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The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish genomically intact proviruses against a large background of defective ones, and its application has yielded insights into HIV-1 persistence. Reports of assay failures however, attributed to HIV-1 polymorphism, have recently emerged. Here, we describe a diverse North American cohort of people with HIV-1 subtype B, where the IPDA yielded a failure rate of 28% due to viral polymorphism. We further demonstrate that within-host HIV-1 diversity can lead the IPDA to underestimate intact reservoir size, and provide examples of how this phenomenon could lead to erroneous interpretation of clinical trial data. While the IPDA represents a major methodological advance, HIV-1 diversity should be addressed before its widespread adoption as a principal readout in HIV-1 remission trials. The intact proviral DNA assay quantifies the genomically intact HIV reservoir, but assay failure due to HIV-1 polymorphism has been observed. Here, the authors report a 28% failure rate in a cohort of people with HIV-1, and note within-host HIV-1 diversity as a further challenge to IPDA accuracy.

Background Despite rolling out publicly-funded hepatitis C virus (HCV) treatment across the province of British Columbia (BC), Canada, 35% of people returning positive HCV RNA results in 2020 did not initiate treatment. The HCV epidemic in Canada continues to disproportionately impact people who use drugs and yet, this population has the lowest proportional uptake of HCV treatment. Evidence suggests linkages to healthcare after diagnosis is one of the key factors that impacts uptake of HCV treatment among this priority population. The Hep C Connect pilot project was implemented to characterize HCV testing outcomes and linkage-to-care rates within a low-barrier supervised consumption site (SCS) in Vancouver, BC. Methods All clients (aged ≥ 19 years) attending the Hope to Health SCS in Vancouver, Canada were invited to participate in the pilot study between November 2021 and December 2022. Interviewer-led surveys were conducted and participants were offered same-day HCV point-of-care (POC) antibody (Ab) testing. Participants received a cash honorarium for sharing their time and experiences. Descriptive statistics are shared in order to describe the reach and impact of this pilot project. Results The study enrolled 186 participants including 123(66.1%) men and 59(31.7%) women, with a median age of 42 (Q1,Q3- 34,49). Forty-seven (25.3%) participants stated that they use an SCS regularly and 123(66.1%) stated that they get new rigs every day. Notably, 64(34.4%) participants reported not having a primary care provider yet more than three-quarters of the participants (144, 77.4%) reported having been ever tested for HCV. All 186 participants agreed to HCV POC Ab testing with 59.7% returning a positive HCV POC Ab result. Despite good HCV POC Ab uptake and high rates of HCV knowledge, 49(44.1%) of the HCV Ab positive participants chose not to engage in confirmatory ribonucleic acid (RNA) testing. Conclusions The Hep C Connect pilot explored the gaps evident in the HCV cascade-of-care as it pertains to people who use drugs. Findings suggest that, despite high levels of HCV knowledge, the employment of blood draw RNA testing deterred people from engaging in confirmatory testing. Improving the HCV cascade-of-care will require alternative strategies that are more acceptable to this population.

New HIV infections occur annually in Canada, highlighting the need for pre- and postexposure prophylaxis (PrEP and PEP). Through the Canadian Institutes of Health Research (CIHR) Pan-Canadian Network for HIV/AIDS and STBBI (sexually transmitted and blood-borne infections) Clinical Trials Research, we have updated the 2017 guideline on clinical indications and drug regimens for PrEP and PEP in Canada. Drawing on meetings with community-based organizations representing key populations affected by HIV in Canada, along with evidence from 3 systematic reviews on PrEP, PEP, and HIV risk assessment tools (searches to June 2024), our diverse panel of 19 experts formulated recommendations on PrEP and PEP. We used a formal evidence-to-decision-making framework and the Grading of Recommendations, Assessment, Development, and Evaluation system. We followed the Guidelines International Network principles for managing competing interests. Our guideline development and reporting adhere with Appraisal of Guidelines for Research and Evaluation II. This guideline contains 31 recommendations and 10 good practice statements. Although it is appropriate to prescribe PrEP to adults and adolescents who request it, clinicians are also encouraged to assess HIV risk during routine health visits to identify people who would benefit from PrEP. Clinicians should elicit information about patients’ anatomy and sexual partners in a culturally sensitive and affirming manner to determine which PrEP regimens — daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), on-demand TDF/FTC, daily oral tenofovir alafenamide/emtricitabine, or long-acting injectable cabotegravir — are suitable options. When assessing whether PEP is needed, clinicians should consider the likelihood that the source person has transmissible HIV, as well as the biological risk of HIV transmission based on exposure type. Preferred PEP regimens are dolutegravir plus TDF/FTC, or bictegravir/tenofovir alafenamide/emtricitabine. Multiple safe, effective PrEP and PEP regimens are now available in Canada, making it increasingly possible to find suitable options for all who could benefit. Implementation of this guideline should expand access to biomedical HIV prevention interventions for those at risk and decrease the incidence of HIV in Canada.

The Correlates of Healthy Aging in Geriatric HIV (CHANGE HIV) study, CTN 314, is the first Canadian cohort of people living with HIV aged 65 years and older. The cohort was established with the purpose of characterizing the multidimensional health status of this population and identifying factors influencing healthy aging. The study builds on the World Health Organization (WHO) Aging and Health conceptual framework, generating a comprehensive profile of health domains (physical, social, mental health, cognitive function, and quality of life), health determinants (biologic, personal, and environmental), and HIV-specific factors that may interact with and influence health in people aging with HIV. The data for the first 353 participants are presented, focusing on sociodemographic factors, comorbidities, coinfections, frailty, cognitive function, loneliness, and resilience using a sex/gender stratified analysis. The cohort thus far is 91% men and the median age is 70 years (range from 65 to 85). Several vulnerabilities were observed, including a high prevalence of comorbidities and frailty. Women especially faced financial insecurity and precarious social structures; a large proportion live alone and only 6% are married or in steady relationships. Identifying strategies to address these vulnerabilities will empower people aging with HIV to optimize their health, quality of life, and independence.

In order to cure human immunodeficiency virus (HIV), we need to better understand the within-host evolutionary origins of the small reservoir of genome-intact proviruses that persist within infected cells during antiretroviral therapy (ART). Most prior studies on reservoir evolutionary dynamics, however, did not discriminate genome-intact proviruses from the vast background of defective ones. We reconstructed within-host pre-ART HIV evolutionary histories in six individuals and leveraged this information to infer the ages of intact and defective proviruses sampled after an average of >9 years on ART, along with the ages of rebound and low-level/isolated viremia occurring during this time. We observed that the longest-lived proviruses persisting on ART were exclusively defective, usually due to large deletions. In contrast, intact proviruses and rebound HIV exclusively dated to the years immediately preceding ART. These observations are consistent with genome-intact proviruses having shorter lifespans, likely due to the cumulative risk of elimination following viral reactivation and protein production. Consistent with this, intact proviruses (and those with packaging signal defects) were three times more likely to be genetically identical compared to other proviral types, highlighting clonal expansion as particularly important in ensuring their survival. By contrast, low-level/isolated viremia sequences were heterogeneous in terms of age, with some potentially originating from defective proviruses. Results reveal that the HIV reservoir is dominated by clonally enriched and genetically younger sequences that date to the period of untreated infection when viral populations had been under within-host selection pressures for the longest duration. Knowledge of these qualities may help focus strategies for reservoir elimination. Characterizing the human immunodeficiency virus (HIV) reservoir that endures despite antiretroviral therapy (ART) is critical to cure efforts. We observed that the oldest proviruses persisting during ART were exclusively defective, while intact proviruses (and rebound HIV) dated to nearer ART initiation. This helps explain why studies that sampled sub-genomic proviruses on-ART (which are largely defective) routinely found sequences dating to early infection, whereas those that sampled replication-competent HIV found almost none. Together with our findings that intact proviruses were more likely to be clonal, and that on-ART low-level/isolated viremia originated from proviruses of varying ages (including possibly defective ones), our observations indicate that (i) on-ART and rebound viremia can have distinct within-host origins, (ii) intact proviruses have shorter lifespans than grossly defective ones and thus depend more heavily on clonal expansion for persistence, and (iii) an HIV reservoir predominantly “dating” to near ART initiation will be substantially adapted to within-host pressures, complicating immune-based cure strategies.

People living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccines, but fewer studies have examined cellular immune responses to the vaccinations. Here, we used an activation-induced marker (AIM) assay to quantify SARS-CoV-2 spike-specific CD4+ and CD8+ T cells generated by two and three doses of COVID-19 vaccines in 50 PLWH receiving antiretroviral therapy, compared to 87 control participants without HIV. In a subset of PLWH, T-cell responses were also assessed after post-vaccine breakthrough infections and/or receipt of a fourth vaccine dose. All participants remained SARS-CoV-2 infection-naive until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to a Nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 control participants after the third vaccine dose. Multivariable regression analyses were used to investigate the relationships between sociodemographic, health- and vaccine-related variables, vaccine-induced T-cell responses, and breakthrough infection risk. We observed that a third vaccine dose boosted spike-specific CD4+ and CD8+ T-cell frequencies significantly above those measured after the second dose (all p < 0.0001). Median T-cell frequencies did not differ between PLWH and controls after the second dose (p > 0.1), but CD8+ T-cell responses were modestly lower in PLWH after the third dose (p = 0.02), an observation that remained significant after adjusting for sociodemographic, health- and vaccine-related variables (p = 0.045). In PLWH who experienced a breakthrough infection, median T-cell frequencies increased even higher than those observed after three vaccine doses (p < 0.03), and CD8+ T-cell responses in this group remained higher even after a fourth vaccine dose (p = 0.03). In multivariable analyses, the only factor associated with an increased breakthrough infection risk was younger age, which is consistent with the rapid increase in SARS-CoV-2 seropositivity that was seen among younger adults in Canada after the initial appearance of the Omicron variant. These results indicate that PLWH receiving antiretroviral therapy mount strong T-cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection.

Combination antiretroviral therapy (cART) has extended the longevity of human immunodeficiency virus (HIV)-infected individuals. However, this has resulted in greater awareness of age-associated diseases such as chronic obstructive pulmonary disease (COPD). Accelerated cellular senescence may be responsible, but its magnitude as measured by leukocyte telomere length is unknown and its relationship to HIV-associated COPD has not yet been established. We measured absolute telomere length (aTL) in peripheral leukocytes from 231 HIV-infected adults. Comparisons were made to 691 HIV-uninfected individuals from a population-based sample. Subject quartiles of aTL were assessed for relationships with measures of HIV disease severity, airflow obstruction, and emphysema severity on computed tomographic (CT) imaging. Multivariable regression models identified factors associated with shortened aTL. Compared to HIV-uninfected subjects, the mean aTL in HIV-infected patients was markedly shorter by 27 kbp/genome (p<0.001); however, the slopes of aTL vs. age were not different (p=0.469). Patients with longer known durations of HIV infection (p=0.019) and lower nadir CD4 cell counts (p=0.023) had shorter aTL. Shorter aTL were also associated with older age (p=0.026), smoking (p=0.005), reduced forced expiratory volume in one second (p=0.030), and worse CT emphysema severity score (p=0.049). HIV-infected subjects demonstrate advanced cellular aging, yet in a cART-treated cohort, the relationship between aTL and age appears no different from that of HIV-uninfected subjects.

Background People living with HIV (PLWH) are at increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) independent of cigarette smoking. We hypothesized that dysbiosis in PLWH is associated with epigenetic and transcriptomic disruptions in the airway epithelium. Methods Airway epithelial brushings were collected from 18 COPD + HIV + , 16 COPD − HIV + , 22 COPD + HIV − and 20 COPD – HIV − subjects. The microbiome, methylome, and transcriptome were profiled using 16S sequencing, Illumina Infinium Methylation EPIC chip, and RNA sequencing, respectively. Multi ‘omic integration was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents. A correlation > 0.7 was used to identify key interactions between the ’omes. Results The COPD + HIV −, COPD −HIV + , and COPD + HIV + groups had reduced Shannon Diversity (p = 0.004, p = 0.023, and p = 5.5e−06, respectively) compared to individuals with neither COPD nor HIV, with the COPD + HIV + group demonstrating the most reduced diversity. Microbial communities were significantly different between the four groups (p = 0.001) . Multi ‘omic integration identified correlations between Bacteroidetes Prevotella , genes FUZ, FASTKD3 , and ACVR1B , and epigenetic features CpG-FUZ and CpG-PHLDB3. Conclusion PLWH with COPD manifest decreased diversity and altered microbial communities in their airway epithelial microbiome. The reduction in Prevotella in this group was linked with epigenetic and transcriptomic disruptions in host genes including FUZ, FASTKD3, and ACVR1B.

Background Most opioid use disorder (OUD) treatment guidelines target community medical settings, and the subsequent recommendations were established to prioritize safety and reduce diversion prior to the fentanyl era. For people with OUD who use unregulated fentanyl, slow induction onto opioid agonist therapy (OAT) with gradual dose titration is often ineffective or insufficient for reducing withdrawal symptoms and cravings, thereby hampering engagement and retention in treatment. Given the severe risks associated with continued use of the increasingly toxic unregulated drug supply, new and innovative approaches to the management of OUD are urgently needed. We have developed an alternative induction protocol, using a rapid intravenous symptom-inhibiting fentanyl induction (SIFI) to optimize rotation onto oral OAT. Methods An open-label, single arm, prospective pilot clinical trial is being conducted in an outpatient setting to assess the safety, feasibility, and efficacy of a rapid symptom-inhibiting intravenous fentanyl induction protocol to establish starting doses of methadone or sustained-release oral morphine (SROM) based on individual opioid requirements, as a treatment strategy for individuals with OUD who use unregulated fentanyl. The primary outcome is safety, as defined by occurrence of study drug-related adverse events (including but not limited to opioid toxicity and QT interval prolongation) that require intervention during induction and the first 7 days on OAT. Secondary objectives are to determine whether the SIFI protocol will result in use of higher-than-standard starting doses of methadone and SROM, and to determine whether implementation of this protocol will be acceptable to participants and will result in reduced withdrawal symptoms, improved retention, and better long-term outcomes on OAT. Discussion This is the first study to rapidly and objectively estimate opioid tolerance and use it to calculate individualized starting doses of oral OAT in an outpatient setting among people who use unregulated fentanyl. We predict that starting methadone or SROM with individually-tailored doses will lead to therapeutic target concentrations being achieved quickly, safely, and with good patient satisfaction. This approach has the potential to more effectively and safely initiate OAT, to minimize opioid withdrawal and cravings, and in turn to decrease unregulated fentanyl use and increase retention on life-saving OAT. Trial registration ClinicalTrials.gov, NCT05905367; date of registration: June 15, 2023; latest update posted July 18, 2024. https://clinicaltrials.gov/study/NCT05905367 Protocol version : 4.0, April 22, 2024.