Non-AIDS-defining comorbidities impact health related quality of life among older adults living with HIV.

Introduction: The life expectancy of people living with HIV receiving effective combination antiretroviral therapy is approaching that of the general population and non AIDS-defining age-related comorbidities are becoming of greater concern. In order to support healthy aging of this population, we set out to explore the association between multimorbidity (defined as presence of 2 or more non AIDS-defining comorbidities) and quality of life (QoL). Methods: We performed a cross-sectional analysis using data from the Correlates of Healthy Aging in Geriatric HIV (CHANGE HIV) study, a Canadian cohort of people living with HIV age 65 years and older. Study participants completed two QoL modules, the general QoL and health related QoL (HR-QoL). Results: 433 participants were included in the analysis with a median age of 69 years (interquartile range, IQR 67-72). The median number of comorbidities among study participants was 3 (IQR 2-4), with 78% meeting the definition of multimorbidity. General QoL scores (median 66, IQR 58-76) were lower than HR-QoL scores (median 71, IQR 61-83) and were not associated with multimorbidity after adjusting for age, sex, relationship status, household income, exercise, tobacco smoking history, malnutrition, time since HIV diagnosis, and HIV-related stigma. In contrast, multimorbidity was associated with lower HR-QoL (adjusted ß = -4.57, 95% CI -8.86, -0.28) after accounting for the same variables. Several social vulnerabilities (not having a partner, low household income), health behaviours (lower engagement in exercise, smoking), and HIV-related factors (HIV stigma, longer time since HIV diagnosis) were also associated with lower QoL. Discussion: Overall, our study demonstrated a high burden of multimorbidity among older adults living with HIV in Canada, which has a negative impact on HR-QoL. Interventions aimed at preventing and managing non-AIDS-defining comorbidities should be assessed in people living with HIV to determine whether this can improve their HR-QoL.

Frequent Disengagement and Subsequent Mortality Among People With HIV and Hepatitis C in Canada: A Prospective Cohort Study.

Background: The cascade of care, commonly used to assess HIV and hepatitis C (HCV) health service delivery, has limitations in capturing the complexity of individuals' engagement patterns. This study examines the dynamic nature of engagement and mortality trajectories among people with HIV and HCV. Methods: We used data from the Canadian HIV-HCV Co-Infection Cohort, which prospectively follows 2098 participants from 18 centers biannually. Markov multistate models were used to evaluate sociodemographic and clinical factors associated with transitioning between the following states: (1) lost-to-follow-up (LTFU), defined as no visit for 18 months; (2) reengaged (reentry into cohort after being LTFU); (3) withdrawn from the study (ie, moved); (4) death; otherwise remained (5) engaged-in-care. Results: A total of 1809 participants met the eligibility criteria and contributed 12 591 person-years from 2003 to 2022. LTFU was common, with 46% experiencing at least 1 episode, of whom only 57% reengaged. One in 5 (n = 383) participants died during the study. Participants who transitioned to LTFU were twice as likely to die as those who were consistently engaged. Factors associated with transitioning to LTFU included detectable HCV RNA (adjusted hazards ratio [aHR], 1.37; 95% confidence interval [CI], 1.13-1.67), evidence of HCV treatment but no sustained virologic response result (aHR, 1.99; 95% CI, 1.56-2.53), and recent incarceration (aHR, 1.94; 95% CI, 1.58-2.40). Being Indigenous was a significant predictor of death across all engagement trajectories. Interpretation: Disengagement from clinical care was common and resulted in higher death rates. People LTFU were more likely to require HCV treatment highlighting a priority population for elimination strategies.

Ongoing Gaps in the Hepatitis C Care Cascade during the Direct-Acting Antiviral Era in a Large Retrospective Cohort in Canada: A Population-Based Study.

To achieve hepatitis C virus (HCV) elimination, high uptake along the care cascade steps for all will be necessary. We mapped engagement with the care cascade overall and among priority groups in the post-direct-acting antivirals (DAAs) period and assessed if this changed relative to pre-DAAs. We created a population-based cohort of all reported HCV diagnoses in Quebec (1990-2018) and constructed the care cascade [antibody diagnosed, RNA tested, RNA positive, genotyped, treated, sustained virologic response (SVR)] in 2013 and 2018. Characteristics associated with RNA testing and treatment initiation were investigated using marginal logistic models via generalized estimating equations. Of the 31,439 individuals HCV-diagnosed in Quebec since 1990 and alive as of 2018, there was significant progress in engagement with the care cascade post- vs. pre-DAAs; 86% vs. 77% were RNA-tested, and 64% vs. 40% initiated treatment. As of 2018, a higher risk of not being RNA-tested or treated was observed among individuals born <1945 vs. >1965 [hazard ratio (HR); 95% CI; 1.35 (1.16-1.57)], those with material and social deprivation [1.21 (1.06-1.38)], and those with alcohol use disorder [1.21 (1.08-1.360]. Overall, non-immigrants had lower rates of RNA testing [0.76 (0.67-0.85)] and treatment initiation [0.63 (0.57-0.70)] than immigrants. As of 2018, PWID had a lower risk of not being RNA tested [0.67 (0.61-0.85)] but a similar risk of not being treated, compared to non-PWID. Engagement in the HCV care cascade have improved in the post-DAA era, but inequities remain. Vulnerable subgroups, including certain older immigrants, were less likely to have received RNA testing or treatment as of 2018 and would benefit from focused interventions to strengthen these steps.

Impact of social determinants of health on time to antiretroviral therapy initiation and HIV viral undetectability for migrants enrolled in a multidisciplinary HIV clinic with rapid, free, and onsite B/F/TAF: 'The ASAP study'.

OBJECTIVE: Multidisciplinary care with free, rapid, and on-site bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) dispensation may improve health outcomes among migrants living with HIV. However, models for rapid B/F/TAF initiation are not well studied among migrants living with HIV, and an understanding of how social determinants of health (SDH) may affect HIV-related health outcomes for migrants enrolled in such care models is limited. METHODS: Within a 96-week pilot feasibility prospective cohort study at a multidisciplinary HIV clinic, participants received free B/F/TAF rapidly after care linkage. The effects of SDH (i.e., birth region, sexual orientation, living status, education, employment, French proficiency, health coverage, use of a public health facility outside our clinic for free blood tests, and time in Canada) and other covariates (i.e., age, sex) on median time to antiretroviral therapy (ART) initiation and HIV viral undetectability from care linkage were calculated via survival analyses. RESULTS: Thirty-five migrants were enrolled in this study. Median time to ART initiation and HIV undetectability was 5 days (range 0-50) and 57 days (range 5-365), respectively. Those who took significantly longer to initiate ART were aged <35 years, identified as heterosexual, had less than university-level education, or were unemployed. No factor was found to significantly affect time to undetectability. CONCLUSION: Despite the provision of free B/F/TAF, several SDH were linked to delays in ART initiation. However, once initiated and engaged, migrants living with HIV reached HIV undetectability efficiently. Findings provide preliminary support for adopting this care model with migrants living with HIV and suggest that SDH should be considered when designing clinical interventions for more equitable outcomes.

All-cause mortality before and after DAA availability among people living with HIV and HCV: An international comparison between 2010 and 2019.

BACKGROUND: Among people living with HIV and hepatitis C virus (HCV), people who inject drugs (PWID) have historically experienced higher mortality rates. Direct-acting antivirals (DAA), which have led to a 90 % HCV cure rate independently of HIV co-infection, have improved mortality rates. However, DAA era mortality trends among PWID with HIV/HCV remain unknown. Using data from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC), we compared pre/post-DAA availability mortality changes in three groups: PWID, men who have sex with men (MSM), and all other participants. METHODS: We included InCHEHC participants with HIV/HCV followed between 2010 and 2019 in Canada, France, the Netherlands, Spain, and Switzerland. All-cause mortality hazard was compared in the three groups, using Cox proportional hazards regression models adjusted for sex, age, advanced fibrosis/cirrhosis, and pre/post DAA availability. RESULTS: Of the 11,029 participants, 76 % were men, 46 % were PWID, baseline median age was 46 years (interquartile range [IQR] = 40;51), and median CD4 T-cell count was 490 cells/mm3 (IQR = 327;689). Over the study period (median follow-up = 7.2 years (IQR = 3.7;10.0)), 6143 (56 %) participants received HCV treatment, 4880 (44 %) were cured, and 1322 participants died (mortality rate = 1.81/100 person-years (PY) [95 % confidence interval (CI)=1.72-1.91]). Overall, PWID had higher mortality rates than MSM (2.5/100 PY [95 % CI = 2.3-2.6] vs. 0.8/100 PY [95 % CI = 0.7-0.9], respectively). Unlike women with other transmission modes, those who injected drugs had a higher mortality hazard than men who did not inject drugs and men who were not MSM (adjusted Hazard-Ratio (aHR) [95 % CI] = 1.3[1.0-1.6]). Post-DAA availability, mortality decreased among MSM in the Netherlands, Spain, and Switzerland and increased among PWID in Canada (aHR [95 % CI] = 1.73 [1.15-2.61]). CONCLUSION: Post-DAA availability, all-cause mortality did not decrease in PWID. Determinants of cause-specific deaths (drug-related, HIV-related, or HCV-related) need to be identified to explain persistently high mortality among PWID in the DAA era.

Changes in incidence of hepatitis C virus reinfection and access to direct-acting antiviral therapies in people with HIV from six countries, 2010-19: an analysis of data from a consortium of prospective cohort studies.

BACKGROUND: Reinfection after successful treatment with direct-acting antivirals is hypothesised to undermine efforts to eliminate hepatitis C virus (HCV) infection among people with HIV. We aimed to assess changes in incidence of HCV reinfection among people with HIV following the introduction of direct-acting antivirals, and the proportion of all incident cases attributable to reinfection. METHODS: We pooled individual-level data on HCV reinfection in people with HIV after spontaneous or treatment-induced clearance of HCV from six cohorts contributing data to the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC) in Australia, Canada, France, the Netherlands, Spain, and Switzerland between Jan 1, 2010, and Dec 31, 2019. Participants were eligible if they had evidence of an HCV infection (HCV antibody or RNA positive test) followed by spontaneous clearance or treatment-induced clearance, with at least one HCV RNA test after clearance enabling measurement of reinfection. We assessed differences in first reinfection incidence between direct-acting antiviral access periods (pre-direct-acting antiviral, limited access [access restricted to people with moderate or severe liver disease and other priority groups], and broad access [access for all patients with chronic HCV]) using Poisson regression. We estimated changes in combined HCV incidence (primary and reinfection) and the relative contribution of infection type by calendar year. FINDINGS: Overall, 6144 people with HIV who were at risk of HCV reinfection (median age 49 years [IQR 42-54]; 4989 [81%] male; 2836 [46%] men who have sex with men; 2360 [38%] people who inject drugs) were followed up for 17 303 person-years and were included in this analysis. The incidence of first HCV reinfection was stable during the period before the introduction of direct-acting antivirals (pre-introduction period; 4·1 cases per 100 person-years, 95% CI 2·8-6·0). Compared with the pre-introduction period, the average incidence of reinfection was 4% lower during the period of limited access (incidence rate ratio [IRR] 0·96, 95% CI 0·78-1·19), and 28% lower during the period of broad access (0·72, 0·60-0·86). Between 2015 and 2019, the proportion of incident HCV infections due to reinfection increased, but combined incidence declined by 34%, from 1·02 cases per 100 person-years (95% CI 0·96-1·07) in 2015 to 0·67 cases per 100 person-years (95% CI 0·59-0·75) in 2019. INTERPRETATION: HCV reinfection incidence and combined incidence declined in people with HIV following direct-acting antiviral introduction, suggesting reinfection has not affected elimination efforts among people with HIV in InCHEHC countries. The proportion of incident HCV cases due to reinfection was highest during periods of broad access to direct-acting antivirals, highlighting the importance of reducing ongoing risks and continuing testing in people at risk. FUNDING: Australian National Health and Medical Research Council.

Switch to a raltegravir-based antiretroviral regimen in people with HIV and non-alcoholic fatty liver disease: A randomized controlled trial.

INTRODUCTION: The effect of antiretroviral therapy (ART), particularly integrase strand transfer inhibitors (INSTIs), on non-alcoholic fatty liver disease (NAFLD) in people with HIV remains unclear. We evaluated the effect of switching non-INSTI backbone antiretroviral medications to raltegravir on NAFLD and metabolic parameters. MATERIALS AND METHODS: This was a single-centre, phase IV, open-label, randomized controlled clinical trial. People living with HIV with NAFLD and undetectable viral load while receiving a non-INSTI were randomized 1:1 to the switch arm (raltegravir 400 mg twice daily) or the control arm (continuing ART regimens not containing INSTI). NAFLD was defined as hepatic steatosis by controlled attenuation parameter ≥238 dB/m in the absence of significant alcohol use and viral hepatitis co-infections. Cytokeratin 18 was used as a biomarker of non-alcoholic steatohepatitis. Changes over time in outcomes were quantified as standardized mean differences (SMDs), and a generalized linear mixed model was used to compare outcomes between study arms. RESULTS: A total of 31 people with HIV (mean age 54 years, 74% male) were randomized and followed for 24 months. Hepatic steatosis improved between baseline and end of follow-up in both the switch (SMD -43.4 dB/m) and the control arm (-26.6 dB/m); the difference between arms was not significant. At the end of follow-up, aspartate aminotransferase significantly decreased in the switch arm compared with the control arm (SMD -9.4 vs. 5.5 IU/L). No changes in cytokeratin 18, body mass index, or lipids were observed between study arms. DISCUSSION: Switching to a raltegravir-based regimen improved aspartate aminotransferase but seemed to have no effect on NAFLD, body weight, and lipids compared with remaining on any other ART.

DAA-mediated HCV cure reduces HIV DNA levels in HCV/HIV coinfected people.

IMPORTANCE: Antiretroviral therapy (ART) for human immunodeficiency virus (HIV) can control virus replication and prolong the life of people living with HIV (PLWH). However, the virus remains dormant within immune cells in what is called the HIV reservoir. Furthermore, 2.3 million PLWH are also coinfected with hepatitis C virus (HCV) and are at risk of developing chronic liver disease and cancer. HCV treatment with direct acting antivirals (DAA) can completely cure the infection in more than 95% of treated individuals and improve their long-term health outcomes. In this study, we investigated how HCV treatment and cure affect the HIV reservoir. We demonstrate the beneficial impact of DAA treatment as it reduces the HIV reservoirs in particular in people infected with HCV before HIV. These results support the need for early ART and DAA treatment in HIV/HCV coinfections.

Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration.

BACKGROUND: A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events. METHODS: We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates. FINDINGS: The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15-45) and 52 in non-initiators (39 months; 18-47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (-0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9-29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15-37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference -0·068% (-0·60 to 0·52). INTERPRETATION: We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV. FUNDING: National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.

Determining reinfection rates by hepatitis C testing interval among key populations: A systematic review and meta-analysis.

BACKGROUND & AIMS: Detecting hepatitis C virus (HCV) reinfection among key populations helps prevent ongoing transmission. This systematic review aims to determine the association between different testing intervals during post-SVR follow-up on the detection of HCV reinfection among highest risk populations. METHODS: We searched electronic databases between January 2014 and February 2023 for studies that tested individuals at risk for HCV reinfection at discrete testing intervals and reported HCV reinfection incidence among key populations. Pooled estimates of reinfection incidence were calculated by population and testing frequency using random-effects meta-analysis. RESULTS: Forty-one single-armed observational studies (9453 individuals) were included. Thirty-eight studies (8931 individuals) reported HCV reinfection incidence rate and were included in meta-analyses. The overall pooled estimate of HCV reinfection incidence rate was 4.13 per 100 per person-years (py) (95% confidence interval [CI]: 3.45-4.81). The pooled incidence estimate among people who inject drugs (PWID) was 2.84 per 100 py (95% CI: 2.19-3.50), among men who have sex with men (MSM) 7.37 per 100 py (95% CI: 5.09-9.65) and among people in custodial settings 7.23 per 100 py (95% CI: 2.13-16.59). The pooled incidence estimate for studies reporting a testing interval of ≤6 months (4.26 per 100 py; 95% CI: 2.86-5.65) was higher than studies reporting testing intervals >6 months (5.19 per 100 py; 95% CI: 3.92-6.46). CONCLUSIONS: HCV reinfection incidence was highest in studies of MSM and did not appear to change with retesting interval. Shorter testing intervals are likely to identify more reinfections, help prevent onward transmission where treatment is available and enable progress towards global HCV elimination, but additional comparative studies are required.

Hepatitis B care cascade among people with HIV/HBV coinfection in the North American AIDS Cohort Collaboration on Research and Design, 2012-2016.

A care cascade is a critical tool for evaluating delivery of care for chronic infections across sequential stages, starting with diagnosis and ending with viral suppression. However, there have been few data describing the hepatitis B virus (HBV) care cascade among people living with HIV infection who have HBV coinfection. We conducted a cross-sectional study among people living with HIV and HBV coinfection receiving care between January 1, 2012 and December 31, 2016 within 13 United States and Canadian clinical cohorts contributing data to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). We evaluated each of the steps in this cascade, including: 1) laboratory-confirmed HBV infection, 2) tenofovir-based or entecavir-based HBV therapy prescribed, 3) HBV DNA measured during treatment, and 4) viral suppression achieved via undetectable HBV DNA. Among 3,953 persons with laboratory-confirmed HBV (median age, 50 years; 6.5% female; 43.8% were Black; 7.1% were Hispanic), 3,592 (90.9%; 95% confidence interval, 90.0-91.8%) were prescribed tenofovir-based antiretroviral therapy or entecavir along with their antiretroviral therapy regimen, 2,281 (57.7%; 95% confidence interval, 56.2-59.2%) had HBV DNA measured while on therapy, and 1,624 (41.1%; 95% confidence interval, 39.5-42.6) achieved an undetectable HBV DNA during HBV treatment. Our study identified significant gaps in measurement of HBV DNA and suppression of HBV viremia among people living with HIV and HBV coinfection in the United States and Canada. Periodic evaluation of the HBV care cascade among persons with HIV/HBV will be critical to monitoring success in completion of each step.

Hospital Readmissions Among Persons With Human Immunodeficiency Virus in the United States and Canada, 2005-2018: A Collaboration of Cohort Studies.

BACKGROUND: Hospital readmission trends for persons with human immunodeficiency virus (PWH) in North America in the context of policy changes, improved antiretroviral therapy (ART), and aging are not well-known. We examined readmissions during 2005-2018 among adult PWH in NA-ACCORD. METHODS: Linear risk regression estimated calendar trends in 30-day readmissions, adjusted for demographics, CD4 count, AIDS history, virologic suppression (<400 copies/mL), and cohort. RESULTS: We examined 20 189 hospitalizations among 8823 PWH (73% cisgender men, 38% White, 38% Black). PWH hospitalized in 2018 versus 2005 had higher median age (54 vs 44 years), CD4 count (469 vs 274 cells/µL), and virologic suppression (83% vs 49%). Unadjusted 30-day readmissions decreased from 20.1% (95% confidence interval [CI], 17.9%-22.3%) in 2005 to 16.3% (95% CI, 14.1%-18.5%) in 2018. Absolute annual trends were -0.34% (95% CI, -.48% to -.19%) in unadjusted and -0.19% (95% CI, -.35% to -.02%) in adjusted analyses. By index hospitalization reason, there were significant adjusted decreases only for cardiovascular and psychiatric hospitalizations. Readmission reason was most frequently in the same diagnostic category as the index hospitalization. CONCLUSIONS: Readmissions decreased over 2005-2018 but remained higher than the general population's. Significant decreases after adjusting for CD4 count and virologic suppression suggest that factors alongside improved ART contributed to lower readmissions. Efforts are needed to further prevent readmissions in PWH.

Role of fatty liver in the epidemic of advanced chronic liver disease among people with HIV: protocol for the Canadian LIVEHIV multicentre prospective cohort.

INTRODUCTION: Advanced chronic liver disease (ACLD) is a major cause of death for people with HIV (PWH). While viral hepatitis coinfections are largely responsible for this trend, metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging concern for PWH. We aimed to assess the contribution of MASLD to incident ACLD in PWH. METHODS AND ANALYSIS: This multicentre prospective observational cohort study will enrol 968 consecutive HIV monoinfected patients from four Canadian sites, excluding subjects with alcohol abuse, liver disease other than MASLD, or ACLD at baseline. Participants will be followed annually for 4 years by clinical evaluation, questionnaires, laboratory testing and Fibroscan to measure liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). The primary outcome will be incidence of ACLD, defined as LSM>10 kPa, by MASLD status, defined as CAP≥285 dB/m with at least one metabolic abnormality, and to develop a score to classify PWH according to their risk of ACLD. Secondary outcomes will include health-related quality of life (HRQoL) and healthcare resource usage. Kaplan-Meier survival method and Cox proportional hazards regression will calculate the incidence and predictors of ACLD, respectively. Propensity score methods and marginal structural models will account for time-varying exposures. We will split the cohort into a training set (to develop the risk score) and a validation set (for validation of the score). HRQoL scores and healthcare resource usage will be compared by MASLD status using generalised linear mixed effects model. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committees of all participating institutions. Written informed consent will be obtained from all study participants. The results of this study will be shared through scientific publications and public presentations to advocate for the inclusion of PWH in clinical trials of MASLD-targeted therapies and case-finding of ACLD in PWH.

Effects of Oral Cannabinoids on Systemic Inflammation and Viral Reservoir Markers in People with HIV on Antiretroviral Therapy: Results of the CTN PT028 Pilot Clinical Trial.

Chronic HIV infection is characterized by persistent inflammation despite antiretroviral therapy (ART). Cannabinoids may help reduce systemic inflammation in people with HIV (PWH). To assess the effects of oral cannabinoids during HIV, ten PWH on ART were randomized (n = 5/group) to increasing doses of oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (2.5:2.5-15:15 mg/day) capsules or CBD-only (200-800 mg/day) capsules for 12 weeks. Blood specimens were collected prospectively 7-21 days prior to treatment initiation and at weeks 0 to 14. Plasma cytokine levels were determined via Luminex and ELISA. Immune cell subsets were characterized by flow cytometry. HIV DNA/RNA were measured in circulating CD4 T-cells and sperm by ultra-sensitive qPCR. Results from both arms were combined for statistical analysis. Plasma levels of IFN-γ, IL-1ß, sTNFRII, and REG-3α were significantly reduced at the end of treatment (p ˂ 0.05). A significant decrease in frequencies of PD1+ memory CD4 T-cells, CD73+ regulatory CD4 T-cells, and M-DC8+ intermediate monocytes was also observed (p ˂ 0.05), along with a transient decrease in CD28-CD57+ senescent CD4 and CD8 T-cells. Ki-67+ CD4 T-cells, CCR2+ non-classical monocytes, and myeloid dendritic cells increased over time (p ˂ 0.05). There were no significant changes in other inflammatory markers or HIV DNA/RNA levels. These findings can guide future large clinical trials investigating cannabinoid anti-inflammatory properties.

Public reimbursement policies in Canada for direct-acting antiviral treatment of hepatitis C virus infection: A descriptive study.

Background: Direct-acting antiviral (DAA) therapies have simplified HCV treatment, and publicly funded Canadian drug plans have eliminated disease-stage restrictions for reimbursement of DAA therapies. However other policies which complicate, delay, or prevent treatment initiation still persist. We aim to describe these plans' existing reimbursement criteria and appraise whether they hinder treatment access. Methods: We reviewed DAA reimbursement policies of 16 publicly funded drug plans published online and provided by contacts with in-depth knowledge of prescribing criteria. Data were collected from May to July 2022. Primary outcomes were: (1) if plans have arranged to accept point-of-care HCV RNA testing for diagnosis; testing requirements for (2) HCV genotype, (3) fibrosis stage, and (4) chronic infection; (5) time taken and method used to approve reimbursement requests; (6) providers eligible to prescribe DAAs; and (7) restrictions on re-treatment. Results: Fifteen (94%) plans have at least one policy in place which limits simplified HCV treatment. Many plans continue to require results of genotype or fibrosis staging, limit eligible prescribers, and take longer than 1 day to approve coverage requests. One plan discourages treatment for re-infection. Conclusion: Reimbursement criteria set by publicly funded Canadian drug plans continue to limit timely, equitable access to HCV treatment. Eliminating clinically irrelevant pre-authorization testing, expanding eligible prescribers, expediting claims processing, and broadening coverage of treatment for reinfection will improve access to DAAs. The federal government could further enhance efforts by introducing a federal HCV elimination strategy or federal high-cost drug PharmaCare program.

A time-dependent Poisson-Gamma model for recruitment forecasting in multicenter studies.

Forecasting recruitments is a key component of the monitoring phase of multicenter studies. One of the most popular techniques in this field is the Poisson-Gamma recruitment model, a Bayesian technique built on a doubly stochastic Poisson process. This approach is based on the modeling of enrollments as a Poisson process where the recruitment rates are assumed to be constant over time and to follow a common Gamma prior distribution. However, the constant-rate assumption is a restrictive limitation that is rarely appropriate for applications in real studies. In this paper, we illustrate a flexible generalization of this methodology which allows the enrollment rates to vary over time by modeling them through B-splines. We show the suitability of this approach for a wide range of recruitment behaviors in a simulation study and by estimating the recruitment progression of the Canadian Co-infection Cohort.

Increased Serum Fibroblast Growth Factor 23 Predicts Mortality in People With HIV/HCV Coinfection.

BACKGROUND: People with HIV and hepatitis C virus (HCV) coinfection experience excess mortality because of multiple causes. Identification of biomarkers associated with mortality beyond that attributable to liver fibrosis may be relevant for prognostication. Fibroblast growth factor 23 (FGF23), a phosphotropic hormone, predicts adverse outcomes in several chronic conditions. We aimed to investigate whether elevated FGF23 predicts all-cause mortality in patients with HIV/HCV coinfection. METHODS: We included patients with HIV/HCV coinfection from the Canadian Coinfection Cohort with available serum FGF23, fibrosis biomarker fibrosis-4 (FIB-4), and at least 1-year follow-up. Elevated FGF23 and advanced liver fibrosis were defined as FGF23 > 241 reference unit/mL and FIB-4 > 3.25, respectively. All-cause mortality was analyzed using survival analysis. The effect of advanced liver fibrosis as a mediator on mortality was estimated by mediation analysis. RESULTS: Three hundred twenty-one patients were included (24% with elevated FGF23, 19% with advanced liver fibrosis). During a mean follow-up period of 8.4 years, 34% of the cohort died. The incidence rate of all-cause mortality was higher in patients with elevated FGF23 (66.1 per 1000 person-years, 95% confidence interval 45.8 to 92.3) relative to patients without elevated FGF23 (37.5 per 1000 person-years, 95% confidence interval 29.6 to 46.9). After adjusting for potential confounders, elevated FGF23 was associated with significant direct and indirect effects (mediated through advanced liver fibrosis) on all-cause mortality, with 57% of deaths not mediated through advanced fibrosis. CONCLUSIONS: In patients with HIV/HCV coinfection, FGF23 may be used as prognostic biomarker for risk stratification accounting also for death causes other than those attributable to liver fibrosis.

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients.

BACKGROUND AND AIMS: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone.

A population-based study of reported hepatitis C diagnoses from 1998 to 2018 in immigrants and nonimmigrants in Quebec, Canada.

Immigrants living in low hepatitis C (HCV) prevalence countries bear a disproportionate HCV burden, but there are limited HCV population-based studies focussed on this population. We estimated rates and trends of reported HCV diagnoses over a 20-year period in Quebec, Canada, to investigate subgroups with the highest rates and changes over time. A population-based cohort of all reported HCV diagnoses in Quebec (1998-2018) linked to health administrative and immigration databases. HCV rates, rate ratios (RR) and trends overall and stratified by immigrant status and country of birth were estimated using Poisson regression. Among 38,348 HCV diagnoses, 14% occurred in immigrants, a median of 7.5 years after arrival. The average annual HCV rate/100,000 decreased for immigrants and nonimmigrants, but the risk (RR) among immigrants increased over the study period [35.7 vs. 34.5 (RR = 1.03) and 18.4 vs. 12.7 (1.45) between 1998-2008 and 2009-2018]. Immigrants from middle-income Europe & Central Asia [55.8 (RR = 4.39)], sub-Saharan Africa [51.7 (RR = 4.06)] and South Asia [32.8 (RR = 2.58)] had the highest rates between 2009 and 2018. Annual HCV rates decreased more slowly among immigrants vs. nonimmigrants (-5.9% vs. -8.9%, p < 0.001), resulting in a 2.5-fold (9%-21%) increase in the proportion of HCV diagnoses among immigrants (1998-2018). The slower decline in HCV rates among immigrants over the study period highlights the need for targeted screening for this population, particularly those from sub-Saharan Africa, Asia and middle-income Europe. These data can inform micro-elimination efforts in Canada and other low-HCV-prevalence countries.