31). These issues were highlighted in a presentation by Dr Morris Sherman (University Health Network, Toronto, Ontario, chairman of the Canadian Liver Foundation). He noted that several populations have a relatively high incidence of HCV: immigrants, individuals born between 1945 and 1975, those with a current or past history of incarceration, intravenous drug users, and other groups with lifestyle risks (32–34). He emphasized that increased screening of these individuals will allow for increased identification of HCV-infected individuals and will facilitate engagement in HCV care. Once these populations are identified, modelling suggests that, assuming more than 10,000 patients are treated annually, significant control of HCV can be achieved within two decades. Successful HCV management programs in Egypt and Australia were cited as models that may inform efforts in Canada (35,36).
To facilitate rapid and widespread HCV diagnosis, development of simpler and more accessible diagnostic tools is essential. Dr Jason Grebely (The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia) presented on a study that used a novel detection technique: the Xpert® HCV Viral Load point-of-care test. This study found that capillary whole-blood samples collected by finger-stick yielded viable and rapid (108 min) virus detection, rather than just confirming exposure as with other serology-based point-of-care tests. The rapid turnover time of this test, and its preference by tested individuals, could be highly beneficial in improving HCV detection and diagnosis (37).
This session highlighted that despite significant advances in the HCV treatment landscape in the DAA era, future strategies to ultimately achieve eradication of this global health care challenge need to be considered.
Health Services
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Dr Tim Caulfield (University of Alberta, Edmonton, Alberta) presented an enlightened perspective on how media, pop culture, and celebrities are able to create and effectively disseminate messages that are not supported by scientific evidence (38). These messages, and their messengers, are further emboldened when they are supported by populist politicians. This presentation also focused on vaccine hesitancy and how misinformation based on popular beliefs delivered by celebrities and advocates counterbalances scientific evidence, effectively creating a war on science, which effectively justifies the creation of pseudoscientific ideas that are easily disseminated by mainstream and social media.
Dr Mark Tyndall (BC Centre for Disease Control, Vancouver, British Columbia) discussed HCV surveillance and how it should be used to understand transmission risk factors and outcomes including cirrhosis, HCC, mortality, and costs; monitor intervention effectiveness including assessing the cascade of prevention and care and the efficacy of various programs, including opioid substitution therapy; measure the impact of treatment-based cures on outcomes such as cirrhosis and mortality and track onward transmission; and be able to determine that programs are equitable by showing that disparities and vulnerabilities that affect acquisition risk, access to services, and overall outcomes can be mitigated. Dr Tyndall presented data from the British Columbia Hepatitis Testers Cohort, derived from 1.5 million HCV-tested individuals, updating their recent report (39). These data highlight the disproportionate mortality among those infected with HCV and the existence of parallel epidemics, with baby boomers accounting for the majority of infections and younger people who inject drugs (PWID) at highest risk of illicit drug use, mental illness, and HIV co-infection. Finally, he highlighted the dramatic increase in overdose deaths since 2016 in British Columbia and across Canada. The study concluded that although protecting PWID from HCV is important, competing risks that result in PWID dying from preventable overdoses and other acquisition risks need to be addressed. Dr Tyndall emphasized that the war on drugs has failed and that it is time to shift the prevention paradigm to a suite of services able to meet the needs of PWID and other vulnerable populations.
Mary Guyton (Toronto Community Hep C Program, Toronto, Ontario) presented a nursing perspective on HCV infection using limited real-world cohort data from a community program that consists of a partnership between three community health centres that provide multidisciplinary and integrated case management, including mental health counselling. Preliminary data demonstrate that factors independently associated with poorer adherence include moderate to heavy alcohol use and treatment duration. The Toronto Community Hep C Program's community-based model of HCV treatment supported treatment of PWID, and 85% achieved sustained virologic response rates.
In the final talk of this session, Dr Lisa Barrett (Dalhousie University, Halifax, Nova Scotia) presented on a provincial HCV elimination strategy in Nova Scotia. Key elements of Nova Scotia's programmatic approach involved engaging health outcome specialists, developing a provincial registry, engaging providers and communities in designing treatment, and following up with a focus on using partnerships to deliver treatment under an assessment and research framework. All HCV patients are automatically referred to the provincial program, triage and work-up are centralized, referrals for ancillary services are provided when necessary, and the timing of treatment is planned. The package includes comprehensive education and evaluation. Programmatic approaches to HCV prevention, care, and treatment are critical to achieve the World Health Organization's 2030 HCV elimination target. However, Dr Barrett also noted that whether Nova Scotia's approach to HCV care and treatment can be generalized to the rest of Canada is unknown.
Social, Cultural, Environmental, and Population Health Research
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Dr Evan Wood (BC Centre for Excellence in HIV/AIDS and University of British Columbia, Vancouver, British Columbia) discussed barriers to integrating evidence-based public health and addiction treatment interventions. Despite evidence supporting harm reduction strategies to reduce injecting risk behaviours (40,41), opposing groups have continuously compromised efforts to expand implementation and access (42,43). Dr Wood highlighted that although prohibition of alcohol led to corruption and violence and failed to prevent health issues, prohibition is still applied to illicit substances. Consequently, expenditures for enforcement-based drug supply reduction efforts have continuously increased, whereas illicit drug prices have gone down and purity has increased (44). In British Columbia, the outbreak of fatal overdoses has been associated with the emergence of fentanyl and carfentanil, leading to the British Columbia public health office declaring a public health emergency for the first time in Canadian history (45). Decriminalization and regulation of illicit substances has the potential to improve public health outcomes (45). However, this is unlikely to occur in Canada. Given that coverage for addiction treatment remains low (46), improved access to and quality of evidence-based addiction services should be prioritized. For instance, addiction services should be better integrated into medical education, offered by primary care providers, and more adequately publicly funded (47,48). Improved access to evidence-based public health and addiction treatment interventions will be crucial to provide a stronger foundation to enhance HCV care for PWID.
In accord with Dr Wood, Dr Holly Hagan (New York University, New York, New York, USA) discussed interventions to prevent HCV infection, including needle and syringe programs (NSPs). Combined opioid substitution treatment and high NSP coverage (often defined as receiving as many sterile syringes as the number of injections) can reduce HCV incidence by as much as 80% (40,49–55). However, there is little evidence that NSPs alone can protect against HCV infection, in part because of the transmissibility of HCV through injecting equipment other than syringes and the fact that, unlike HIV, HCV has the capacity to remain stable on different injecting equipment and surfaces for days to weeks and to survive under temperatures higher than those required for drug preparation (56–59). In one meta-analysis, the pooled risk ratios of the association of syringe sharing and other equipment sharing with HCV infection among PWID were similar (range of odds ratios 1.9–2.6), yet the proportion of HCV infections attributable to syringe sharing was lowest (25%) compared with sharing drug cookers (43%), cotton (42%), and rinse water (31%) (60). Dr Hagan stated that further research should examine the effect of NSPs on HCV infection in relation to syringe and other injecting equipment on the basis of evidence that coverage of injecting equipment is often poorer than that of needles and syringes. She argued in favour of future studies to examine the effect of enhanced harm reduction strategies.
For most PWID, injecting trajectories have been characterized by transitions in and out of injecting (61,62). Emmanuel Fortier (Centre de Recherche du Centre hospitalier de l'Université de Montréal, Montreal, Quebec) shared an analysis of the Hepatitis Cohort of PWID in Montreal, delineating the association between HCV acquisition and engagement in short injecting cessation episodes (unpublished). Short injecting cessation episodes were common and were associated with a reduced HCV risk compared with continuous injecting. Although PWID experiencing short cessations are potentially more aware of or concerned about injecting harm, it is also possible that such episodes trigger safer behaviours by improving socioeconomic conditions that would otherwise compromise safe injecting. Mr Fortier concluded by arguing that relapse to injecting should not be approached as a failure by health care providers given the demonstrated benefits of injecting cessation episodes.
Dr Mamata Pandey (Regina Qu'Appelle Health Region, Regina, Saskatchewan) highlighted some barriers to HCV care for people residing in the rural and remote Big River First Nations community in Saskatchewan, using qualitative data from individual and group interviews with HCV-infected individuals, elders, administrative staff members, health care providers, and community representatives. Obstacles included distance from tertiary health care centres where HCV care is offered, lack of adequate transportation, and lack of child care. Moreover, racism, lack of cultural support, and issues with confidentiality were raised as important barriers to treatment adherence. This session concluded with a suggestion that culturally appropriate standardised HCV care could be brought to First Nations communities through mobile clinics and could be offered by nursing staff already providing services for the community, including timely screening, counselling at diagnosis, and directly observed therapy to ensure adherence.
Panel Discussion on Hepatitis C in Indigenous People
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The Indigenous health care panel consisted of Dr Alexandra King (Nipissing First Nation; internist with an interest in HCV), Alika Lafontaine (Cree and Anishinaabe; anesthesiologist), Carrielynn Lund (Métis; community-based research and interventions for Indigenous peoples), Norma Rabbitskin (Cree Big River First Nation; senior health nurse for the Sturgeon Lake First Nation), and Renée Masching (Six Nations of Grand River; director of research and policy for the Canadian Aboriginal AIDS Network). Highlighting that the conference was held on Treaty 7 territory and building on HCV health care issues among First Nations Territories, the panel discussed the implementation of research programs beneficial to both communities. Programs that work with Indigenous peoples in a holistic manner have continued to develop and achieve success; however, barriers to effective diagnosis and treatment continue to involve stigma. Care continua that support and ensure equitable treatment of all are still needed. This Indigenous panel discussion brought forward understandings of health and wellness and research approaches that respect community ways of knowing and doing as a necessary component of working with Indigenous people and their communities to achieve better health care in the context of HCV. In clinical practice, profiling serves a vital role in minimizing the time elapsed between consultation and a working diagnosis. However, profiling can be tainted by bias, which leads to poor diagnosis and treatment. Many colonial words used to describe Indigenous peoples continue to have negative connotations. Health care practitioners must act on the duty to treat patients equitably regardless of who they are, where they live, or structural issues such as different health systems (eg, provincial vs federal bodies). Increased cultural competency and cultural safety provide an opportunity for practitioners to examine how personal bias may play a role in creating health disparities. Physicians, who are instrumental gatekeepers to the health care system, can contribute to or alleviate the generated health inequities experienced by Indigenous people.
Many historical health research projects have left communities feeling abandoned or used. The new models, which are being supported by Indigenous communities, are opportunities for the communities themselves to design, pilot, and evaluate interventions that are delivered with appropriate cultural safety. Holistic programs recognize that the active and meaningful participation of the community is integral to every step of the research, development, implementation, and evaluation processes. A dialogue that positions Western academics and traditional leaders as equals allows the development of culturally safe methods and practices that may be championed and respected in the community. The precise methods and values of working "in a good way" are as diverse as the individuals and communities participating in hepatitis C research and treatment; however, a few commonalities exist.
Recognition of the land and its traditional guardians is an important step for both the visitors and the traditional inhabitants. Engagement with and participation in diverse ceremonies provide opportunities for newcomers to gain improved cultural understanding and for the community to share its collective soul. To work together in a positive way, project leaders (both academic and community) must not only seek to understand individual and systemic values, but also to reach a consensus as to the project goals.
The responsible development and administration of any health care model requires investigation of previous models as well as the relevant strengths and weaknesses present in the model. The complexity of research should never be an accepted obstacle to community participation. Previous efforts have demonstrated that collaborative efforts are able to bridge gaps to find the words, metaphors, and stories that all can understand. There remain several knowledge gaps with regard to various aspects of research by and with Indigenous people, including data collection and governance, ethics, appropriate methodologies, and ensuring equity in all treatment strategies. Efforts must continue to identify upstream interventions that can be contextualized and enhanced as required.
Outcomes of the 6th Canadian Symposium on Hcv
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To address its theme, "Delivering a Cure for Hepatitis C Infection: What Are the Remaining Gaps?" the 6th Canadian Symposium on HCV, organized by the CanHepC, highlighted exciting HCV-related research from across Canada and around the world. The meeting hosted 264 attendees, including scientists, clinicians, affected community members, policy-makers, front-line workers, and trainees. Meeting topics covered subjects such as host–virus interactions, cutting-edge imaging technologies, DAA treatment challenges, and HCV-related social issues, including perspectives on HCV care in Indigenous communities. This meeting of minds facilitated knowledge exchange among a unique array of experts and developing scientists, and affirmed the concerted effort being made in Canada and beyond to address remaining challenges in the detection, treatment, and control of HCV infection.
Acknowledgements
The authors acknowledge the CanHepC mentors, knowledge users, and members of the administrative and extended CanHepC team: CanHepC investigators: Michel Alary (Centre de recherche du CHU de Québec), Dan Allman (University of Toronto), Fernando Alverez (CHU Sainte-Justine), Louise Balfour (The Ottawa Hospital), Lisa Barrett (Nova Scotia Health Authority/Dalhousie University), Marc Bilodeau (Université de Montréal), Julie Bruneau (co-principal investigator, Université de Montréal), Carla Coffin (University of Calgary), Brian Conway (Vancouver Infectious Diseases Centre), Curtis Cooper (University of Ottawa), Angela Crawley (The Ottawa Hospital Research Institute), Jordan Feld (co-principal investigator, University Health Network), Benedickt Fischer (Centre for Addiction and Mental Health), Jennifer Flemming (Queen's University), Mattias Götte (University of Alberta), Jason Grebely (University of New South Wales Australia), Christina Greenway (McGill University), Kanna Hayashi (University of British Columbia), Michael Houghton (University of Alberta), Anita Howe (Centre For Excellence in HIV/AIDS), Naveed Safar Janjua (University of British Columbia), Didier Jutras-Aswad (Université de Montréal), Thomas Kerr (University of British Columbia), Alexandra King (Simon Fraser University), Marina Klein (McGill University), Norman Kneteman (University of Alberta), Murray Krahn (University of Toronto), Mel Krajden (co-principal investigator, University of British Columbia), Jeff Kwong (University of Toronto), Alain Lamarre (Institut National de las Recherche Scientifique–Institut Armand-Frappier), Daniel Lamarre (Université de Montréal), Samuel Lee (University of Calgary), Seung-Hwan Lee (University of Ottawa), Simon Ling (University of Toronto), Qiang Liu (University of Saskatchewan), Valérie Martel-Laferrière (Centre de recherche du CHUM), Andrew Mason (University of Alberta), Ian McGilvray (University of Toronto), Sonya MacParland (University of Toronto), Thomas Michalak (Memorial University), M-J Milloy (University of British Columbia), Gerry Mugford (Memorial University), Mario Ostrowski (University of Toronto), John Pezacki (University of Ottawa), Christopher Richarson (co-principal investigator, Dalhousie University), Eve Roberts (University of Toronto), Élise Roy (Université de Sherbrooke), Rod Russell (Memorial University), Selena Sagan (McGill University), Beate Sander (University of Toronto), Luis Schang (University of Alberta), Dena Schanzer (Public Health Agency of Canada), Giada Sebastiani (McGill University), Nazia Selzner (Toronto General Hospital), Morris Sherman (University Health Network), Naglaa Shoukry (nominated principal investigator, Université de Montréal), Daniel Smyth (Dalhousie University), Hugo Soudeyns (Université de Montréal), Rosie Thein (University of Toronto), Mark Tyndall (University of British Columbia), Lorne Tyrrell (University of Alberta), Marie-Louise Vachon (Université Laval), Joyce Wilson (University of Saskatchewan), Wendy Wobeser (Queen's University), William Wong (University of Toronto), and Eric Yoshida (University of British Columbia). CanHepC Knowledge Users: Anis Aslam (University of British Columbia), Melisa Dickie (CATIE), Gary Fagan (Canadian Liver Foundation) Janet Hatcher Roberts (Canadian Society for International Health), Bonnie Henry (Office of the Provincial Health Officer, British Columbia), Carrielynn Lund (Canadian Aboriginal AIDS Network), Daryl Luster (Pacific HepC Network), Renee Masching (Canadian Aboriginal AIDS Network), Denise Thomas (CAHN), and Claire Wartelle (Centre de recherche du CHUM).
Conceptualization, SK, AMC; Writing — Original Draft, SK, AB, DD, EF, MK, AK, JG, SMS, CLC, AMC; Writing — Review and Editing, SK, AMC; Visualization, SK; Supervision, AMC.
The Canadian Network on Hepatitis C (CanHepC) is funded by a joint initiative of the Canadian Institutes of Health Research (CIHR) (NHC-142832) and the Public Health Agency of Canada (PHAC) and in partnership with the Canadian Liver Foundation. In addition, CanHepC has received funding for the training program from Abbvie, Bristol-Myers Squibb, Gilead, and Merck. The 6th Canadian Symposium on HCV was supported by the CIHR (CIHR PCS-144012). Additional funding was provided by Gilead, Abbvie, Merck, Bristol-Myers Squibb, Pendopharm, Réseau Sida, the Canadian Association for the Study of the Liver, and Alberta Innovates Health Solutions. The Kirby Institute is funded by the Australian Department of Health and Aging. The views expressed in this publication do not necessarily represent the position of the Australian government. The views expressed in this publication are those of the authors and do not reflect the position of the CIHR, PHAC, or other sources of funding. Sarwat Khan is a two-time recipient of the CanHepC Summer Student Award and currently holds an Ontario Graduate Scholarship.
Dr Cooper reports speaker fees from Gilead, Merck, and Abbvie. Dr Grebely reports grants from Abbvie and grants and personal fees from Gilead, Merck, and Cepheid outside the submitted work. Dr King reports speaker fees from AbbVie, Merck, BMS, and ViiV and speaker fees and a research grant from Gilead. Dr Krajden reports grants from Roche, grants from Hologic, grants from Siemens, outside the submitted work.
This article has been peer reviewed.
References
Section:
| 1. | Joy JB , McCloskey RM , Nguyen T , et al. The spread of hepatitis C virus genotype 1a in North America: a retrospective phylogenetic study. Lancet Infect Dis. 2016;16:698–702. https://doi.org/10.1016/S1473-3099(16)00124-9. Medline:27039040 Google Scholar |
| 2. | van Buuren N , Fradette L , Grebely J , et al. The 5th Canadian Symposium on Hepatitis C Virus: we are not done yet—remaining challenges in hepatitis C. Can J Gastroenterol Hepatol. 2016;2016:7603526. https://doi.org/10.1155/2016/7603526. Medline:27843889 Google Scholar |
| 3. | Westbrook RH , Dusheiko G . Natural history of hepatitis C. J Hepatol. 2014;61(1 Suppl):S58–68. https://doi.org/10.1016/j.jhep.2014.07.012. Medline:25443346 Google Scholar |
| 4. | Diagnosis of acute and chronic hepatitis C. In: EASL Recommendations of Treatment of Hepatitis C. Geneva: European Association for the Study of the Liver; 2015. p. 4. Google Scholar |
| 5. | Grad R , Thombs BD , Tonelli M , et al; Canadian Task Force on Preventive Health Care. Recommendations on hepatitis C screening for adults. CMAJ. 2017;189:E594–604. https://doi.org/10.1503/cmaj.161521. Medline:28438952 Google Scholar |
| 6. | Krieger SE , Zeisel MB , Davis C , et al. Inhibition of hepatitis C virus infection by anti-claudin-1 antibodies is mediated by neutralization of E2-CD81-claudin-1 associations. Hepatology. 2010;51:1144–57. https://doi.org/10.1002/hep.23445. Medline:20069648 Google Scholar |
| 7. | Colpitts CC , Tawar RG , Mailly L , et al. Humanisation of a claudin-1-specific monoclonal antibody for clinical prevention and cure of HCV infection without escape. Gut. 2017;67:736–45. https://doi.org/10.1136/gutjnl-2016-312577. Medline:28360099 Google Scholar |
| 8. | Colpitts CC , Baumert TF . Claudins in viral infection: from entry to spread. Pflugers Arch. 2017;469(1):27–34. https://doi.org/10.1007/s00424-016-1908-4. Medline:27885488 Google Scholar |
| 9. | Ni Y , Lempp FA , Mehrle S , et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology. 2014;146:1070–83. https://doi.org/10.1053/j.gastro.2013.12.024. Medline:24361467 Google Scholar |
| 10. | Yan H , Zhong G , Xu G , et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife. 2012;1:e00049. https://doi.org/10.7554/eLife.00049. Medline:23150796 Google Scholar |
| 11. | Verrier ER , Colpitts CC , Bach C , et al. Solute carrier NTCP regulates innate antiviral immune responses targeting hepatitis C virus infection of hepatocytes. Cell Reports. 2016;17:1357–68. https://doi.org/10.1016/j.celrep.2016.09.084. Medline:27783949 Google Scholar |
| 12. | Fabre T , Kared H , Friedman SL , et al. IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK-dependent manner. J Immunol. 2014;193:3925–33. https://doi.org/10.4049/jimmunol.1400861. Medline:25210118 Google Scholar |
| 13. | Saitoh T , Komano J , Saitoh Y , et al. Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. Cell Host Microbe. 2012;12:109–16. https://doi.org/10.1016/j.chom.2012.05.015. Medline:22817992 Google Scholar |
| 14. | Kolaczkowska E , Jenne CN , Surewaard BG , et al. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nat Commun. 2015;6(1):6673. https://doi.org/10.1038/ncomms7673. Medline:25809117 Google Scholar |
| 15. | Myers RP , Shah H , Burak KW , et al. An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol. 2015;29:19–34. https://doi.org/10.1155/2015/692408. Medline:25585348 Google Scholar |
| 16. | Moradpour D , Grakoui A , Manns MP . Future landscape of hepatitis C research—Basic, translational and clinical perspectives. J Hepatol. 2016;65(1 Suppl):S143–55. https://doi.org/10.1016/j.jhep.2016.07.026. Medline:27641984 Google Scholar |
| 17. | J.-M. Pawlotsky, J.J. Feld, S. Zeuzem, and J.H. Hoofnagle, "From non-A, non-B hepatitis to hepatitis C virus cure." J Hepatol 2015; 62(1 Suppl):S87–99. https://doi.org/10.1016/j.jhep.2015.02.006. Google Scholar |
| 18. | Khan ST , McGuinty M , Corsi DJ , et al. Liver enzyme normalization predicts success of hepatitis C oral direct-acting antiviral treatment. Clin Invest Med. 2017;40:E73–80. https://doi.org/10.25011/cim.v40i2.28198. Medline:28447580 Google Scholar |
| 19. | Afdhal N , Reddy KR , Nelson DR , et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483–93. https://doi.org/10.1056/NEJMoa1316366. Medline:24725238 Google Scholar |
| 20. | Nelson DR , Cooper JN , Lalezari JP , et al; ALLY-3 Study Team. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61:1127–35. https://doi.org/10.1002/hep.27726. Medline:25614962 Google Scholar |
| 21. | Leroy V , Angus P , Bronowicki J-P , et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: a randomized phase III study (ALLY-3+). Hepatology. 2016;63(5):1430–41. https://doi.org/10.1002/hep.28473. Medline:26822022 Google Scholar |
| 22. | Foster GR , Irving WL , Cheung MCM , et al; HCV Research, UK. Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol. 2016;64:1224–31. https://doi.org/10.1016/j.jhep.2016.01.029. Medline:26829205 Google Scholar |
| 23. | Curry MP , O'Leary JG , Bzowej N , et al; ASTRAL-4 Investigators. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373:2618–28. https://doi.org/10.1056/NEJMoa1512614. Medline:26569658 Google Scholar |
| 24. | Foster GR , Afdhal N , Roberts SK , et al; ASTRAL-2 Investigators, ASTRAL-3 Investigators. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373:2608–17. https://doi.org/10.1056/NEJMoa1512612. Medline:26575258 Google Scholar |
| 25. | Kwo PY , Poordad F , Asatryan A , et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol. 2017;67:263–71. https://doi.org/10.1016/j.jhep.2017.03.039. Medline:28412293 Google Scholar |
| 26. | Jacobson IM , Lawitz E , Gane EJ , et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology. 2017;153:113–22. https://doi.org/10.1053/j.gastro.2017.03.047. Medline:28390869 Google Scholar |
| 27. | European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2016. J Hepatol. 2017;66:153–94. https://doi.org/10.1016/j.jhep.2016.09.001. Medline:27667367 Google Scholar |
| 28. | Chhatwal J , Samur S , Kues B , et al. Optimal timing of hepatitis C treatment for patients on the liver transplant waiting list. Hepatology. 2017;65:777–88. https://doi.org/10.1002/hep.28926. Medline:27906468 Google Scholar |
| 29. | Pawlotsky J-M . Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens. Gastroenterology. 2016;151:70–86. https://doi.org/10.1053/j.gastro.2016.04.003. Medline:27080301 Google Scholar |
| 30. | Zeuzem S , Mizokami M , Pianko S , et al. NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: prevalence and effect on treatment outcome. J Hepatol. 2017;66:910–8. https://doi.org/10.1016/j.jhep.2017.01.007. Medline:28108232 Google Scholar |
| 31. | M . Rotermann, Langlois K ., Andonov A ., Trubnikov M ., "Seroprevalence of hepatitis B and C virus infections: results from the 2007 to 2009 and 2009 to 2011 Canadian Health Measures Survey." Health Rep. 2013;24(11):3–13 Google Scholar |
| 32. | Greenaway C , Thu Ma A , Kloda LA , et al. The seroprevalence of hepatitis C antibodies in immigrants and refugees from intermediate and high endemic countries: a systematic review and meta-analysis. PLoS One. 2015;10(11):e0141715. https://doi.org/10.1371/journal.pone.0141715. Medline:26558905 Google Scholar |
| 33. | Kouyoumdjian FG , McIsaac KE . Persons in correctional facilities in Canada: a key population for hepatitis C prevention and control. Can J Public Health. 2015;106(6):e454–6. https://doi.org/10.17269/cjph.106.5132. Medline:26680439 Google Scholar |
| 34. | Trubnikov M , Yan P , Njihia J , et al. Identifying and describing a cohort effect in the national database of reported cases of hepatitis C virus infection in Canada (1991-2010): an age-period-cohort analysis. CMAJ Open. 2014;2:E281–7. https://doi.org/10.9778/cmajo.20140041. Medline:25485255 Google Scholar |
| 35. | El-Akel W , El-Sayed MH , El Kassas M , et al. National treatment programme of hepatitis C in Egypt: hepatitis C virus model of care. J Viral Hepat. 2017;24:262–7. https://doi.org/10.1111/jvh.12668. Medline:28145032 Google Scholar |
| 36. | "Initiations of new treatment." Monitoring Hepatitis C Treatment Uptake in Australia 2017;(7). Google Scholar |
| 37. | Grebely J , Lamoury FMJ , Hajarizadeh B , et al; LiveRLife Study Group. Evaluation of the Xpert HCV Viral Load point-of-care assay from venepuncture-collected and finger-stick capillary whole-blood samples: a cohort study. Lancet Gastroenterol Hepatol. 2017;2:514–20. https://doi.org/10.1016/S2468-1253(17)30075-4. Medline:28442271 Google Scholar |
| 38. | Caulfield TA . 2015. Is Gwyneth Paltrow Wrong about Everything? How the Famous Sell Us Elixirs of Health, Beauty and Happiness. Boston: Beacon Press. Google Scholar |
| 39. | Janjua NZ , Kuo M , Chong M , et al. Assessing hepatitis C burden and treatment effectiveness through the British Columbia Hepatitis Testers Cohort (BC-HTC): design and characteristics of linked and unlinked participants. PLoS One. 2016;11(3):e0150176. https://doi.org/10.1371/journal.pone.0150176. Medline:26954020 Google Scholar |
| 40. | MacArthur GJ , van Velzen E , Palmateer N , et al. Interventions to prevent HIV and hepatitis C in people who inject drugs: a review of reviews to assess evidence of effectiveness. Int J Drug Policy. 2014;25:34–52. https://doi.org/10.1016/j.drugpo.2013.07.001. Medline:23973009 Google Scholar |
| 41. | Kerr T , Tyndall M , Li K , et al. Safer injection facility use and syringe sharing in injection drug users. Lancet. 2005;366:316–8. https://doi.org/10.1016/S0140-6736(05)66475-6. Medline:16039335 Google Scholar |
| 42. | Hathaway AD , Tousaw KI . Harm reduction headway and continuing resistance: insights from safe injection in the city of Vancouver. Int J Drug Policy. 2008;19:11–6. https://doi.org/10.1016/j.drugpo.2007.11.006. Medline:18164610 Google Scholar |
| 43. | Heller D , Paone D . Access to sterile syringes for injecting drug users in New York City: politics and perception (1984-2010). Subst Use Misuse. 2011;46:140–9. https://doi.org/10.3109/10826084.2011.523319. Medline:21303234 Google Scholar |
| 44. | Werb D , Kerr T , Nosyk B , et al. The temporal relationship between drug supply indicators: an audit of international government surveillance systems. BMJ Open. 2013;3(9):e003077. https://doi.org/10.1136/bmjopen-2013-003077. Medline:24080093 Google Scholar |
| 45. | Rolles S , Murkin G . How to Regulate Cannabis: A Practical Guide. Bristol, UK: Transform Drug Policy Foundation; 2013. Google Scholar |
| 46. | Substance Abuse and Mental Health Services Administration. 2016. Behavioral Health Barometer: United States, 2015. HHS Publication No. SMA-16-Baro-2015. Rockville, MD: Substance Abuse and Mental Health Services Administration. Google Scholar |
| 47. | O'Connor PG , Nyquist JG , McLellan AT . Integrating addiction medicine into graduate medical education in primary care: the time has come. Ann Intern Med. 2011;154:56–9. https://doi.org/10.7326/0003-4819-154-1-201101040-00008. Medline:21200039 Google Scholar |
| 48. | Compton WM , Blanco C , Wargo EM . Integrating addiction services into general medicine. JAMA. 2015;314:2401–2. https://doi.org/10.1001/jama.2015.12741. Medline:26647261 Google Scholar |
| 49. | Hagan H , Pouget ER , Des Jarlais DC . A systematic review and meta-analysis of interventions to prevent hepatitis C virus infection in people who inject drugs. J Infect Dis. 2011;204:74–83. https://doi.org/10.1093/infdis/jir196. Medline:21628661 Google Scholar |
| 50. | Turner KM , Hutchinson S , Vickerman P , et al. The impact of needle and syringe provision and opiate substitution therapy on the incidence of hepatitis C virus in injecting drug users: pooling of UK evidence. Addiction. 2011;106:1978–88. https://doi.org/10.1111/j.1360-0443.2011.03515.x. Medline:21615585 Google Scholar |
| 51. | van den Berg CH , Smit C , Bakker M , et al. Major decline of hepatitis C virus incidence rate over two decades in a cohort of drug users. Eur J Epidemiol. 2007;22:183–93. https://doi.org/10.1007/s10654-006-9089-7. Medline:17334821 Google Scholar |
| 52. | Platt L , Reed J , Minozzi S , et al. Effectiveness of needle/syringe programmes and opiate substitution therapy in preventing HCV transmission among people who inject drugs. Cochrane Database Syst Rev. 2016;2016(1):1. Medline:27127417 Google Scholar |
| 53. | Nolan S , Dias Lima V , Fairbairn N , et al. The impact of methadone maintenance therapy on hepatitis C incidence among illicit drug users. Addiction. 2014;109:2053–9. https://doi.org/10.1111/add.12682. Medline:25041346 Google Scholar |
| 54. | White B , Dore GJ , Lloyd AR , et al. Opioid substitution therapy protects against hepatitis C virus acquisition in people who inject drugs: the HITS-c study. Med J Aust. 2014;201:326–9. https://doi.org/10.5694/mja13.00153. Medline:25222455 Google Scholar |
| 55. | Tsui JI , Evans JL , Lum PJ , et al. Association of opioid agonist therapy with lower incidence of hepatitis C virus infection in young adult injection drug users. JAMA Intern Med. 2014;174:1974–81. https://doi.org/10.1001/jamainternmed.2014.5416. Medline:25347412 Google Scholar |
| 56. | Doerrbecker J , Friesland M , Ciesek S , et al. Inactivation and survival of hepatitis C virus on inanimate surfaces. J Infect Dis. 2011;204:1830–8. https://doi.org/10.1093/infdis/jir535. Medline:22013220 Google Scholar |
| 57. | Paintsil E , He H , Peters C , et al. Survival of hepatitis C virus in syringes: implication for transmission among injection drug users. J Infect Dis. 2010;202:984–90. https://doi.org/10.1086/656212. Medline:20726768 Google Scholar |
| 58. | Clatts MC , Heimer R , Abdala N , et al. HIV-1 transmission in injection paraphernalia: heating drug solutions may inactivate HIV-1. J Acquir Immune Defic Syndr. 1999;22:194–9. https://doi.org/10.1097/00042560-199910010-00013. Medline:10843535 Google Scholar |
| 59. | Thibault V , Bara JL , Nefau T , et al. Hepatitis C transmission in injection drug users: could swabs be the main culprit? J Infect Dis. 2011;204:1839–42. https://doi.org/10.1093/infdis/jir650. Medline:22013222 Google Scholar |
| 60. | Pouget ER , Hagan H , Des Jarlais DC . Meta-analysis of hepatitis C seroconversion in relation to shared syringes and drug preparation equipment. Addiction. 2012;107:1057–65. https://doi.org/10.1111/j.1360-0443.2011.03765.x. Medline:22168373 Google Scholar |
| 61. | Xia Y , Seaman S , Hickman M , et al. Factors affecting repeated cessations of injecting drug use and relapses during the entire injecting career among the Edinburgh Addiction Cohort. Drug Alcohol Depend. 2015;151:76–83. https://doi.org/10.1016/j.drugalcdep.2015.03.005. Medline:25869544 Google Scholar |
| 62. | Genberg BL , Gange SJ , Go VF , et al. Trajectories of injection drug use over 20 years (1988-2008) in Baltimore, Maryland. Am J Epidemiol. 2011;173:829–36. https://doi.org/10.1093/aje/kwq441. Medline:21320867 Google Scholar |
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