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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. [ABSTRACT FROM AUTHOR]

The article discusses the guideline on pre-exposure prophylaxis (PrEP) and non-occupational post-exposure prophylaxis (nPEP) for the prevention of HIV infection in Canada. Topics discussed include PrEP using tenofovir disoproxil fumarate/emtricitabine, indications for PrEP including men who have sex with men (MSM), heterosexual exposure and people who inject drugs (PWID) exposure, and preferred and alternate agents for nPEP.

The increased longevity afforded by combination antiretroviral therapy in developed countries has led to an increased concern regarding senescence-related diseases in patients with human immunodeficiency virus (HIV) infection. Previous epidemiologic analyses have demonstrated an increased risk of chronic obstructive pulmonary disease, as well as a significant burden of respiratory symptoms in HIV-infected patients. We performed the St. George's Respiratory Questionnaire (SGRQ) in 199 HIV-positive men, and determined the predominant factors contributing to poor respiratory-related health status. In univariate analyses, worse SGRQ scores were associated with respiratory-related variables such as greater smoking pack-year history ( p=0.028), lower forced expiratory volume in 1 second (FEV1) ( p<0.001), and worse emphysema severity as quantified by computed tomographic imaging ( p=0.017). In addition, HIV-specific variables, such as a history of plasma viral load >100,000 copies/mL ( p=0.043), lower nadir CD4 cell count ( p=0.040), and current CD4 cell count ≤350 cells/μL ( p=0.005), as well as elevated levels of inflammatory markers, specifically plasma interleukin (IL)-6 ( p=0.002) and alpha-1 antitrypsin ( p=0.005) were also associated with worse SGRQ scores. In a multiple regression model, FEV1, current CD4 count ≤350 cells/μL, and IL-6 levels remained significant contributors to reduced respiratory-related health status. HIV disease activity as measured by HIV-related immunosuppression in conjunction with the triggering of key inflammatory pathways may be important determinants of worse respiratory health status among HIV-infected individuals. Limitations of this analysis include the absence of available echocardiograms, diffusion capacity and lung volume testing, and an all-male cohort due to the demographics of the clinic population. [ABSTRACT FROM AUTHOR]

Background. The goal of the present study was to characterize outcome and predictors of outcome of treatment interruption (TI) in highly active antiretroviral therapy (HAART)-treated patients. Methods. A systematic chart/database review was conducted to identify patients with nadir CD4 cell counts >200 cells/mm³ and without acquired immunodeficiency syndrome-defining illnesses who underwent a TI. Collected data included duration and reason for TI, demographic characteristics, CD4 cell count, and plasma viral load. Human immunodeficiency virus (HIV) envelope (V3) loop genotyping was performed on plasma HIV RNA. The presence of basic residues at aa 11 and/or 25 (the "11/25" genotype) was a further possible prognostic variable of interest. Cox proportional hazards models were used to assess characteristics associated with time to HAART reinitiation after TI. Results. A total of 208 of 4461 (4.7%) patients underwent TI. The study group consisted of 197 (94.7%) of 208 participants for whom V3 genotyping was successful. The median CD4 cell count at time of the initiation of TI was 620 cells/mm³. A total of 59 (29.9%) patients reinitiated HAART after a median of 15 months. At the time of the reinitiation of HAART, the median plasma viral load was >100,000 copies/mL, and the median CD4 cell count was 260 cells/mm³. Among the 197 study patients, there were 6 deaths, none of which was attributable to the TI. A total of 81 % had plasma viral loads <50 copies/mL by 15 months of follow-up after reinitiation of HAART. In multivariate analysis, a nadir CD4 cell count ⩽250 cells/mm³ (risk ratio [RR], 2.79 [95% confidence interval {CI}, 1.60-4.86]; P< .001) and the presence of the 11/25 genotype (RR, 2.07 [95% CI, 1.07-4.02]; P = .031) were positively and independently associated with faster time to HAART reinitiation, after adjusting for age and plasma virus load at the start of TI. Conclusions. Our study suggests that TI is a viable option for HIV-positive adults with nadir CD4 cell counts >250 cells/mm³. A nadir CD4 cell count of 200-250 cells/mm³ and the 11/25 viral genotype were found to be associated with a faster HAART reinitiation. [ABSTRACT FROM AUTHOR]

To characterize survival and to compare rates of disease progression to death of human immunodeficiency virus (HIV)-infected patients, between those initiating multiple-drug rescue therapy (MDRT) and those antiretroviral-inexperienced initiating triple-drug antiretroviral therapy (ART), we conducted a population-based analysis of HIV-infected men and women aged ≥18 years in British Columbia, Canada. Cumulative mortality rates were estimated by use of Kaplan-Meier methods, and Cox-proportional hazard regression was used to model the simultaneous effect of prognostic variables on survival. Cumulative mortality at 36 months was 14.2% ±2.0% and 10.9% ±1.0% for the MDRT and triple-drug ART groups, respectively (P =.105, log-rank test). After adjustment for other baseline prognostic variables, MDRT was found not to be a predictor of increased all-cause mortality (relative risk, 1.17; 95% confidence interval, 0.82-1.66) in multivariate analysis. Over the short-term, patients receiving MDRT had relatively low mortality. After adjustment for baseline prognostic factors, rates of survival were comparable with those in patients initiating triple-drug ART. [ABSTRACT FROM AUTHOR]

Focuses on a study which investigated the steady-state pharmacokinetics of elfavirenz and nevirapine when used in combination to treat human immunodeficiency virus type 1 (HIV-1)-infected subjects. Bioanalysis of nevirapine and efavirenz; Results; Discussion.

[Display omitted] While combination antiretroviral therapy (cART) durably suppresses HIV replication, virus persists in CD4+ T-cells that harbor latent but spontaneously inducible and replication-competent provirus. One strategy to inactivate these viral reservoirs involves the use of agents that continue to reinforce HIV latency even after their withdrawal. To identify new chemical leads with such properties, we investigated a series of naturally-occurring flavones (chrysin, apigenin, luteolin, and luteolin-7-glucoside (L7G)) and functionally-related cyclin dependent kinase 9 (CDK9) inhibitors (flavopiridol and atuveciclib) which are reported or presumed to suppress HIV replication in vitro. We found that, while all compounds inhibit provirus expression induced by latency-reversing agents in vitro , only aglycone flavonoids (chrysin, apigenin, luteolin, flavopiridol) and atuveciclib, but not the glycosylated flavonoid L7G, inhibit spontaneous latency reversal. Aglycone flavonoids and atuveciclib, but not L7G, also inhibit CDK9 and the HIV Tat protein. Aglycone flavonoids do not reinforce HIV latency following their in vitro withdrawal, which corresponds with their ability to also inhibit class I/II histone deacetylases (HDAC), a well-established mechanism of latency reversal. In contrast, atuveciclib and flavopiridol, which exhibit little or no HDAC inhibition, continue to reinforce latency for 9 to 14+ days, respectively, following their withdrawal in vitro. Finally, we show that flavopiridol also inhibits spontaneous ex vivo viral RNA production in CD4+ T cells from donors with HIV. These results implicate CDK9 inhibition (in the absence of HDAC inhibition) as a potentially favorable property in the search for compounds that durably reinforce HIV latency. [ABSTRACT FROM AUTHOR]

Background: Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human DNA polymerase γ. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia. Methods: Total DNA was extracted from blood cells. A nuclear gene and a mitochondrial gene were quantified by real-time polymerase chain reaction. Three groups were studied: 24 controls not infected with the human immunodeficiency virus (HIV), 47 HIV-infected asymptomatic patients who had never been treated with antiretroviral drugs, and 8 HIV-infected patients who were receiving antiretroviral drugs and had symptomatic hyperlactatemia. The patients in the last group were studied longitudinally before, during, and after antiretroviral therapy. Results: Symptomatic hyperlactatemia was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68 percent lower than those of non–HIV-infected controls and 43 percent lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA (P=0.02). In the patients followed longitudinally, the decline in mitochondrial DNA preceded the increase in venous lactate levels. Conclusions: Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside-related hyperlactatemia, an effect that resolves on the discontinuation of therapy. (N Engl J Med 2002;346:811-20.) [ABSTRACT FROM AUTHOR]

Background: Advancements in treatment have resulted in improved survival among people living with HIV. However, additional years of life are not necessarily spent in good health, as frailty tends to develop at a younger age among people living with HIV. We set out to examine the prevalence of frailty and its correlates among older adults living with HIV in Canada, with a primary interest in nadir CD4 count., Methods: We performed a cross-sectional analysis of the Correlates of Healthy Aging in Geriatric HIV (CHANGE HIV) study, a Canadian cohort of people living with HIV aged 65 years or older. Participants were assessed using the Fried Frailty Phenotype at cohort entry, and those meeting ≥3 criteria were characterized as frail. We used Poisson regression with robust standard errors to estimate the association between nadir CD4 count and frailty, as well as age, gender, time since HIV diagnosis, comorbidities, marital status, and loneliness., Results: Among 439 participants included in this analysis (median age 69 years, interquartile ranges 67-73), prevalence of frailty was 16.6%. Frailty was not associated with nadir CD4 count. Not being in a relationship (aRR 2.09, 95% CI 1.01 to 4.30) and greater degree of loneliness (aRR 1.25 per 10 point increase on UCLA loneliness scale, 95% CI 1.09 to 1.44) were associated with frailty., Conclusions: Frailty occurred in 16.6% of older adults living with HIV in this cohort. While nadir CD4 count did not correlate with frailty, being single and lonely did, highlighting the importance of recognizing and addressing these social vulnerabilities among people aging with HIV., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The immunogenic nature of coronavirus disease 2019 (COVID-19) mRNA vaccines led to some initial concern that these could stimulate the HIV reservoir. We analyzed changes in plasma HIV loads (pVL) and reservoir size following COVID-19 mRNA vaccination in 62 people with HIV (PWH) receiving antiretroviral therapy (ART), and analyzed province-wide trends in pVL before and after the mass vaccination campaign., Design: Longitudinal observational cohort and province-wide analysis., Methods: Sixty-two participants were sampled prevaccination, and one month after their first and second COVID-19 immunizations. Vaccine-induced anti-SARS-CoV-2-Spike antibodies in serum were measured using the Roche Elecsys Anti-S assay. HIV reservoirs were quantified using the intact proviral DNA assay; pVL were measured using the cobas 6800 (lower limit of quantification: 20 copies/ml). The province-wide analysis included all 290 401 pVL performed in British Columbia, Canada between 2012 and 2022., Results: Prevaccination, the median intact reservoir size was 77 [interquartile range (IQR): 20-204] HIV copies/million CD4 + T-cells, compared to 74 (IQR: 27-212) and 65 (IQR: 22-174) postfirst and -second dose, respectively (all comparisons P > 0.07). Prevaccination, 82% of participants had pVL <20 copies/ml (max: 110 copies/ml), compared to 79% postfirst dose (max: 183 copies/ml) and 85% postsecond dose (max: 79 copies/ml) ( P  > 0.4). There was no evidence that the magnitude of the vaccine-elicited anti-SARS-CoV-2-Spike immune response influenced pVL nor changes in reservoir size ( P  > 0.6). We found no evidence linking the COVID-19 mass vaccination campaign to population-level increases in detectable pVL frequency among all PWH in the province, nor among those who maintained pVL suppression on ART., Conclusion: We found no evidence that COVID-19 mRNA vaccines induced changes in HIV reservoir size nor plasma viremia., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

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.

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.

COVID-19 breakthrough infection (BTI) can occur despite vaccination. Using a multi-centre, prospective, observational Canadian cohort of people with HIV (PWH) receiving ≥2 COVID-19 vaccines, we compared the SARS-CoV-2 spike (S) and receptor-binding domain (RBD)-specific IgG levels 3 and 6 months post second dose, as well as 1 month post third dose, in PWH with and without BTI. BTI was defined as positivity based on self-report measures (data up to last study visit) or IgG data (up to 1 month post dose 3). The self-report measures were based on their symptoms and either a positive PCR or rapid antigen test. The analysis was restricted to persons without previous COVID-19 infection. Persons without BTI remained COVID-19-naïve until ≥3 months following the third dose. Of 289 participants, 92 developed BTI (31.5 infections per 100 person-years). The median days between last vaccination and BTI was 128 (IQR 67, 176), with the most cases occurring between the third and fourth dose (n = 59), corresponding to the Omicron wave. In analyses adjusted for age, sex, race, multimorbidity, hypertension, chronic kidney disease, diabetes and obesity, a lower IgG S/RBD (log10 BAU/mL) at 1 month post dose 3 was significantly associated with BTI, suggesting that a lower IgG level at this time point may predict BTI in this cohort of PWH.

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., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JSGM’s Treatment as Prevention (TasP®) research, paid to his institution, has received support from the BC Ministry of Health, Health Canada, Canadian Institutes of Health Research, Public Health Agency of Canada, Genome Canada, Genome BC, Vancouver Coastal Health and VGH Foundation. Institutional grants have been provided by Gilead Sciences Inc, Janssen, Merck Sharp & Dohme LLC, and ViiV Healthcare. MH has received honoraria, administered by the institution, for consulting fees and advisory board participation from Gilead Sciences Canada, Merck Canada, and ViiV Healthcare. All other authors declare they have no conflicts of interest.

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., Competing Interests: Pouya Azar is a consultant on Indivior-led buprenorphine extended-release studies, which are unrelated to this case report. The other authors report no conflicts of interest., (Copyright © 2023 American Society of Addiction Medicine.)

Importance: 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., Competing Interests: The authors declare no conflict of interest.

Objective: To assess antiretroviral therapy (ART) adherence among people with HIV (PWH) in Canada and identify baseline characteristics associated with suboptimal adherence (<95%)., Design: Retrospective observational study using data from the National Prescription Drug Utilization Information System and Régie de l'assurance maladie Quebec (RAMQ) Public Prescription Drug Insurance Plan., Methods: This analysis included PWH aged 18 years or older who initiated an ART regimen and were followed for at least 12 months (2010-2020). Patient characteristics were summarized using medical/pharmacy claims data from seven provinces (Alberta, Manitoba, New Brunswick, Newfoundland and Labrador, Ontario, Saskatchewan, and Quebec). ART regimen at index date (first dispensing of a regimen including a core agent) was defined as a single-tablet or multitablet regimen (MTR). Adherence was calculated using a Proportion of Days Covered approach, based on ART dispensing, recorded between April 2010 and the last available date. Multivariate linear regression analysis was used to determine correlations between suboptimal adherence and baseline characteristics., Results: We identified 19 322 eligible PWH, 44.7% of whom had suboptimal adherence (<95%). Among 12 594 PWH with evaluable baseline data, 10 673 (84.8%) were ART-naive, 74.2% were men, mean age was 42.9 years, and 54.1% received a MTR as their ART. Based on multivariate regression analysis, suboptimal adherence was significantly associated with multitablet ART ( P  < 0.001) and younger age ( P  < 0.001) but not sex., Conclusion: Almost half of adult PWH in Canada had suboptimal adherence to ART. Better understanding of factors influencing adherence may help address gaps in current care practices that may impact adherence., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Here, we compare coronavirus disease 2019 (COVID-19) vaccine-induced antibody neutralization capacity in PWH vs. HIV-negative individuals following two vaccine doses., Design: In Canadian prospective observational cohorts, including a multicentre study of PWH receiving at least two COVID-19 vaccinations (mRNA or ChAdOx1-S), and a parallel study of HIV-negative controls (Stop the Spread Ottawa Cohort), we measured vaccine-induced neutralization capacity 3 months post dose 2 (±1 month)., Methods: COVID-19 neutralization efficiency was measured by calculating the half maximal inhibitory dilution (ID50) using a high-throughput protein-based neutralization assay for Ancestral (Wuhan), Delta and Omicron (BA.1) spike variants. Univariable and multivariable quantile regression were used to compare COVID-19-specific antibody neutralization capacity by HIV status., Results: Neutralization assays were performed on 256 PWH and 256 controls based on specimen availability at the timepoint of interest, having received two vaccines and known date of vaccination. There was a significant interaction between HIV status and previous COVID-19 infection status in median ID50. There were no differences in median ID50 for HIV+ vs. HIV-negative persons without past COVID-19 infection. For participants with past COVID-19 infection, median ICD50 was significantly higher in controls than in PWH for ancestral SARS-CoV-2 and Omicron variants, with a trend for the Delta variant in the same direction., Conclusion: Vaccine-induced SARS-CoV-2 neutralization capacity was similar between PWH vs. HIV-negative persons without past COVID-19 infection, demonstrating favourable humoral-mediated immunogenicity. Both HIV+ and HIV-negative persons demonstrated hybrid immunity., Trial Registration: clinicaltrials.gov NCT04894448., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: MH has received consulting or advisory fees and honoraria administered by her institution from Gilead Sciences Canada, Merck Canada, and ViiV Healthcare.

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., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Limited data exist regarding longer term antibody responses following three-dose coronavirus disease 2019 (COVID-19) vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). We quantified wild-type-specific, Omicron BA.1-specific and Omicron BA.5-specific responses up to 6 months post-third dose in 64 PWH and 117 controls who remained COVID-19-naive or experienced their first SARS-CoV-2 infection during this time., Design: Longitudinal observational cohort., Methods: We quantified wild-type-specific and Omicron-specific anti-Spike receptor-binding domain IgG concentrations, ACE2 displacement activities and live virus neutralization at 1, 3 and 6 months post-third vaccine dose., Results: Third doses boosted all antibody measures above two-dose levels, but BA.1-specific responses remained significantly lower than wild-type-specific ones, with BA.5-specific responses lower still. Serum IgG concentrations declined at similar rates in COVID-19-naive PWH and controls post-third dose (median wild-type-specific and BA.1-specific half-lives were between 66 and 74 days for both groups). Antibody function also declined significantly yet comparably between groups: 6 months post-third dose, BA.1-specific neutralization was undetectable in more than 80% of COVID-19 naive PWH and more than 90% of controls. Breakthrough SARS-CoV-2 infection boosted antibody concentrations and function significantly above vaccine-induced levels in both PWH and controls, though BA.5-specific neutralization remained significantly poorer than BA.1 even post-breakthrough., Conclusion: Following three-dose COVID-19 vaccination, antibody response durability in PWH receiving ART is comparable with controls. PWH also mounted strong responses to breakthrough infection. Due to temporal response declines, however, COVID-19-naive individuals, regardless of HIV status, would benefit from a fourth dose within 6 months of their third., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Our objective was to compare COVID-19 vaccine immunogenicity in PWH to HIV-negative individuals., Design: In a Canadian multi-center prospective, observational cohort of PWH receiving at least two COVID-19 vaccinations, we measured vaccine-induced immunity at 3 and 6 months post 2nd and 1-month post 3rd doses., Methods: The primary outcome was the percentage of PWH mounting vaccine-induced immunity [co-positivity for anti-IgG against SARS-CoV2 Spike(S) and receptor-binding domain proteins] 6 months post 2nd dose. Univariable and multivariable logistic regressions were used to compare COVID-19-specific immune responses between groups and within subgroups., Results: Data from 294 PWH and 267 controls were analyzed. Immunogenicity was achieved in over 90% at each time point in both groups. The proportions of participants achieving comparable anti-receptor-binding domain levels were similar between the group at each time point. Anti-S IgG levels were similar by group at month 3 post 2nd dose and 1-month post 3rd dose. A lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose [92% vs. 99%; odds ratio: 0.14 (95% confidence interval: 0.03, 0.80; P = 0.027)]. In multivariable analyses, neither age, immune non-response, multimorbidity, sex, vaccine type, or timing between doses were associated with reduced IgG response., Conclusion: Vaccine-induced IgG was elicited in the vast majority of PWH and was overall similar between groups. A slightly lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose demonstrating the importance of timely boosting in this population., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Age-related comorbidities such as chronic obstructive pulmonary disease (COPD) are common in people living with human immunodeficiency virus (PLWH). We investigated the relationship between COPD and the epigenetic age of the airway epithelium and peripheral blood of PLWH., Methods: Airway epithelial brushings from 34 PLWH enrolled in the St. Paul's Hospital HIV Bronchoscopy cohort and peripheral blood from 378 PLWH enrolled in The Strategic Timing of Antiretroviral Treatment (START) study were profiled for DNA methylation. The DNA methylation biomarker of age and healthspan, GrimAge, was calculated in both tissue compartments. We tested the association of GrimAge with COPD in the airway epithelium and airflow obstruction as defined by an FEV 1 /FVC<0.70, and FEV 1 decline over 6 years in blood., Findings: The airway epithelium of PLWH with COPD was associated with greater GrimAge residuals compared to PLWH without COPD (Beta=3.18, 95%CI=1.06-5.31, P=0.005). In blood, FEV 1 /FVC1 decline was inversely correlated with GrimAge residuals in blood (r=-0.13, P=0.012). PLWH who had normal lung function but who subsequently developed an FEV 1 /FVC<0.70 over the course of 6 years had higher GrimAge residuals at baseline (Beta=2.33, 95%CI=0.23-4.44, P=0.031)., Interpretation: GrimAge may reflect lung and systemic epigenetic changes that occur with advanced airflow obstruction and may help to identify PLWH with a higher risk of developing COPD., Funding: Canadian Institutes of Health Research and the British Columbia Lung Association. The START substudy was funded by NIH grants: UM1-AI068641, UM1-AI120197, and RO1HL096453., Competing Interests: Declaration of interests SH reports consulting fees from the non-profit organization, Epigenetic Clock Development Foundation, and royalty income from patents surrounding epigenetic clocks. HK reports consulting fees and payments from AbbVie, Janssen, MSD, ViiV, Gilead, and Intercept, outside of the submitted work. KK reports consulting fees and payments from Allergan and Nuvaira, outside of the submitted work. DS reports payments from AstraZeneca, GSK, and Boehringer Ingelheim, outside of the submitted work. MH reports consulting fees and payments from Gilead, Merck, and ViiV, outside of the submitted work. RMN reports payments from ViiV, Gilead, and Theratechnologies, outside of the submitted work. J Montaner reports grants from Gilead, Merck, ViiV, the Public Health Agency of Canada, and the BC Ministry of Health, outside of the submitted work. JML reports a grant from AstraZeneca, outside of the submitted work. The remaining authors report no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Women living with HIV (WLWH) experience higher rates of human papillomavirus (HPV) infection and cervical cancer than women without HIV. Changes in the vaginal microbiome have been implicated in HPV-related disease processes such as persistence of high-risk HPV infection but this has not been well defined in a population living with HIV., Methods: Four hundred and 20 girls and WLWH, age ≥9, across 14 clinical sites in Canada were enrolled to receive three doses of quadrivalent HPV vaccine for assessment of vaccine immunogenicity. Blood, cervical cytology, and cervico-vaginal swabs were collected. Cervico-vaginal samples were tested for HPV DNA and underwent microbiota sequencing., Results: Principal component analysis (PCA) and hierarchical clustering generated community state types (CSTs). Relationships between taxa and CSTs with HPV infection were examined using mixed-effects logistic regressions, Poisson regressions, or generalized linear mixed-effects models, as appropriate. Three hundred and fifty-six cervico-vaginal microbiota samples from 172 women were sequenced. Human papillomavirus DNA was detected in 211 (59%) samples; 110 (31%) contained oncogenic HPV. Sixty-five samples (18%) were taken concurrently with incident oncogenic HPV infection and 56 (16%) were collected from women with concurrent persistent oncogenic HPV infection., Conclusions: No significant associations between taxa, CST, or microbial diversity and HPV-related outcomes were found. However, we observed weak associations between a dysbiotic microbiome and specific species, including Gardnerella , Porphyromonas , and Prevotella species, with incident HPV infection.

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.

Objectives: To characterize the annual prevalence of antiretroviral/nonantiretroviral drug interactions in relation to antiretroviral therapy (ART)-prescribing patterns, and to describe drug interaction-related ART changes., Design/methods: This cohort study included ART-treated adults in British Columbia, Canada between 01 January 2010 and 31 December 2016. Medication dispensing records were abstracted from a population-based, linked administrative-health dataset and used to identify antiretroviral-comedication drug interactions ('caution'/'avoid' drug interactions in HIV-focused drug interaction checkers). We identified temporal trends in annual drug interaction prevalence and quantified the association between taking higher drug interaction-risk ART and receiving nonrecommended antiretroviral-comedication combinations using Poisson regression models, modified for binary outcomes and correlated data. Clinician-reported, drug interaction-related ART changes and associated adverse events were abstracted from an HIV drug treatment registry and summarized descriptively., Results: Among 8571 ART-treated adults who received nonantiretroviral comedications, prevalence of having any drug interaction or receiving nonrecommended drug combination(s) significantly declined from 85 to 71% and 5.6 to 3.2%, respectively, between 2010 and 2016 ( P  < 0.001). This paralleled a shift from higher drug interaction-risk ART (e.g. ritonavir/cobicistat-boosted protease inhibitors) to lower drug interaction-risk ART (e.g. unboosted integrase inhibitors). Risk of receiving a nonrecommended antiretroviral-comedication combination was greater for persons taking higher vs. lower drug interaction-risk ART [adjusted risk ratio (aRR) 3.12, 95% confidence interval (CI) 2.24-4.35]. Boosted antiretroviral-inhaled corticosteroid drug interactions accounted for the most commonly dispensed, nonrecommended drug combinations, and the most commonly reported drug interaction-related adverse events (adrenal insufficiency)., Conclusion: The prevalence of antiretroviral-comedication drug interactions is declining as ART shifts towards antiretrovirals with lower drug interaction potential but nonrecommended drug combinations remain a concern. Healthcare providers should screen for drug interactions whenever drugs are prescribed or dispensed., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely characterized. We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain (RBD), ACE2 displacement and viral neutralization activities one month following the first and second COVID-19 vaccine doses, and again 3 months following the second dose, in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm 3 , though nadir CD4+ T-cell counts ranged as low as <10 cells/mm 3 . After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was associated with lower anti-RBD antibody concentrations and ACE2 displacement activity after one vaccine dose. Following two doses however, HIV was not significantly associated with the magnitude of any humoral response after multivariable adjustment. Rather, older age, a higher burden of chronic health conditions, and dual ChAdOx1 vaccination were associated with lower responses after two vaccine doses. No significant correlation was observed between recent or nadir CD4+ T-cell counts and responses to two vaccine doses in PLWH. These results indicate that PLWH with well-controlled viral loads and CD4+ T-cell counts in a healthy range generally mount strong initial humoral responses to dual COVID-19 vaccination. Factors including age, co-morbidities, vaccine brand, response durability and the rise of new SARS-CoV-2 variants will influence when PLWH will benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment or who have low CD4+ T-cell counts are needed, as are longer-term assessments of response durability., (© 2022. The Author(s).)

Introduction: Most existing vaccines require higher or additional doses or adjuvants to provide similar protection for people living with HIV (PLWH) compared with HIV-uninfected individuals. Additional research is necessary to inform COVID-19 vaccine use in PLWH., Methods and Analysis: This multicentred observational Canadian cohort study will enrol 400 PLWH aged > 16 years from Montreal, Ottawa, Toronto and Vancouver. Subpopulations of PLWH of interest will include individuals: (1) >55 years of age; (2) with CD4 counts <350 cells/mm 3 ; (3) with multimorbidity ( > 2 comorbidities) and (4) 'stable' or 'reference' PLWH (CD4 T cells >350 cells/mm 3 , suppressed viral load for > 6 months and < 1 comorbidity). Data for 1000 HIV-negative controls will be obtained via a parallel cohort study (Stop the Spread Ottawa), using similar time points and methods. Participants receiving > 1 COVID-19 vaccine will attend five visits: prevaccination; 1 month following the first vaccine dose; and at 3, 6 and 12 months following the second vaccine dose. The primary end point will be the percentage of PLWH with COVID-19-specific antibodies at 6 months following the second vaccine dose. Humoral and cell-mediated immune responses, and the interplay between T cell phenotypes and inflammatory markers, will be described. Regression techniques will be used to compare COVID-19-specific immune responses to determine whether there are differences between the 'unstable' PLWH group (CD4 <350 cells/mm3), the stable PLWH cohort and the HIV-negative controls, adjusting for factors believed to be associated with immune response. Unadjusted analyses will reveal whether there are differences in driving factors associated with group membership., Ethics and Dissemination: Research ethics boards at all participating institutions have granted ethics approval for this study. Written informed consent will be obtained from all study participants prior to enrolment. The findings will inform the design of future COVID-19 clinical trials, dosing strategies aimed to improve immune responses and guideline development for PLWH., Trial Registration Number: NCT04894448., Competing Interests: Competing interests: The authors declare that they have no competing interests, (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Background: Increasing the use of advanced practice nurses may be one of the most viable options to meeting the burgeoning health care demands of older Americans and impending provider shortage over the next two decades. However, keeping the millennial workforce engaged and retained continues to be a significant challenge for health care administrators., Purpose: The purpose of this study was to understand the intergenerational advanced practice registered nurse (APRN) workforce and assess what job satisfaction factors impact APRN intention to stay, and explore how variables such as resiliency style and age affect retention in these young careerists., Methods: This was a single-center, cross-sectional descriptive study using survey methodology. A total of 405 APRNs from all specialties and practice sites from a large Midwestern Academic Medical Center were eligible to participate. A total of 165 APRNs completed the survey, which was a 41% response rate., Results: There were no significant differences in mean resiliency scores by age cohort (p > .05) or a higher intention to leave in millennial-aged APRNs versus older APRNs (p > .05); however, there were significant mean differences in job satisfaction responses that warrant consideration in millennial versus older "baby boomer" APRNs on items such as professional growth, compensation, monetary bonuses, and expanding procedures and skills within scope of practice., Implications for Practice: Understanding generational differences in APRN job satisfaction assists hospital leaders to develop strategies to support, engage, and retain younger careerists, which may help mitigate turnover., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2020 American Association of Nurse Practitioners.)

Background: People aging with HIV are at risk for loneliness, with stigmatization and economic marginalization added to the health challenges arising from chronic infection. This study provides evidence for the extent, contributors, and consequences of loneliness in people living with HIV, focusing on brain health and quality of life., Setting: Cross-sectional data from 856 middle-aged and older adults living with HIV recruited from 5 urban specialty clinics in Canada were drawn from the inaugural visit of the Positive Brain Health Now cohort study., Methods: Participants completed an extensive assessment of biopsychosocial variables. The prevalence, severity, and quality of life impact of self-reported loneliness were described. Clinical and environmental factors hypothesized as contributing to loneliness, and the consequences of loneliness on health and function were identified using logistic, ordinal, and linear regression., Results: Eighteen percent reported being "quite often" and 46% "sometimes" lonely. Those with more loneliness were younger, less mobile, suffered more financial hardship, and were more likely to use opioids. HIV symptoms, pain, fatigue, low motivation, stigma, and unemployment were related to loneliness. Loneliness increased the odds of cognitive impairment, low mood, stress, and poor physical health. Those who were "quite often" lonely were over 4 times more likely to report poor or very poor quality of life than those who were "almost never" lonely., Conclusion: Loneliness is common in middle-aged and older people living with HIV in Canada. Many of the associated factors are modifiable, offering novel targets for improving brain health, general health, and quality of life in HIV.

Background: Due to stigma and discrimination, gay, bisexual and other men who have sex with men (gbMSM) potentially carry a heightened burden of loneliness. This analysis investigates loneliness among gbMSM and its relationship with self-rated physical health, along with the mediating effect of depression., Methods: Participants were recruited using respondent-driven sampling into the Momentum Health Study (February 2012-February 2015) with follow-up visits occurring every 6 months till February 2018. Using computer-assisted self-interviews, measures of loneliness were assessed using a 6-item Loneliness Scale for Emotional and Social Loneliness (lonely vs not lonely). Current physical health was self-assessed (poor, fair, good, very good or excellent). A multivariable generalised linear-mixed model with a logit link function was used to examine the relationship between loneliness and self-rated physical health. We further investigated the mediating effect of depressive symptomatology on this relationship via the Hospital Anxiety and Depression Scale., Results: Of the 770 participants included, we found that 61% (n=471) experienced loneliness at baseline. Of the 674 (88%) who reported good/very good/excellent physical health, 59% (n=391) reported loneliness, compared with 87% (n=80) of those in poor/fair self-rated physical health who reported feeling lonely. After adjustment for confounding, loneliness was associated with poor self-rated physical health (adjusted OR 1.71; 95% CI 1.13 to 2.60). Depressive symptomatology was found to partially mediate this relationship., Conclusion: There may be a need for the integration of social, mental and physical health programming, targeted towards gbMSM, to alleviate the degree of loneliness experienced and its co-occurrence with poor self-rated physical health., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Human papillomavirus (HPV) vaccines have promising safety and immunogenicity data in women living with HIV (WLWH). However, it is critical to understand the residual burden of oncogenic HPV within WLWH to inform postvaccination cervical screening needs. We assessed rates of persistent infection with nonquadrivalent HPV (qHPV) oncogenic types in a cohort of qHPV-vaccinated WLWH., Setting: Multicentre, longitudinal cohort across Canada., Methods: WLWH were scheduled to receive 3 doses of qHPV vaccine. Participants provided health data and HPV DNA samples. Persistent cases of HPV were defined as new HPV in samples from ≥2 consecutive visits or as HPV present in the last sample. HPV31/33/35/39/45/51/52/56/58/59/68/82 were considered to have oncogenic potential. Median follow-up time was 4 years after initial vaccine dose., Results: A total of 284 participants were eligible for this analysis with 1205 person-years (PY) of follow-up (≥1 dose of vaccine, ≥1 HPV DNA result after vaccination). The highest incidence of persistent infection was with HPV51 (1.38/100 PY), followed by HPV52 (1.18/100 PY), and HPV39 (1.06/100 PY). The incidence of persistent infection with pooled HPV types added in the nonavalent vaccine (HPV31/33/45/52/58) was lower than the incidence of persistent oncogenic HPV types not contained within available vaccines (HPV35/39/51/56/59/68) (2.4/100 PY versus 3.6/100 PY, respectively)., Conclusions: qHPV-vaccinated WLWH continue to face a burden of persistent oncogenic HPV infection. Although the nonavalent vaccine could alleviate some of this burden, 2 of the top 3 persistent oncogenic HPVs in this cohort are not contained within any available vaccine. This highlights the need for ongoing cervical screening in HPV-vaccinated WLWH.

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., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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 Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: This study evaluated treatment satisfaction, gastrointestinal tolerability, depressive symptoms and alterations in laboratory parameters before and after switching from ritonavir capsule to tablet formulation., Methods: HIV+ adults switching from ritonavir capsules to tablets were eligible for the study. The HIV Treatment Satisfaction Questionnaire (HIVTSQ), Gastrointestinal Symptom Rating Scale (GSRS) and CES-D Depression inventory were self-administered before, and 3-4 months after switching. Results of laboratory tests within three months of each questionnaire were collected. A subset underwent plasma drug level sampling. Wilcoxon signed rank sum test was used for comparison of continuous variables and McNemar's test for dichotomised data., Results: Most of the 71 participants were Caucasian men, median age 51 years. Participants were taking ritonavir in combination with either atazanavir (n=48 [67.6%]), darunavir (n=18 [25.4%]), fosamprenavir (n=3 [4.2%]) or saquinavir (n=2 [2.8%]). In general after the switch to tablets, participants reported improved treatment satisfaction (median [interquartile range] HIVTSQ score 53/60 [48, 58] after vs 49/60 [45, 54] before, p <0.001), fewer gastrointestinal symptoms (GSRS score 4/45 [1, 9] vs 5/45 [3,13], p < 0.001) and had higher HDL cholesterol (1.22 mmol/L [1.07, 1.45] vs 1.09 mmol/L [0.90,1.32], p = 0.003) and lower total cholesterol/HDL ratio (3.82 [3.05, 4.40] vs 4.23 [3.45, 4.84], p<0.001). There were no significant changes in plasma viral load, CD4 counts, depression scores, or atazanavir or ritonavir trough levels., Conclusion: Results of this study suggest that the newer tablet formulation of ritonavir is better tolerated and has fewer gastrointestinal side effects than the older capsule formulation.

Objectives: Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV antiretroviral therapy can inhibit human telomerase reverse transcriptase. We therefore investigated whether in utero or childhood exposure to NRTIs affects leukocyte telomere length (LTL), a marker of cellular aging., Methods: In this cross-sectional CARMA cohort study, we investigated factors associated with LTL in HIV-1-infected (HIV(+)) children (n = 94), HIV-1-exposed uninfected (HEU) children who were exposed to antiretroviral therapy (ART) perinatally (n = 177), and HIV-unexposed uninfected (HIV(-)) control children (n = 104) aged 0-19 years. Univariate followed by multivariate linear regression models were used to examine relationships of explanatory variables with LTL for: a) all subjects, b) HIV(+)/HEU children only, and c) HIV(+) children only., Results: After adjusting for age and gender, there was no difference in LTL between the 3 groups, when considering children of all ages together. In multivariate models, older age and male gender were associated with shorter LTL. For the HIV(+) group alone, having a detectable HIV viral load was also strongly associated with shorter LTL (p = 0.007)., Conclusions: In this large study, group rates of LTL attrition were similar for HIV(+), HEU and HIV(-) children. No associations between children's LTL and their perinatal ART exposure or HIV status were seen in linear regression models. However, the association between having a detectable HIV viral load and shorter LTL suggests that uncontrolled HIV viremia rather than duration of ART exposure may be associated with acceleration of blood telomere attrition.

Bone mineral density (BMD) abnormalities are observed frequently among human immunodeficiency virus (HIV)-infected patients. Risk factors for reduced BMD in the setting of HIV have been previously studied, but detailed antiretroviral treatment history is often not available. A cross-sectional observational study was conducted between 2005 and 2007 among unselected HIV-infected adults attending an ambulatory urban HIV clinic. Dual-energy X-ray absorptiometry (DXA) scans of lumbar spine and femoral neck, full laboratory profile, detailed questionnaire, and antiretroviral history were obtained. Univariate and multivariate logistic regression analyses were performed to investigate factors associated with BMD below the expected range for age. Two hundred ninety patients completed the study: 80% Caucasians, 89% males, with median age of 49 yr. Low BMD as assessed by Z-score was present in 19.7% of the patients. By multivariate analysis, only lower body mass index (BMI) was an independent risk factor for low BMD. Cumulative exposure to protease inhibitors, non-nucleosides, and individual nucleoside and nucleotide analogs were not independently associated with low BMD. In conclusion, a 19.7% prevalence of abnormal BMD by DXA scan was identified in an unselected group of HIV-infected adults. Lower BMI was independently associated with low BMD. No correlation was found between abnormal BMD and cumulative exposure to any antiretroviral agents., (Copyright © 2010 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

This paper examines the ethical probity of Health Canada's Special Access Program (SAP). The SAP is designed for patients with life-threatening conditions who require "emergency" access to drugs that are not authorized for use in Canada when conventional therapies have failed. We argue that the SAP inappropriately uses the tenets of evidence-based decision-making in situations where evidence-based decision-making is unfeasible. The SAP should abandon its pretence of evidence-based decision-making and adopt a transparent process in which the values guiding decisions are explicit and corrigible. We recommend the ethical principles of autonomy, non-maleficence, beneficence and justice.

Background: The goal of the present study was to characterize outcome and predictors of outcome of treatment interruption (TI) in highly active antiretroviral therapy (HAART)-treated patients., Methods: A systematic chart/database review was conducted to identify patients with nadir CD4 cell counts >200 cells/mm(3) and without acquired immunodeficiency syndrome-defining illnesses who underwent a TI. Collected data included duration and reason for TI, demographic characteristics, CD4 cell count, and plasma viral load. Human immunodeficiency virus (HIV) envelope (V3) loop genotyping was performed on plasma HIV RNA. The presence of basic residues at aa 11 and/or 25 (the "11/25" genotype) was a further possible prognostic variable of interest. Cox proportional hazards models were used to assess characteristics associated with time to HAART reinitiation after TI., Results: A total of 208 of 4461 (4.7%) patients underwent TI. The study group consisted of 197 (94.7%) of 208 participants for whom V3 genotyping was successful. The median CD4 cell count at time of the initiation of TI was 620 cells/mm(3). A total of 59 (29.9%) patients reinitiated HAART after a median of 15 months. At the time of the reinitiation of HAART, the median plasma viral load was >100,000 copies/mL, and the median CD4 cell count was 260 cells/mm(3). Among the 197 study patients, there were 6 deaths, none of which was attributable to the TI. A total of 81% had plasma viral loads <50 copies/mL by 15 months of follow-up after reinitiation of HAART. In multivariate analysis, a nadir CD4 cell count < or =250 cells/mm(3) (risk ratio [RR], 2.79 [95% confidence interval [CI], 1.60-4.86]; P < .001) and the presence of the 11/25 genotype (RR, 2.07 [95% CI, 1.07-4.02]; P = .031) were positively and independently associated with faster time to HAART reinitiation, after adjusting for age and plasma virus load at the start of TI., Conclusions: Our study suggests that TI is a viable option for HIV-positive adults with nadir CD4 cell counts >250 cells/mm(3). A nadir CD4 cell count of 200-250 cells/mm(3) and the 11/25 viral genotype were found to be associated with a faster HAART reinitiation.

Treatment-experienced patients with HIV may harbor virus that has accumulated several mutations conferring decreased susceptibility to one or more antiretroviral drugs. For clinicians treating these patients, identifying a tolerable antiretroviral regimen with a reasonable chance of a durable virologic effect represents a major challenge. The first priority is to identify and correct the mechanisms responsible for previous treatment failure. Resistance testing and drug level monitoring may be useful in this setting. The patient's history of antiretroviral drug tolerability, comorbidities, and concomitant medications should be considered. Patients embarking on multiple-drug regimens will require close monitoring for adherence, toxicities, and drug-drug interactions. The guiding principle when constructing a rescue or salvage regimen is to achieve a cumulative activity score greater than 2, recognizing that some agents will have only partial activity. Some new drugs are available that may be helpful if used carefully with an active background regimen.