Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact.

Hepatitis C virus (HCV) infection represents the major cause of chronic liver disease, leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. It is the leading indication for liver transplantation worldwide. In addition, there is a growing body of evidence concerning the role of HCV in extrahepatic manifestations, including immune-related disorders and metabolic abnormalities, such as insulin resistance and steatosis. HCV depends on its host cells to propagate successfully, and every aspect of the HCV life cycle is closely related to human lipid metabolism. The virus circulates as a lipid-rich particle, entering the hepatocyte via lipoprotein cell receptors. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation (steatosis) and circulating hypocholesterolemia. Patients with chronic HCV are at increased risk for hepatic steatosis, dyslipidemia, and cardiovascular disease, including accelerated atherosclerosis. This review aims to describe different aspects of the HCV viral life cycle as it impacts host lipoproteins and lipid metabolism. It then discusses the mechanisms of HCV-related hepatic steatosis, hypocholesterolemia, and accelerated atherosclerosis.

Education increases COVID-19 vaccine uptake among people in Canadian federal prisons in a prospective randomized controlled trial: The EDUCATE study.

Education is key to behavioural adoption and acceptability of health interventions. We evaluated the impact of an educational intervention administered 1:1 to individuals incarcerated in four Canadian federal prisons on COVID-19 vaccine uptake. Eligible individuals (those who had refused all COVID-19 vaccines) were randomized 2:1 to receive the educational intervention or not (control group); those who received the intervention completed questionnaires assessing COVID-19 vaccine-related knowledge, attitudes, and beliefs pre- and post-educational intervention. The primary and secondary outcome measures were COVID-19 vaccine uptake and vaccine confidence, respectively. Between May 3 and September 9, 2022, 202 participants were randomized to receive the intervention, of whom 127 (63 %) agreed to participate. Participants who were randomized to the intervention had higher COVID-19 vaccine uptake vs. the control group (5 % vs 1 %, p = 0.046). COVID-19 vaccine-related knowledge, attitudes, and beliefs improved post-intervention. Education increases COVID-19 vaccine uptake and confidence among people in Canadian federal correctional facilities.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Concurrent HIV viral blips during two episodes of multicentric Castleman disease in an adult on antiretroviral therapy: Implication for HIV persistence.

Human herpesvirus-8 (HHV8)-associated multicentric Castleman disease (HHV8-MCD) is a rare nonmalignant lymphoproliferative disorder most commonly observed in PLWH. Herein, we describe an HIV-infected adult male from Cameroon with relapsing HHV8-MCD (HIV+MCD). The patient developed constitutional symptoms, diffuse lymphadenopathy, thrombocytopenia and autoimmune hemolytic anemia. Excisional lymph node biopsy findings were consistent with HHV8-MCD. He was successfully treated with corticosteroids and rituximab. One year later, he developed relapsing disease and was successfully treated again with rituximab. Interestingly, HIV viral load blips correlate with MCD flares, suggesting that low-level viremia is linked with T-cell clonal expansion and/or inflammation, rather than a lack of effective antiretroviral therapy. Rituximab either alone or in combination with chemotherapy for aggressive disease is the standard of care, with approximately 95% of treated patients achieving complete remission. Despite highly effective therapy, HIV+MCD often presents with a relapsing and remitting disease course and carries an increased risk for the development of HHV8-associated lymphoma.

Barriers and Facilitators Affecting the HIV Care Cascade for Migrant People Living with HIV in Organization for Economic Co-Operation and Development Countries: A Systematic Mixed Studies Review.

Migrants in countries affiliated with the Organization for Economic Co-operation and Development (OECD) have a higher risk of acquiring HIV, experience delayed HIV diagnosis, and have variable levels of engagement with HIV care and treatment when compared to native-born populations. A systematic mixed studies review was conducted to generate a multilevel understanding of the barriers and facilitators affecting HIV Care Cascade steps for migrant people living with HIV (MLWH) in OECD countries. Medline, Embase, Scopus, CINAHL, and the Cochrane Library were searched on March 25, 2020. Screening, critical appraisal, and analysis were conducted independently by two authors. We used qualitative content analysis and the five-level Socio-Ecological Model (i.e., individual, interpersonal, organizational, community, and policy) to categorize barriers and facilitators. Fifty-nine studies from 17 OECD countries were included. MLWH faced similar barriers and facilitators regardless of their host country, ethnic and geographic origins, or legal status. Most barriers and facilitators were associated with the individual and organizational levels and centered around retention in HIV care and treatment. Adapting clinical environments to better address MLWH's competing needs via multidisciplinary models would address retention issues across OECD countries.

Implementing opt-out hepatitis C virus (HCV) screening in Canadian provincial prisons: A model-based cost-effectiveness analysis.

BACKGROUND: Implementing opt-out hepatitis C virus (HCV) screening across Canadian provincial prisons is crucial to achieving micro-elimination. Given short incarceration lengths, the most cost-effective screening strategy remains unknown. We compared the cost-effectiveness of current standard of care (venipuncture-based HCV-antibody+HCV RNA) and 13 alternative strategies in Quebec's largest provincial prison. METHODS: A prison cohort was simulated with a Markov micro-simulation model. Strategies differed in the biomarkers, sampling methods, and number of tests used. The model considered incarceration lengths, time to linkage to care (LTC), nursing costs, and tests' costs, performances, acceptability and turnaround times. Outcomes included costs (Canadian dollars, CAD$), number of true positives linked to care, and incremental cost-effectiveness ratios (ICERs, additional $/additional TP-L). A one-year time horizon and health-payer perspective were adopted. RESULTS: Across all analyses, three strategies consistently provided the best value for money: venipuncture-based HCV-antibody+HCV-core antigen, venipuncture-based HCV-core antigen (base-case ICER=~ $720), and point-of-care HCV-antibody+HCV RNA (base-case ICER=$4,310). However, these strategies linked only 23%-29% viremic individuals to care. Main drivers of cost-effectiveness were the seroprevalence, proportion viremic, and time to LTC. CONCLUSION: Alternative strategies would be more cost-effective than standard of care for implementing opt-out screening in provincial prisons. However, interventions to maximize LTC should be explored.

Acceptability of a Patient Portal (Opal) in HIV Clinical Care: A Feasibility Study.

Opal (opalmedapps.com), a patient portal in use at the Cedars Cancer Centre of the McGill University Health Centre (MUHC) (Montreal, Canada), gives cancer patients access to their medical records, collects information on patient-reported outcome measures (PROMs), and has demonstrated patient satisfaction with care. This feasibility study aims to evaluate Opal's potential acceptability in the context of HIV care. People living with HIV (PLWH) and their healthcare providers (HCPs) completed cross-sectional surveys from August 2019 to February 2020 at large HIV centers, including the Chronic Viral Illness Service of the MUHC, and other HIV clinical sites in Montreal and Paris, France. This study comprised 114 PLWH (mean age 48 years old, SD = 12.4), including 74% men, 24% women, and 2% transgender or other; and 31 HCPs (mean age 46.5 years old, SD = 11.4), including 32% men, 65% women, and 3% other. Ownership of smartphones and tablets was high (93% PLWH, 96% HCPs), and participants were willing to use Opal (74% PLWH, 68% HCPs). Participants were interested in most Opal functions and PROMs, particularly PROMs capturing quality of life (89% PLWH, 77% HCPs), experience of healthcare (86% PLWH, 97% HCPs), and HIV self-management (92% PLWH, 97% HCPs). This study suggests Opal has high acceptability and potential usefulness as perceived by PLWH and HCPs.

Liver Fibrosis in Human Immunodeficiency Virus (HIV)-Hepatitis C Virus (HCV) Coinfection Before and After Sustained Virologic Response: What Is the Best Noninvasive Marker for Monitoring Regression?

BACKGROUND: Noninvasive markers of liver fibrosis such as aspartate aminotransferase-to-platelet ratio (APRI) and transient elastography (TE) have largely replaced liver biopsy for staging hepatitis C virus (HCV). As there is little longitudinal data, we compared changes in these markers before and after sustained virologic response (SVR) in human immunodeficiency virus (HIV)-HCV coinfected patients. METHODS: Participants from the Canadian Coinfection Cohort study who achieved SVR after a first treatment with either interferon/ribavirin or direct acting antivirals (DAAs), with at least 1 pre- and posttreatment fibrosis measure were selected. Changes in APRI or TE (DAA era only) were modeled using a generalized additive mixed model, assuming a gamma distribution and adjusting for sex, age at HCV acquisition, duration of HCV infection, and time-dependent body mass index, binge drinking, and detectable HIV RNA. RESULTS: Of 1981 patients, 151 achieved SVR with interferon and 553 with DAAs; 94 and 382 met inclusion criteria, respectively. In the DAA era, APRI increased (0.03 units/year; 95% credible interval (CrI): -.05, .12) before, declined dramatically during, and then changed minimally (-0.03 units/year; 95% CrI: -.06, .01) after treatment. TE values, however, increased (0.74 kPa/year; 95% CrI: .36, 1.14) before treatment, changed little by the end of treatment, and then declined (-0.55 kPa/year; 95% CrI: -.80, -.31) after SVR. CONCLUSIONS: TE should be the preferred noninvasive tool for monitoring fibrosis regression following cure. Future studies should assess the risk of liver-related outcomes such as hepatocellular carcinoma according to trajectories of fibrosis regression measured using TE to determine if and when it will become safe to discontinue screening.

Barriers and facilitators associated with steps of the HIV care cascade for migrants in OECD countries: a systematic mixed studies review protocol.

INTRODUCTION: In 2019, the United Nations signalled a substantial rise in the number of international migrants, up to 272 million globally, about half of which move to only 10 countries, including 8 member nations of the Organization for Economic Co-operation and Development (OECD). Migrants in OECD countries are often at higher risk for acquiring HIV and have a higher frequency of delayed HIV diagnosis. The barriers and facilitators that migrant people living with HIV (PLWH) in OECD countries face in relation to HIV care are insufficiently understood. The five-step HIV Care Cascade Continuum (HCCC) is an effective model to identify gaps, barriers and facilitators associated with HIV care. The purpose of this study is to generate a comprehensive, multilevel understanding of barriers and facilitators regarding the five steps of the HCCC model in OECD countries by migration status. METHODS AND ANALYSIS: A systematic mixed studies review using a data-based convergent design will be conducted. Medline, Embase, Scopus, CINAHL and the Cochrane Library will be searched on 25 March 2020. Screening and critical appraisal will be conducted independently by the first author. Authors 3-5 will act as second reviewers, each independently conducting 33% of the screening and appraisal. Quantitative data will be transformed to qualitative data and be synthesised using thematic analysis. The Mixed Methods Appraisal Tool will be used for quality assessment. An advisory committee, composed of four migrant PLWH, will be involved in screening and appraising 5% of articles to build knowledge and experience with systematic reviews. They will also be involved in analysis and dissemination. ETHICS AND DISSEMINATION: Ethics approval was obtained from the McGill University Health Centre (15-188-MUHC, 2016-1697, eReviews 4688). Publications arising from this study will be open-access. PROSPERO REGISTRATION NUMBER: CRD42020172122.

Delayed linkage to HIV care among asylum seekers in Quebec, Canada.

BACKGROUND: Migrants represent an increasing proportion of people living with HIV in many developed countries. We aimed to describe the HIV care cascade and baseline genotypic resistance for newly diagnosed asylum seekers referred to the McGill University Health Centre (MUHC) in Montreal, Quebec, Canada. METHODS: We conducted a retrospective cohort study of patients linked to the MUHC from June 1, 2017 to October 31, 2018. We calculated the median time (days; interquartile range (IQR)) from: 1) entry into Canada to immigration medical examination (IME) (i.e. HIV screening); 2) IME to patient notification of diagnosis; 3) notification to linkage to HIV care (defined as a CD4 or viral load (VL) measure); 4) linkage to HIV care to combination antiretroviral therapy (cART) prescription; and 5) cART prescription to viral suppression (defined as a VL < 20 copies/mL). We reviewed baseline genotypes and interpreted mutations using the Stanford University HIV Drug Resistance Database. We calculated the proportion with full resistance to > 1 antiretroviral. RESULTS: Overall, 43% (60/139) of asylum seekers were newly diagnosed in Canada. Among these, 62% were late presenters (CD4 < 350 cells/µl), 22% presented with advanced HIV (CD4 < 200 cells/µl), and 25% with high-level viremia (VL > 100,000 copies/ml). Median time from entry to IME: 27 days [IQR:13;55]; IME to notification: 28 days [IQR:21;49]; notification to linkage: 6 days [IQR:2;19]; linkage to cART prescription: 11 days [IQR:6;17]; and cART to viral suppression: 42 days [IQR:31;88]; 45% were linked to HIV care within 30 days. One-fifth (21%) had baseline resistance to at least one antiretroviral agent; the K103 N/S mutation was the most common mutation. CONCLUSIONS: While the majority of newly diagnosed asylum seekers were late presenters, only 45% were linked to care within 30 days. Once linked, care and viral suppression were rapid. Delays in screening and linkage to care present increased risk for onward transmission, and in the context of 21% baseline resistance, consideration of point-of-care testing and immediate referral at IME screening should be made.

Trends in cause-specific mortality in HIV-hepatitis C coinfection following hepatitis C treatment scale-up.

OBJECTIVE: Hepatitis C virus (HCV) treatment may reduce liver-related mortality but with competing risks, other causes of mortality may undermine benefits. We examined changes in cause-specific mortality among HIV-HCV coinfected patients before and after scale-up of HCV treatment. DESIGN: Prospective multicentre HIV-HCV cohort study in Canada. METHODS: Cause-specific deaths, classified using a modified 'Coding of Cause of Death in HIV' protocol, were determined for two time periods, 2003-2012 and 2013-2017, stratified by age (20-49; 50-80 years). Comparison of trends between periods was performed using Poisson regression. To account for competing risks, multinomial regression was used to estimate the cause-specific hazard ratios of time and age on cause of death, from which end-stage liver disease (ESLD)-specific 5-year cumulative incidence functions were estimated. RESULTS: Overall, 1634 participants contributed 8248 person-years of follow-up; 273 (17%) died. Drug overdose was the most common cause of death overall, followed by ESLD and smoking-related deaths. In 2013-2017, ESLD was surpassed by drug overdose and smoking-related deaths among those aged 20-49 and 50-80, respectively. After accounting for competing risks, comparing 2003-2012 to 2013-2017, ESLD deaths declined (adjusted hazards ratio: 0.18, 95% confidence interval 0.05-0.62). However, both early and late period cumulative incidence functions demonstrated increased risk of death from ESLD for patients with poor HIV control and advanced fibrosis. CONCLUSION: The gains made in overall mortality with HCV therapy may be thwarted if modifiable harms are not addressed. Although ESLD-related deaths have decreased over time, treatment should be further expanded, prioritizing those with advanced fibrosis.

Previous incarceration impacts access to hepatitis C virus (HCV) treatment among HIV-HCV co-infected patients in Canada.

INTRODUCTION: The prevalence of hepatitis C virus (HCV) is far higher in prison settings than in the general population; thus, micro-elimination strategies must target people in prison to eliminate HCV. We aimed to examine incarceration patterns and determine whether incarceration impacts HCV treatment uptake among Canadian HIV-HCV co-infected individuals in the direct-acting antiviral (DAA) era. METHODS: The Canadian Co-Infection Cohort prospectively follows HIV-HCV co-infected people from 18 centres. HCV RNA-positive participants with available baseline information on incarceration history were included and followed from 21 November 2013 (when second-generation DAAs were approved by Health Canada) until 30 June 2017. A Cox proportional hazards model was used to assess the effect of time-updated incarceration status on time to treatment uptake, adjusting for patient-level characteristics known to be associated with treatment uptake in the DAA era. RESULTS: Overall, 1433 participants (1032/72% men) were included; 67% had a history of incarceration and 39% were re-incarcerated at least once. Compared to those never incarcerated, previously incarcerated participants were more likely to be Indigenous, earn <$1500 CAD/month, report current or past injection drug use and have poorly controlled HIV. There were 339 second-generation DAA treatment initiations during follow-up (18/100 person-years). Overall, 48% of participants never incarcerated were treated (27/100 person-years) compared to only 31% of previously incarcerated participants (15/100 person-years). Sustained virologic response (SVR) rates at 12 weeks were 95% and 92% respectively. After adjusting for other factors, participants with a history of incarceration (adjusted hazard ratio (aHR): 0.7, 95% CI: 0.5 to 0.9) were less likely to initiate treatment, as were those with a monthly income <$1500 (aHR: 0.7, 95% CI: 0.5 to 0.9) or who reported current injection drug use (aHR: 0.7, 95% CI: 0.4 to 1.0). Participants with undetectable HIV RNA (aHR: 2.1, 95% CI: 1.6 to 2.9) or significant fibrosis (aHR: 1.5, 95% CI: 1.2 to 1.9) were more likely to initiate treatment. CONCLUSIONS: The majority of HIV-HCV co-infected persons had a history of incarceration. Those previously incarcerated were 30% less likely to access treatment in the DAA era even after accounting for several patient-level characteristics. With SVR rates above 90%, HCV elimination may be possible if treatment is expanded for this vulnerable and neglected group.

Chronic obstructive pulmonary disease and HIV: are we appropriately screening?

Individuals with human immunodeficiency virus (HIV) represent a population that is at a higher risk of developing chronic obstructive pulmonary disease (COPD). In this study, we sought to determine the effects of smoking on respiratory symptoms and diseases among HIV-positive patients and to determine if symptomatic patients are being appropriately screened for COPD. HIV-positive individuals completed a self-administered questionnaire. The effects of smoking on respiratory symptoms and diseases were reported as odds ratios (ORs). The COPD screening criteria were adapted from the Canadian Thoracic Society (CTS) guidelines. Two hundred and forty-seven participants were recruited. The median age was 49 years; 75% were male and 92% were on highly active antiretroviral therapy. Smokers represented 66% of the population. Smoking had a statistically significant effect on respiratory symptoms including wheeze (OR 4.8 [95% confidence interval (CI) 1.6-14.2]), phlegm production (OR 4.9 [95% CI: 2.2-10.5]), cough (OR 7.0 [95% CI: 3.0-16.2]), and dyspnea (OR 7.2 [95% CI: 1.7-31.2]). Smoking had a higher odds of respiratory diseases including COPD (OR 4.9 [95% CI: 1.1-21.9]) and bronchitis (OR 3.8 [95% CI: 1.9-7.7]). Among HIV-positive smokers, 40% met the CTS screening criteria, while only 12% self-reported a diagnosis of COPD. The burden of smoking in the HIV population is significant. HIV-positive smokers are more likely to report both respiratory symptoms and diseases than HIV-positive non-smokers. A discrepancy exists between patients who met the CTS screening criteria and those who were diagnosed with COPD, raising the concern for under-recognition and under-diagnosis of COPD in this population.