Prescribing trends in direct-acting antivirals for the treatment of hepatitis C in Ontario, Canada.

Background: Direct-acting antivirals (DAA) offer an opportunity to cure hepatitis C. Reimbursement for DAAs has changed on two occasions since their inclusion on the Ontario public formulary. Whether these changes have appreciably modified prescribing patterns and increased access to DAAs is unknown. Methods: We conducted a repeated cross-sectional study of DAA reimbursement by the Ontario Public Drug Programs from January 1, 2012, to December 31, 2018, to summarize the use of DAAs in Ontario and describe changes in DAA prescribing physician specialties over this period. We measured the total number of users quarterly. Results are reported overall and by prescriber type. Results: A total of 27,116 individuals received a publicly funded prescription for a DAA from the first quarter (Q1) of 2012 to the fourth quarter (Q4) of 2018. Nearly two-thirds (n = 17,813; 65.7%) of all DAAs were prescribed by gastroenterologists, hepatologists, or infectious disease specialists. Use of DAAs over time appears to have had three major phases in uptake: (1) the introduction of DAA treatments on the Ontario public drug formulary as a prior authorization benefit in Q1 2015, (2) expanded listing of all DAAs as limited-use products on the formulary in Q1 2017, and (3) the introduction of newer DAAs in Q2 2018. Conclusions: Changes in listing of these agents had a direct impact on the use of DAAs overall. Generally, broader listing expanded access but did not appear to shift utilization patterns to primary care prescribers. Further understanding of who is not receiving treatment is needed.

Peer outreach point-of-care testing as a bridge to hepatitis C care for people who inject drugs in Toronto, Canada.

BACKGROUND: People who inject drugs have high rates of hepatitis C (HCV) and yet many remain undiagnosed and untreated. HCV treatment guidelines and elimination strategies recommend task-shifting to expand where, and by whom, HCV testing and care is delivered. METHODS: A randomized controlled trial design was used to evaluate if point-of-care (POC) HCV antibody testing by peer outreach workers outside of health and social service spaces would improve engagement in HCV care. People with a lifetime history of injection drug use without prior knowledge of HCV antibody status were randomized to receive HCV outreach plus either POC or referral to community-based HCV program for testing as usual. The study was co-designed by people with lived experience of HCV. RESULTS: 920 people were approached to participate over 14 weeks. After refusals, withdrawals and removal of duplicates, there were 380 study participants. Outreach took place primarily in public spaces (66%) such as parks, coffee shops and apartment lobbies. Participants reported very high rates of poverty, housing instability and recent injection drug use. Despite being at high risk for HCV, 61% had no history or knowledge of past HCV testing (n = 230). Of those who received a POC test 77/195 (39%) were positive for HCV antibodies. There was no change in rates of engagement in HCV care among those who received the POC (n = 6; 3%) compared to those who did not (n = 5; 3%). CONCLUSION: Peer outreach workers were able to efficiently reach a marginalized group of individuals who had a high HCV antibody prevalence and low rates of prior HCV testing. This improved participants' knowledge of their HCV antibody status, but that knowledge in itself did not lead to any change in participant's subsequent engagement in HCV care. Future work is required to evaluate strategies such as incentives or peer navigators to improve linkage to HCV care after diagnosis.

Impact of comprehensive care on health care use among a cohort of marginalized people living with hepatitis C in Toronto.

Background: The majority of new hepatitis C (HCV) cases occur among people who inject drugs. In recent years, multidisciplinary models of HCV treatment have emerged that demonstrate successful treatment outcomes for this population, as well as broad positive individual- and system-level impacts. Our objective was to evaluate changes in health care use among a cohort of people living with HCV before and after engagement with one such program. Methods: Program data were uniquely linked to provincial health administrative databases. Rates of emergency department (ED) visits and hospital admissions of clients from 2011 through 2015 (N = 103) were evaluated using linkages with administrative data for the 2 years before and after program initiation. Data were evaluated using negative binomial regression models with a covariance structure to account for within-individual correlations. Results: Of participants, 72.8% were men (mean age 47 years), and 38% experienced high rates of physical and mental health comorbidity (Aggregated Diagnosis Group score ≥10). Female clients had significantly fewer ED visits 2 years after program initiation (5.04 versus 3.12; risk ratio [RR] 0.61 [95% CI 0.44% to 0.86%]). ED visits for infectious diseases and soft tissue injury were significantly lower for the cohort overall (RRs 0.58 0.51 [95% CIs 0.35% to 0.95% and 0.29% to 0.90%], respectively). Conclusion: Co-locating HCV treatment within comprehensive primary care and harm reduction services appears to have benefits beyond HCV, including a reduction in ED visits among women and a decrease in ED visits for soft tissue infections for all participants.

Understanding real-world adherence in the directly acting antiviral era: A prospective evaluation of adherence among people with a history of drug use at a community-based program in Toronto, Canada.

BACKGROUND: Direct acting antiviral (DAA) treatments for Hepatitis C (HCV) are now widely available with sustained virologic response (SVR) rates of >90%. A major predictor of response to DAAs is adherence, yet few real-world studies evaluating adherence among marginalized people who use drugs and/or alcohol exist. This study evaluates patterns and factors associated with non-adherence among marginalized people with a history of drug use who were receiving care through a primary care, community-based HCV treatment program where opiate substitution is not offered on-site. METHODS: Prospective evaluation of chronic HCV patients initiating DAA treatment. Self-report medication adherence questionnaires were completed weekly. Pre/post treatment questionnaires examined socio-demographics, program engagement and substance use. Missing adherence data was counted as a missed dose. RESULTS: Of the 74 participants, who initiated treatment, 76% were male, the average age was 54 years, 69% reported income from disability benefits, 30% did not have stable housing and only 24% received opiate substitution therapy. Substance use was common in the month prior to treatment initiation with, 11% reported injection drug use, 30% reported non-injection drug use and 18% moderate to heavy alcohol use. The majority (85%) were treatment naïve, with 76% receiving sofosbuvir/ledipasvir (8-24 weeks) and 22% Sofosbuvir/Ribarvin (12-24 weeks). The intention to treat proportion with SVR12 was 87% (60/69). In a modified ITT analysis (excluding those with undetectable RNA at end of treatment), 91% (60/66) achieved SVR12. Overall, 89% of treatment weeks had no missed doses. 41% of participants had at least one missed dose. In multivariate analysis the only factor independently associated with weeks with missed doses was moderate to heavy alcohol use (p=0.05). CONCLUSION: This study demonstrates that strong adherence and SVR with DAAs is achievable, with appropriate supports, even in the context of substance use, and complex health/social issues.

Inhibition of calpain attenuates encephalitogenicity of MBP-specific T cells.

Multiple sclerosis (MS) is a T-cell mediated autoimmune disease of the CNS, possessing both immune and neurodegenerative events that lead to disability. Adoptive transfer (AT) of myelin basic protein (MBP)-specific T cells into naïve female SJL/J mice results in a relapsing-remitting (RR) form of experimental autoimmune encephalomyelitis (EAE). Blocking the mechanisms by which MBP-specific T cells are activated before AT may help characterize the immune arm of MS and offer novel targets for therapy. One such target is calpain, which is involved in activation of T cells, migration of immune cells into the CNS, degradation of axonal and myelin proteins, and neuronal apoptosis. Thus, the hypothesis that inhibiting calpain in MBP-specific T cells would diminish their encephalitogenicity in RR-EAE mice was tested. Incubating MBP-specific T cells with the calpain inhibitor SJA6017 before AT markedly suppressed the ability of these T cells to induce clinical symptoms of RR-EAE. These reductions correlated with decreases in demyelination, inflammation, axonal damage, and loss of oligodendrocytes and neurons. Also, calpain : calpastatin ratio, production of truncated Bid, and Bax : Bcl-2 ratio, and activities of calpain and caspases, and internucleosomal DNA fragmentation were attenuated. Thus, these data suggest calpain as a promising target for treating EAE and MS.

Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients.

Multiple sclerosis (MS) is a devastating autoimmune demyelinating disease of the central nervous system (CNS). This study investigated whether expression and activity of the calcium-activated protease calpain correlated with Th1/Th2 dysregulation in MS patients during states of relapse and remission. Calpain expression and activity were significantly increased in peripheral blood mononuclear cells (PBMCs) from MS patients, compared to controls, with the highest expression and activity noted during relapse. Th1 cytokines were highest and Th2 cytokines were lowest in MS patients during relapse. Treatment with calpain inhibitor, calpeptin, decreased Th1 cytokines in PBMCs from MS patients. Calpain inhibitor also reduced degradation of myelin basic protein (MBP) by inhibiting the calpain secreted from MBP-specific T cells. Taken together, these results suggested calpain involvement in Th1/Th2 dysregulation in MS patients.