People With Human Immunodeficiency Virus Receiving Suppressive Antiretroviral Therapy Show Typical Antibody Durability After Dual Coronavirus Disease 2019 Vaccination and Strong Third Dose Responses.

BACKGROUND: Longer-term humoral responses to 2-dose coronavirus disease 2019 (COVID-19) vaccines remain incompletely characterized in people living with human immunodeficiency virus (HIV) (PLWH), as do initial responses to a third dose. METHODS: We measured antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, angiotensin-converting enzyme 2 (ACE2) displacement, and viral neutralization against wild-type and Omicron strains up to 6 months after 2-dose vaccination, and 1 month after the third dose, in 99 PLWH receiving suppressive antiretroviral therapy and 152 controls. RESULTS: Although humoral responses naturally decline after 2-dose vaccination, we found no evidence of lower antibody concentrations or faster rates of antibody decline in PLWH compared with controls after accounting for sociodemographic, health, and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after 2 doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though Omicron-specific responses were consistently weaker than responses against wild-type virus. Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses. CONCLUSION: PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after 2- and 3-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.

Baseline characteristics of a prospective cohort study of aging and cardiovascular diseases among people living with HIV.

OBJECTIVES: Our objective was to report the baseline characteristics of participants in the Canadian HIV and Aging Cohort Study (CHACS) and present amendments to the initial protocol. METHODS: CHACS is a multi-centred prospective cohort study that was initially set from 2011 to 2016 and will now continue recruitment until 2024. Four additional years of follow-up have been added, and additional outcomes and covariates will be prospectively collected. Frailty will be assessed using a modified version of the Fried's frailty phenotype. The four interrelated aspects of gender-gender roles, gender identity, gender relationships, and institutionalized gender-will be measured using the GENESIS-PRAXY questionnaire. Diet will be assessed using a validated, web-based, self-administered food frequency questionnaire. RESULTS: A total of 1049 participants (77% people living with HIV) were recruited between September 2011 and September 2019. Median age at baseline was 54 years (interquartile range 50-61). Most participants were male (84%) and white (83%). Compared with participants without HIV, those with HIV were more likely to be male; to report lower education levels and incomes; to be more sedentary; to use tobacco, recreational, and prescription drugs; to report a personal history of cardiovascular diseases; and to be frail. CONCLUSIONS: The new assessments added to the CHACS protocol will allow for an even more detailed portrait of the pathways leading to accentuated aging for people living with HIV. Participants in the CHACS cohort display important differences in socio-economic and cardiovascular risk factors according to HIV serostatus. These imbalances must be taken into account for all further inferential analyses.

Microbial dysbiosis and the host airway epithelial response: insights into HIV-associated COPD using multi'omics profiling.

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.

Airway Aging and Methylation Disruptions in HIV-associated Chronic Obstructive Pulmonary Disease.

Rationale: Age-related diseases like chronic obstructive pulmonary disease (COPD) occur at higher rates in people living with human immunodeficiency virus (PLWH) than in uninfected populations. Objectives: To identify whether accelerated aging can be observed in the airways of PLWH with COPD, manifest by a unique DNA methylation signature. Methods: Bronchial epithelial brushings from PLWH with and without COPD and HIV-uninfected adults with and without COPD (N = 76) were profiled for DNA methylation and gene expression. We evaluated global Alu and LINE-1 methylation and calculated the epigenetic age using the Horvath clock and the methylation telomere length estimator. To identify genome-wide differential DNA methylation and gene expression associated with HIV and COPD, robust linear models were used followed by an expression quantitative trait methylation (eQTM) analysis. Measurements and Main Results: Epigenetic age acceleration and shorter methylation estimates of telomere length were found in PLWH with COPD compared with PLWH without COPD and uninfected patients with and without COPD. Global hypomethylation was identified in PLWH. We identified 7,970 cytosine bases located next to a guanine base (CpG sites), 293 genes, and 9 expression quantitative trait methylation-gene pairs associated with the interaction between HIV and COPD. Actin binding LIM protein family member 3 (ABLIM3) was one of the novel candidate genes for HIV-associated COPD highlighted by our analysis. Conclusions: Methylation age acceleration is observed in the airway epithelium of PLWH with COPD, a process that may be responsible for the heightened risk of COPD in this population. Their distinct methylation profile, differing from that observed in patients with COPD alone, suggests a unique pathogenesis to HIV-associated COPD. The associations warrant further investigation to establish causality.

Factors partitioning physical frailty in people aging with HIV: A classification and regression tree approach.

OBJECTIVE: To estimate the extent to which comorbidity and lifestyle factors were associated with physical frailty in middle-aged and older Canadians living with HIV. DESIGN: Cross-sectional analysis of 856 participants from the Canadian Positive Brain Health Now cohort. METHODS: The frailty indicator phenotype was adapted from Fried's criteria using self-report items. Univariate logistic regression and classification and regression tree (CaRT) models were used to identify the most relevant independent contributors to frailty. RESULTS: In all, 100 men (14.0%) and 26 women (19.7%) were identified as frail (≥ 3/5 criteria) for an overall prevalence of 15.2%. Nine comorbidities showed an influential association with frailty. The most influential comorbidities were hypothyroidism [odds ratio (OR) = 2.55, 95% confidence interval (CI): 1.29-5.03] and arthritis (OR = 2.54, 95% CI: 1.58-4.09). Additionally, tobacco (OR = 1.79, 95% CI: 1.05-3.04) showed an association. Any level of alcohol consumption showed a protective effect for frailty. The CaRT model showed nine pathways that led to frailty. Arthritis was the most discriminatory variable followed by alcohol, hypothyroidism, tobacco, cancer, cannabis, liver disease, kidney disease, osteoporosis, lung disease and peripheral vascular disease. The prevalence of physical frailty for people with arthritis was 27.4%; with additional cancer or tobacco and alcohol the prevalence rates were 47.1% and 46.1%, respectively. The protective effect of alcohol consumption evident in the univariate model appeared again in the CaRT model, but this effect varied. Cognitive frailty (19.5% overall) and emotional frailty (37.9% overall) were higher than the prevalence of physical frailty. CONCLUSIONS: Specific comorbidities and tobacco use were implicated in frailty, suggesting that it is comorbidities causing frailty. However, some frailty still appears to be HIV-related. The higher prevalence of cognitive and emotional frailty highlights the fact that physical frailty should not be the only focus in HIV.

A longitudinal view of successful aging with HIV: role of resilience and environmental factors.

PURPOSE: The purpose of this study is to estimate the extent to which people aging with HIV meet criteria for successful aging as operationalized through HRQL and maintain this status over time. A second objective is to identify factors that place people at promise for continued successful aging, including environmental and resilience factors. METHODS: Participants were members of the Positive Brain Health Now (BHN) cohort. People ≥ 50 years (n = 513) were classified as aging successfully if they were at or above norms on 7 or 8 of 8 health-related quality of life domains from the RAND-36. Group-based trajectory analysis, regression tree analysis, a form of machine learning, and logistic regression were applied to identify factors predicting successful aging. RESULTS: 73 (14·2%) met criteria for successful aging at entry and did not change status over time. The most influential factor was loneliness which split the sample into two groups with the prevalence of successful aging 28·4% in the "almost never" lonely compared to 4·6% in the "sometimes/often" lonely group. Other influential factors were feeling safe, social network, motivation, stigma, and socioeconomic status. These factors identified 17 sub-groups with at least 30 members with the proportions classified as aging successfully ranging from 0 to 79·4%. The nine variables important to classifying successful aging had a predictive accuracy of 0.862. Self-reported cognition but not cognitive test performance improved this accuracy to 0.895. The two groups defined by successful aging status did not differ on age, sex or viral load, nadir and current. CONCLUSION: The results indicate the important role of social determinants of health in successful aging among people living with HIV.

The African natural product knipholone anthrone and its analogue anthralin (dithranol) enhance HIV-1 latency reversal.

A sterilizing or functional cure for HIV is currently precluded by resting CD4+ T cells that harbor latent but replication-competent provirus. The "shock-and-kill" pharmacological ap-proach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency reversal agent (LRA) to date effectively clears viral reservoirs in humans, suggesting a need for new LRAs and LRA combinations. Here, we screened 216 compounds from the pan-African Natural Product Library and identified knipholone anthrone (KA) and its basic building block anthralin (dithranol) as novel LRAs that reverse viral latency at low micromolar concentrations in multiple cell lines. Neither agent's activity depends on protein kinase C; nor do they inhibit class I/II histone deacetylases. However, they are differentially modulated by oxidative stress and metal ions and induce distinct patterns of global gene expression from established LRAs. When applied in combination, both KA and anthralin synergize with LRAs representing multiple functional classes. Finally, KA induces both HIV RNA and protein in primary cells from HIV-infected donors. Taken together, we describe two novel LRAs that enhance the activities of multiple "shock-and-kill" agents, which in turn may inform ongoing LRA combination therapy efforts.

Genetic Diversity, Compartmentalization, and Age of HIV Proviruses Persisting in CD4+ T Cell Subsets during Long-Term Combination Antiretroviral Therapy.

The HIV reservoir, which comprises diverse proviruses integrated into the genomes of infected, primarily CD4+ T cells, is the main barrier to developing an effective HIV cure. Our understanding of the genetics and dynamics of proviruses persisting within distinct CD4+ T cell subsets, however, remains incomplete. Using single-genome amplification, we characterized subgenomic proviral sequences (nef region) from naive, central memory, transitional memory, and effector memory CD4+ T cells from five HIV-infected individuals on long-term combination antiretroviral therapy (cART) and compared these to HIV RNA sequences isolated longitudinally from archived plasma collected prior to cART initiation, yielding HIV data sets spanning a median of 19.5 years (range, 10 to 20 years) per participant. We inferred a distribution of within-host phylogenies for each participant, from which we characterized proviral ages, phylogenetic diversity, and genetic compartmentalization between CD4+ T cell subsets. While three of five participants exhibited some degree of proviral compartmentalization between CD4+ T cell subsets, combined analyses revealed no evidence that any particular CD4+ T cell subset harbored the longest persisting, most genetically diverse, and/or most genetically distinctive HIV reservoir. In one participant, diverse proviruses archived within naive T cells were significantly younger than those in memory subsets, while for three other participants we observed no significant differences in proviral ages between subsets. In one participant, "old" proviruses were recovered from all subsets, and included one sequence, estimated to be 21.5 years old, that dominated (>93%) their effector memory subset. HIV eradication strategies will need to overcome within- and between-host genetic complexity of proviral landscapes, possibly via personalized approaches.IMPORTANCE The main barrier to HIV cure is the ability of a genetically diverse pool of proviruses, integrated into the genomes of infected CD4+ T cells, to persist despite long-term suppressive combination antiretroviral therapy (cART). CD4+ T cells, however, constitute a heterogeneous population due to their maturation across a developmental continuum, and the genetic "landscapes" of latent proviruses archived within them remains incompletely understood. We applied phylogenetic techniques, largely novel to HIV persistence research, to reconstruct within-host HIV evolutionary history and characterize proviral diversity in CD4+ T cell subsets in five individuals on long-term cART. Participants varied widely in terms of proviral burden, genetic diversity, and age distribution between CD4+ T cell subsets, revealing that proviral landscapes can differ between individuals and between infected cell types within an individual. Our findings expose each within-host latent reservoir as unique in its genetic complexity and support personalized strategies for HIV eradication.

Phylogenetic approach to recover integration dates of latent HIV sequences within-host.

Given that HIV evolution and latent reservoir establishment occur continually within-host, and that latently infected cells can persist long-term, the HIV reservoir should comprise a genetically heterogeneous archive recapitulating within-host HIV evolution. However, this has yet to be conclusively demonstrated, in part due to the challenges of reconstructing within-host reservoir establishment dynamics over long timescales. We developed a phylogenetic framework to reconstruct the integration dates of individual latent HIV lineages. The framework first involves inference and rooting of a maximum-likelihood phylogeny relating plasma HIV RNA sequences serially sampled before the initiation of suppressive antiretroviral therapy, along with putative latent sequences sampled thereafter. A linear model relating root-to-tip distances of plasma HIV RNA sequences to their sampling dates is used to convert root-to-tip distances of putative latent lineages to their establishment (integration) dates. Reconstruction of the ages of putative latent sequences sampled from chronically HIV-infected individuals up to 10 y following initiation of suppressive therapy revealed a genetically heterogeneous reservoir that recapitulated HIV's within-host evolutionary history. Reservoir sequences were interspersed throughout multiple within-host lineages, with the oldest dating to >20 y before sampling; historic genetic bottleneck events were also recorded therein. Notably, plasma HIV RNA sequences isolated from a viremia blip in an individual receiving otherwise suppressive therapy were highly genetically diverse and spanned a 20-y age range, suggestive of spontaneous in vivo HIV reactivation from a large latently infected cell pool. Our framework for reservoir dating provides a potentially powerful addition to the HIV persistence research toolkit.

Relationships between cognition, function, and quality of life among HIV+ Canadian men.

OBJECTIVE: To estimate the extent to which HIV-related variables, cognition, and other brain health factors interrelate with other HIV-associated symptoms to influence function, health perception, and QOL in older HIV+ men in Canada. DESIGN: Cross-sectional structural equation modelling (SEM) of data from the inaugural visit to the Positive Brain Health Now Cohort. SETTING: HIV clinics at 5 Canadian sites. SUBJECTS: 707 men, age ≥ 35 years, HIV+ for at least one year, without clinically diagnosed dementia. MAIN OUTCOME MEASURES: Five latent and 21 observed variables from the World Health Organization's biopsychosocial model for functioning and disability and the Wilson-Cleary Model were analysed. SEM was used to link disease factors to symptoms, impairments, function, health perception, and QOL with a focus on cognition. RESULTS: QOL was explained directly by depression, social role, health perception, social support, and quality of the environment. Measured cognitive performance had direct effects on activity/function and indirect effects on participation, HP and QOL, acting through self-reported cognitive difficulties and meaningful activities. CONCLUSION: The biopsychosocial model showed good fit, with RMSEA < 0.05. This is the first time the full model has been tested in HIV. All of the domains included in the model are theoretically amenable to intervention and many have evidence-based interventions that could be harnessed to improve QOL.

The Efficacy of the Quadrivalent Human Papillomavirus Vaccine in Girls and Women Living With Human Immunodeficiency Virus.

BACKGROUND: Human papillomavirus (HPV) vaccination is safe and efficacious in women without human immunodeficiency virus (HIV). Although good immunogenicity has been observed in women living with HIV (WLWH), efficacy data in this population are needed. METHODS: We enrolled 420 females aged ≥9 years (range, 9-65) living with HIV. Participants were to receive 3 doses of qHPV vaccine (0/2/6 months). The main endpoint was vaccine failure (ie, incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher [CIN2+], or genital warts). We compared these rates to published rates in vaccinated and unvaccinated women without HIV as well as unvaccinated WLWH. RESULTS: Among 279 eligible women, median follow-up was 2 years. In the intention-to-treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person-years (/100PY) (95% confidence interval [CI], 1.1-4.1), and IR of genital warts was 2.3/100PY (95% CI, 1.2-4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI, 0.3-2.6) and of genital warts was 1.0/100PY (95% CI, 0.3-2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within vaccinated women without HIV, unvaccinated women without HIV, and vaccinated WLWH: 0.1 (95% CI, 0.02-0.03), 1.5 (95% CI, 1.1-2.0), and 1.2 (95% CI, 0.2-3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs 6.0/100PY). CONCLUSIONS: Vaccinated WLWH may be at higher risk for vaccine failure than vaccinated women without HIV. However, overall rates of vaccine failure were low, and rates of persistent qHPV were lower than in unvaccinated WLWH.

Decreased microbiome diversity in the HIV small airway epithelium.

BACKGROUND: Persons living with human immunodeficiency virus (PLWH) face an increased burden of chronic obstructive pulmonary disease (COPD). Repeated pulmonary infections, antibiotic exposures, and immunosuppression may contribute to an altered small airway epithelium (SAE) microbiome. METHODS: SAE cells were collected from 28 PLWH and 48 HIV- controls through bronchoscopic cytologic brushings. DNA extracted from SAE cells was subjected to 16S rRNA amplification and sequencing. Comparisons of alpha and beta diversity between HIV+ and HIV- groups were performed and key operational taxonomic units (OTUs) distinguishing the two groups were identified using the Boruta feature selection after Random Forest Analysis. RESULTS: PLWH demonstrated significantly reduced Shannon diversity compared with HIV- volunteers (1.82 ± 0.10 vs. 2.20 ± 0.073, p = 0.0024). This was primarily driven by a reduction in bacterial richness (23.29 ± 2.75 for PLWH and 46.04 ± 3.716 for HIV-, p < 0.0001). Phyla distribution was significantly altered among PLWH, with an increase in relative abundance of Proteobacteria (p = 0.0003) and a decrease in Bacteroidetes (p = 0.0068) and Firmicutes (p = 0.0002). Six discriminative OTUs were found to distinguish PLWH from HIV- volunteers, aligning to Veillonellaceae, Fusobacterium, Verrucomicrobiaceae, Prevotella, Veillonella, and Campylobacter. CONCLUSIONS: Compared to HIV- controls, PLWH's SAE microbiome is marked by reduced bacterial diversity and richness with significant differences in community composition.

The Canadian HIV and aging cohort study - determinants of increased risk of cardio-vascular diseases in HIV-infected individuals: rationale and study protocol.

BACKGROUND: With potent antiretroviral drugs, HIV infection is becoming a chronic disease. Emergence of comorbidities, particularly cardiovascular disease (CVD) has become a leading concern for patients living with the infection. We hypothesized that the chronic and persistent inflammation and immune activation associated with HIV disease leads to accelerated aging, characterized by CVD. This will translate into higher incidence rates of CVD in HIV infected participants, when compared to HIV negative participants, after adjustment for traditional CVD risk factors. When characterized further using cardiovascular imaging, biomarkers, immunological and genetic profiles, CVD associated with HIV will show different characteristics compared to CVD in HIV-negative individuals. METHODS/DESIGN: The Canadian HIV and Aging cohort is a prospective, controlled cohort study funded by the Canadian Institutes of Health Research. It will recruit patients living with HIV who are aged 40 years or older or have lived with HIV for 15 years or more. A control population, frequency matched for age, sex, and smoking status, will be recruited from the general population. Patients will attend study visits at baseline, year 1, 2, 5 and 8. At each study visit, data on complete medical and pharmaceutical history will be captured, along with anthropometric measures, a complete physical examination, routine blood tests and electrocardiogram. Consenting participants will also contribute blood samples to a research biobank. The primary outcome is incidence of a composite of: myocardial infarction, coronary revascularization, stroke, hospitalization for angina or congestive heart failure, revascularization or amputation for peripheral artery disease, or cardiovascular death. Preplanned secondary outcomes are all-cause mortality, incidence of the metabolic syndrome, incidence of type 2 diabetes, incidence of renal failure, incidence of abnormal bone mineral density and body fat distribution. Patients participating to the cohort will be eligible to be enrolled in four pre-planned sub-studies of cardiovascular imaging, glucose metabolism, immunological and genetic risk profile. DISCUSSION: The Canadian HIV and Aging Cohort will provide insights on pathophysiological pathways leading to premature CVD for patients living with HIV.

HIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) plus darunavir: a pharmacokinetic study.

BACKGROUND: As a simplification strategy for treatment-experienced HIV-infected patients who have achieved virologic suppression on a multi-drug, multi-class antiretroviral regimen, the aim of this study was to evaluate the safety, efficacy, and pharmacokinetics of once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) with darunavir. METHODS: A single arm, open-label 48-week study was conducted of regimen simplification to E/C/F/TDF plus darunavir 800 mg daily from stable therapy including two nucleoside/nucleotide reverse transcriptase inhibitors, a ritonavir-boosted protease inhibitor, and an integrase inhibitor. Participants had plasma HIV viral load consistently < 200 copies/mL for ≥ 6 months, estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, and no genotypic resistance to major components of the study regimen. Plasma viral load was measured at weeks 2 and 4, then every 4 weeks throughout the study. Safety laboratory assessments were conducted at baseline and at weeks 12, 24, 36, and 48. Antiretroviral drug concentrations were measured at baseline and once ≥ 2 weeks after the regimen change. RESULTS: Ten HIV-infected adults (8 male and 2 female; median age 50.5 years) were enrolled. All maintained virologic suppression on the new regimen for 48 weeks. One subject experienced a decrease in eGFR from 62 mL/min at baseline to 52 mL/min at week 12; study medications were continued and his eGFR remained stable (50-59 mL/min) thereafter. No subjects discontinued study medications for renal function changes or other adverse events. Darunavir trough concentration were lower on the new regimen than on darunavir/ritonavir 800/100 mg (n = 5; p < 0.05). CONCLUSIONS: Despite low darunavir trough concentrations, treatment simplification to a two-pill, once-daily regimen of E/C/F/TDF plus darunavir was safe and effective for 48 weeks among 10 selected treatment-experienced HIV-infected patients. Trial registration The study protocol was registered with ClinicalTrials.gov (NCT02199613) on July 22, 2014.

How Generalizable Are the Results From Trials of Direct Antiviral Agents to People Coinfected With HIV/HCV in the Real World?

BACKGROUND: Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have been described as revolutionary. However, it remains uncertain how effective these drugs will be for individuals coinfected with human immunodeficiency virus (HIV)-HCV. Bridging this gap between efficacy and effectiveness requires a focus on the generalizability of clinical trials. METHODS: Generalizability of DAA trials was assessed by applying the eligibility criteria from 5 efficacy trials: NCT01479868, PHOTON-1 (NCT01667731), TURQUOISE-I (NCT01939197), ION-4 (NCT02073656), and ALLY-2 (NCT02032888) that evaluated simeprevir; sofosbuvir; ombitasvir, paritaprevir/ritonavir/dasabuvir; sofosbuvir/ledipasvir; and daclatasvir/sofosbuvir, respectively, to the Canadian Coinfection Cohort, representing approximately 23% of the total coinfected population in care in Canada. RESULTS: Of 874 active participants, 70% had chronic HCV, of whom 410, 26, 94, and 11 had genotypes 1, 2, 3, and 4, respectively. After applying trial eligibility criteria, only 5.9% (24/410) would have been eligible for enrollment in the simeprevir trial, 9.8% (52/530) in PHOTON-1, 6.3% (26/410) in TURQUOISE-I, and 8.1% (34/421) in ION-4. The ALLY-2 study was more inclusive; 43% (233/541) of the cohort would have been eligible. The most exclusive eligibility criteria across all trials with the exception of ALLY-2 were restriction to specific antiretroviral therapies (63%-79%) and active illicit drug use (53%-55%). CONCLUSIONS: DAA trial results may have limited generalizability, since the majority of coinfected individuals were not eligible to participate. Exclusions appeared to be related to improving treatment outcomes by not including those at higher risk of poor adherence and reinfection--individuals for whom real-world data are urgently needed.

The bronchial epithelial cell bacterial microbiome and host response in patients infected with human immunodeficiency virus.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is an important comorbidity in patients living with human immunodeficiency virus (HIV). Previous bacterial microbiome studies have shown increased abundance of specific bacterium, like Tropheryma whipplei, and no overall community differences. However, the host response to the lung microbiome is unknown in patients infected with HIV. METHODS: Two bronchial brush samples were obtained from 21 HIV-infected patients. One brush was used for bacterial microbiome analysis using the Illumina MiSeqTM platform, while the other was used to evaluate gene expression patterns of the host using the Affymetrix Human Gene ST 2.0 array. Weighted gene co-expression network analysis was used to determine the relationship between the bacterial microbiome and host gene expression response. RESULTS: The Shannon Diversity was inversely related to only one gene expression module (p = 0.02); whereas evenness correlated with five different modules (p ≤ 0.05). After FDR correction only the Firmicutes phylum was significantly correlated with any modules (FDR < 0.05). These modules were enriched for cilia, transcription regulation, and immune response. Specific operational taxonomic units (OTUs), such as OTU4 (Pasteurellaceae), were able to distinguish HIV patients with and without COPD and severe emphysema. CONCLUSION: These data support the hypothesis that the bacterial microbiome in HIV lungs is associated with specific host immune responses. Whether or not these responses are also seen in non-HIV infected individuals needs to be addressed in future studies.

48-hour Induction of Transdermal Buprenorphine to Extended-release Buprenorphine.

ABSTRACT: Buprenorphine extended-release (BUP-XR) provides sustained delivery of buprenorphine to control withdrawal and craving symptoms in the form of a monthly injectable and has been shown to improve health outcomes in patients with opioid use disorder. It is recommended that patients are stabilized with a transmucosal buprenorphine product, for at least 7 days per the product monograph; however, clinically, this timeline may be expedited. We report a case of a hospitalized patient with unregulated fentanyl use who underwent a successful transdermal buprenorphine induction for 48 hours to initiate BUP-XR with minimal levels of withdrawal and without precipitating opioid withdrawal. The approach described could provide a practical, patient-centered, accelerated induction strategy that, once independently validated, could considerably facilitate the use of BUP-XR.

DNA Methylation Demonstrates Bronchoalveolar Cell Senescence in People Living with HIV: An Observational Cohort Study.

BACKGROUND: DNA methylation may be a link between HIV, aging, and the increased risk of lung comorbidities. We investigated whether bronchoalveolar lavage (BAL) cells of people living with HIV (PLWH) demonstrate epigenetic disruptions and advanced epigenetic aging. METHODS: BAL cell DNA methylation from 25 PLWH and 16 HIV-uninfected individuals were tested for differential methylation of Alu and LINE-1 sites, markers of aging. We used a weighted gene correlation network analysis to identify HIV- and age-associated co-methylation networks. We tested the effect of HIV on DNA methylation using a robust linear model (false discovery rate < 0.10). RESULTS: The BAL cells of PLWH were marked by global hypomethylation in both Alu and LINE-1 elements. Six co-methylated CpG networks were identified that were significantly associated with age; of these, the red module was significantly differentially methylated in PLWH and enriched pathways (e.g., Ras signaling and T-cell receptors). We identified 6428 CpG sites associated with HIV. CONCLUSIONS: We have shown here for the first time that alterations in the DNA methylation of BAL cells in the lung with HIV show a pattern of advanced aging. This study strongly supports that HIV may contribute to an increased the risk of lung comorbidities through the epigenetics of aging.

Adverse drug reactions attributed to generic substitution of antiretroviral medications among HIV treatment and pre-exposure prophylaxis clients in British Columbia, Canada.

BACKGROUND: In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs. METHODS: Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods. RESULTS: During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, p = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs. CONCLUSIONS: Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.

T-Cell Responses to COVID-19 Vaccines and Breakthrough Infection in People Living with HIV Receiving Antiretroviral Therapy.

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.