AIDS

Pilot study assessing the rotterdam healthy aging score in a cohort of human immunodeficiency virus positive adults in Toronto, Canada Objective: The Rotterdam Healthy Aging Score (HAS) is a validated multidimensional index constructed from five health domains. We describe the HAS distribution in a cohort of HIV-positive adults and correlate it with health outcomes. Design: A cross-sectional pilot study of 101 adults aged ≥40 years, on suppressive antiretroviral therapy attending a tertiary HIV clinic in Toronto, Canada.. Methods: Participants completed questionnaires to calculate their HAS (range 0–14). Demographics, HAS and sub-scores were compared by age and sex. The HAS was compared to results of the Fried Frailty Score, Short Performance Physical Battery score (SPPB) and measures of health utilization. Kruskal-Wallis Rank-Sum and Fisher's Exact tests were used for all comparisons. Results: Median (IQR) age was 56 (50, 62), 81 (80%) male and 50 (50%) born in Canada. Median (IQR) CD4 was 574 (417, 794) cells/mm3. Median (IQR) HAS was 12 (10,13) with 39 (39%) achieving a score > 12 (considered healthy aging). Younger participants experienced more depression, while women had greater pain. The HAS score correlated with the Fried Frailty Score (p=.008) and trended with the SPPB Score (p = .077). Those with the poorest HAS scores were more likely to have been hospitalized in the preceding 6 months (p = .034). Conclusions: The HAS ranged from 5–14 in this cohort of older HIV adults with 39% attaining scores in the “healthy” range. The HAS correlated with measures of physical performance and health utilization. Further validation of an objective outcome in HIV-positive patients will facilitate evaluation of interventional studies to improve healthy aging. Correspondence to Sharon L. Walmsley, 13EN room 214, 200 Elizabeth Street, Toronto, Ontario, Canada, M5G2C4. Tel: +4163403871; e-mail: Sharon.walmsley@uhn.ca Received 23 November, 2019 Revised 10 January, 2020 Accepted 23 January, 2020 This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2020 Wolters Kluwer Health, Inc.

Early ART-treated perinatally HIV-infected seronegative children demonstrate distinct long-term persistence of HIV-specific T and B cell memory Objective: To investigate long-term persistence of HIV-specific lymphocyte immunity in perinatally HIV-infected children treated within the first year of life. Design: Twenty perinatally HIV-infected children who received ART therapy within the first year of life (early treated) and with stable viral control (>5 years) were grouped according to their serological response to HIV. Methods: Western blot analysis and ELISA defined 14 HIV-seropositive and 6 seronegative patients. Frequencies of gp140-specific T-cell and B-cell, and T-cell cytokine production were quantified by flow cytometry in both seronegatives and seropositives. Transcriptional signatures in purified gp140-specific B-cell subsets, in response to in-vitro stimulation with HIV peptides was evaluated by multiplex RT-PCR. Results: Gp140-specific T cells and B cells persist at similar levels in both groups. A higher production of IL-21 in gp140-specific T cells was found in seropositives vs. seronegatives (P = 0.003). Gene expression in switched IgM−IgD− gp140-specific memory B cells after stimulation with HIV peptides in vitro demonstrated a differential expression of genes involved in signal transduction and activation after BCR/TLR triggering and B-cell activation. Genes relating to antibody production (PRDM1) and T–B cognate stimulation (CXCR4, IL21R) were differentially induced after in-vitro stimulation in seronegatives vs. seropositives suggesting a truncated process of B-cell maturation. Conclusion: HIV-specific memory B and T cells persist in early treated regardless their serological status. Seronegatives and seropositives are distinguished by gp140-specific T-cell function and by distinct transcriptional signatures of gp140-specific B cells after in-vitro stimulation, presumably because of a different antigen exposure. Such qualitative insights may inform future immunotherapeutic interventions. Correspondence to Paolo Palma, MD, PhD, Children's Hospital ‘Bambino Gesù’, Rome, Italy. Tel: +39 66859 3649 3080; e-mail: paolo.palma@opbg.net Received 20 August, 2019 Revised 10 December, 2019 Accepted 14 December, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2020 Wolters Kluwer Health, Inc.

Incident HIV among pregnant and breastfeeding women in sub-Saharan Africa: a systematic review and meta-analysis Objectives: A previous meta-analysis reported high HIV incidence among pregnant and breastfeeding women in sub-Saharan Africa (SSA), but limited evidence of elevated risk of HIV acquisition during pregnancy or breastfeeding when compared to non-pregnant periods. The rapidly evolving HIV prevention and treatment landscape since publication of this review may have important implications for maternal HIV incidence. Design: Systematic review and meta-analysis. Methods: We searched four databases and abstracts from relevant conferences through December 1, 2018, for literature on maternal HIV incidence in SSA. We used random-effects meta-analysis to summarize incidence rates and ratios, and to estimate 95% prediction intervals (PI). We evaluated potential sources of heterogeneity with random-effects meta-regression. Results: Thirty-seven publications contributed 100,758 person-years (PY) of follow-up. The estimated average HIV incidence rate among pregnant and breastfeeding women was 3.6 per 100PY (95%PI: 1.2, 11.1), while the estimated average associations between pregnancy and risk of HIV acquisition, and breastfeeding and risk of HIV acquisition, were close to the null. Wide 95% PIs around summary estimates, however, highlighted the variability of HIV incidence across populations of pregnant and breastfeeding women in SSA. Average HIV incidence was associated with age, partner HIV status, and calendar time. Average incidence was highest among studies conducted pre-2010 (4.1/100PY, 95%PI: 1.1, 12.2) and lowest among studies conducted post-2014 (2.1/100PY, 95%PI: 0.7, 6.5). Conclusions: Substantial HIV incidence among pregnant and breastfeeding women in SSA, even in the current era of combination HIV prevention and treatment, underscores the need for prevention tailored to high-risk pregnant and breastfeeding women. Correspondence to Lauren A. Graybill, MSc, Department of Epidemiology, University of North Carolina, 170 Rosenau Hall, Campus Box #7435, 135 Dauer Drive, Chapel Hill, NC, 27599; e-mail: lag111@email.unc.edu Received 17 September, 2019 Revised 26 December, 2019 Accepted 9 January, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2020 Wolters Kluwer Health, Inc.

Measuring retention in HIV care: the impact of data sources and definitions using routine data in South Africa Objectives: Measuring retention is critical for antiretroviral therapy (ART) management and program monitoring, however many definitions and data sources, usually from single health facilities, are used. We used routine electronic data, linked across facilities, to examine the impact of definitions and data sources on retention estimates among women in Cape Town, South Africa. Design: Retrospective cohort study Methods: We compiled routine electronic laboratory, pharmacy and clinic visit data for 617 women who started ART during pregnancy (2013–2014) and estimated 24-month retention using different definitions and data sources. We used logistic regression to assess consistency of associations between risk factors and retention, and Receiver Operating Characteristics (ROC) analyses to describe how different retention estimates predict viremia at 12 months on ART. Results: Using all available data sources, retention ranged from 41% (no gap > 180 days) to 72% (100% 12-month visit constancy). Laboratory data (expected infrequently) underestimated retention compared to clinic visit data that identified > 80% of women considered retained in all definitions. In all estimates, associations with known risk factors for non-retention remained consistent and retention declined over time: 77%, 65% and 58% retained using all data sources in months 6–12, 12–18 and 18–24, respectively (p < 0.001). The 180-day gap definition was most strongly associated with viremia (OR 24.3 95%CI 12.0–48.9, all data sources). Conclusion: Researchers must carefully consider the most appropriate retention definition and data source depending on available data. Presenting more than one approach may be warranted to obtain estimates that are context-appropriate and comparable across settings. Correspondence to Tamsin K. Phillips, Level 5 Falmouth Building, School of Public Health & Family Medicine, University of Cape Town, Cape Town, South Africa. Tel: ++27 21 650 1646; e-mail: tk.phillips@uct.ac.za Received 29 July, 2019 Revised 2 January, 2020 Accepted 9 January, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2020 Wolters Kluwer Health, Inc.

Plasma NRTI concentration and their associations with liver and renal parameters in people living with HIV Associations between markers of liver and renal dysfunction and NRTI plasma exposure are ill-defined. As part of a large cohort study (POPPY), we analysed associations between ALT and eGFR results in people living with HIV on tenofovir (TFV) disoproxil fumarate (TDF), emtricitabine (FTC), abacavir (ABC) and lamivudine (3TC). While we found no associations between NRTI concentrations and ALT, lower eGFR values were associated with greater TFV, FTC and 3TC exposure, whereas ABC showed no associations. Correspondence to Xinzhu Wang, Jefferies Research Trust Laboratories, Wright-Fleming Institute, Imperial College London, Dept. of Medicine, St Mary's Campus, Norfolk Place, London W2 1PG, UK. e-mail: xinzhu.wang@imperial.ac.uk Received 2 December, 2019 Accepted 16 December, 2019 Copyright © 2020 Wolters Kluwer Health, Inc.

Presence of asymptomatic CMV and EBV DNA in blood of persons with HIV starting antiretroviral therapy are associated with non-AIDS clinical events Background: Even with antiretroviral therapy (ART), persons with HIV (PWH) experience increased morbidity/mortality. Cytomegalovirus (CMV) and Epstein-Barr-Virus (EBV) co-infections likely exacerbate inflammatory-related diseases. Objective: To determine if presence of detectable CMV or EBV DNA in peripheral blood mononuclear cells (PBMC) is associated with non-AIDS events among PWH receiving modern ART. Design: We performed a case-control study of PWH starting ART and HIV-suppressed at year 1 and thereafter, 140 cases who experienced non-AIDS events and 305 matched controls. Events included myocardial infarction, stroke, malignancy, serious bacterial infection or death. Methods: Blood samples were studied pre-ART, 1-year post-ART and pre-event. Controls had an event-free follow-up equal or greater than cases. CMV and EBV levels were measured in PBMC. Conditional logistic regression analysis assessed associations and adjusted for relevant covariates; Spearman's correlations compared CMV and EBV levels with other biomarkers. Results: CMV was detected in PBMC of 25% of participants, EBV was detected in > 90%. Higher EBV levels were associated with increased risk of events at all time points (odds ratio (OR) per one IQR = 1.5–1.7, all p < 0.009). At year 1, detectable CMV was associated with increased risk of events in most adjusted models (OR = 1.4–1.8, p-values ranging 0.03–0.17). Higher levels of CMV and EBV correlated with multiple inflammatory markers and lower CD4/CD8 ratio. Conclusions: In PWH starting ART, CMV and EBV in PBMC were associated with development of non-AIDS events. Clinical trials will be needed to understand causal mechanisms and ways to interrupt them. Correspondence to Sara Gianella, MD, Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA 92093-0679, USA. E-mail: gianella@ucsd.edu Received 5 August, 2019 Revised 5 December, 2019 Accepted 14 December, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2020 Wolters Kluwer Health, Inc.

The impact of self-selection based on HIV risk on the cost-effectiveness of pre-exposure prophylaxis in South Africa Objectives: We explored the impact and cost-effectiveness of pre-exposure prophylaxis (PrEP) provision to different populations in South Africa, with and without effective self-selection by individuals at highest risk of contracting HIV (through concurrent partnerships and/or commercial sex). Design and methods: We used a previously-developed HIV transmission model to analyse the epidemiological impact of PrEP provision to adolescents, young adults, pregnant women, female sex workers (FSWs) and men who have sex with men (MSM), and data from South African PrEP programmes to estimate the cost and cost-effectiveness of PrEP (cost in 2019 USD per HIV infection averted over 20 years, 2019–38). PrEP uptake followed data from early implementation sites, scaled-up linearly over 3 years, with target coverage set to 18% for adolescents, young adults and pregnant women, 30% for FSW and 54% for MSM. Results: The annual cost of PrEP provision ranges between $75-$134 per person. PrEP provision adolescents and young adults, regardless of risk behaviour, will each avert 3.2%-4.8% of HIV infections over 20 years; provision to high-risk individuals only has similar impact at lower total cost. The incremental cost per HIV infection averted is lower in high-risk vs. all-risk sub-populations within female adolescents ($507 vs. $4,537), male adolescents ($2,108 vs. $5,637), young women ($1,592 vs. $10,323) and young men ($2,605 vs. $7,715), becoming cost saving within 20 years for high-risk adolescents, young women, MSM and FSWs. Conclusions: PrEP is an expensive prevention intervention, but uptake by those at highest risk of HIV infection will make it more cost-effective, and cost-saving after 14–18 years. Correspondence to Lise Jamieson, MSc, Statistics, Health Economics and Epidemiology Research Office, Johannesburg, South Africa. E-mail: ljamieson@heroza.org Received 30 September, 2019 Revised 14 December, 2019 Accepted 20 December, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2020 Wolters Kluwer Health, Inc.

Plasma and antibody glycomic biomarkers of time to HIV rebound and viral setpoint Objective: HIV cure research urgently needs to identify pre-Analytic Treatment Interruption (ATI) biomarkers of time-to-viral-rebound and viral setpoint to mitigate the risk of ATI and accelerate development of a cure. We previously reported that galactosylated IgG glycans, G2, negatively correlate with cell-associated HIV DNA and RNA during antiretroviral therapy (ART). We hypothesized that this and other plasma glycomic traits can predict time-to-viral-rebound and viral setpoint upon ART cessation. Design: We profiled the circulating glycomes (plasma and bulk IgG) of two geographically-distinct cohorts: (1) Philadelphia Cohort – 24 HIV-infected, ART-suppressed individuals who had participated in an open-ended ATI study without concurrent immunomodulatory agents. (2) Johannesburg Cohort – 23 HIV-infected, ART-suppressed individuals who had participated in a two-week ATI. Methods: Capillary electrophoresis and lectin microarray were used for glycomic analyses. Cox proportional-hazards model and log-rank test were used for statistical analyses. Results: Higher pre-ATI levels of the IgG glycan, G2, were significantly associated with a longer time-to-viral-rebound (hazard ratio (HR) = 0.12, P = 0.05). In addition to G2, we identified several predictive glycomic traits in plasma, e.g., levels of FA2BG1, a non-sialylated, core-fucosylated glycan, associated with a longer time-to-viral-rebound (HR = 0.023, P = 0.05), whereas FA2G2S1, a sialylated glycan, associated with a shorter time-to-viral-rebound (HR = 24.1, P = 0.028). Additionally, pre-ATI plasma glycomic signatures associated with lower viral setpoint, e.g., T-antigen (Galβ1-3GalNAc) (r = 0.75, P = 0.0007), or higher viral setpoint, e.g., polylactosamine (r = -0.58, P = 0.01). These results were initially validated in the Johannesburg Cohort. Conclusions: We describe first-in-class, non-invasive, plasma and IgG glycomic biomarkers that inform time-to-viral-rebound and viral setpoint in two geographically-distinct cohorts. Correspondence to Mohamed Abdel-Mohsen, PhD, Assistant Professor, Vaccine and Immunotherapy Center, The Wistar Institute Wistar Assistant Professor, Perelman School of Medicine at the University of Pennsylvania 3601 Spruce Street Philadelphia, PA 19104. Tel: +215 898 6008; e-mail: mmohsen@Wistar.org Received 19 November, 2019 Revised 21 December, 2019 Accepted 11 January, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2020 Wolters Kluwer Health, Inc.

Depot medroxyprogesterone acetate (Depo-Provera) administration increases cervical CCR5+CD4+ T cells and induces immunosuppressive milieu at the cervicovaginal mucosa: a 3-month longitudinal study Objectives: Depot medroxyprogesterone acetate (Depo-Provera) is the most commonly used injectable hormone contraceptive in Sub-Sahara Africa where HIV incidence is high. We determined the impact of Depo-Provera on cervical immune cells and mediators in healthy women. Methods: In this longitudinal study, vaginal, endocervical, and rectal swabs were collected at baseline (visit 1), one month (visit 2), and three months (visit 3) after Depo-Provera injection. Cervical cells were collected by cytobrush and immune markers on cervical CD4+ T cells were analyzed by multicolor flow cytometry at 3 different visits. The levels of immune mediators in cytobrush supernatants as well as vaginal, cervical, and rectal secretions from swabs were analyzed by multiplex assays and ELISA. Results: Compared to baseline levels we found a significant increase in the frequency of cervical CCR5+CD4+ T cells and a significant decrease in the frequency of cervical central memory CD4+ T cells. Depo-Provera treatment had little effect on expression of immune mediators in rectal mucosa but significantly suppressed numerous immune mediators at cervicovaginal mucosa. Levels of MCP-1, G-CSF, IL-6, IL-10, GM-CSF, and IP-10 were significantly decreased in both vaginal and cervical secretions after Depo-Provera injection. In cervical samples collected by cytobrush, we found reduced levels of 22 of 25 immune mediators after Depo-Provera injection. Changes in immune mediators differed between vaginal and cervical mucosa, demonstrating compartment-specific responses. Conclusion: Depo-Provera altered immune profiles of cervical CD4+ T cells and suppressed host immune response at cervicovaginal mucosa, suggesting its likely effect on transmission of sexually transmitted infections including HIV. Correspondence to Theresa L. Chang, Public Health Research Institute, Rutgers, New Jersey Medical School, 225 Warren Street, Newark, NJ 07103, USA. Tel: +973 854 3265; fax: +973 854 3101; e-mail: Theresa.chang@rutgers.edu Received 2 August, 2019 Revised 31 December, 2019 Accepted 4 January, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2020 Wolters Kluwer Health, Inc.

High levels of genetically-intact HIV in HLA-DR+ memory T-cells indicates their value for reservoir studies Objective: The contribution of HLA-DR+ memory CD4+ T-cells to the HIV reservoir during prolonged antiretroviral therapy is unclear as these cells are commonly excluded when assessing for replication-competent HIV. To address this issue, we examined the distribution of genetically intact HIV DNA within HLA-DR- and HLA-DR+ memory CD4+ T-cells and the RNA transcriptional profile of these cells during ART. Design/Methods: Full-length DNA sequencing was used to examine the HIV DNA landscape within HLA-DR+ and HLA-DR- memory CD4+ T-cells. RNA quantification and sequencing was used to interrogate the relationship between HLA-DR status and HIV RNA transcription. Results: HLA-DR+ CD4+ T-cells contained a high frequency of genetically-intact HIV genomes, contributing over half of the genetically-intact viral sequences to the reservoir. Expansions of genetically identical sequences were identified in all T-cell subsets, indicating that cellular proliferation maintains genetically-intact and defective viral DNA during therapy. Intracellular HIV RNA levels in HLA-DR+ and HLA-DR- T-cells were not statistically different by either LTR qPCR quantification or single-genome RNA sequencing of the p6-RT region. Conclusions: The high proportion of intact viral DNA sequences in the proliferative HLA-DR+ subset suggests they are critical in maintaining HIV infection during effective therapy. As such, these cells should be included in any immune intervention targeting HIV during effective therapy. Correspondence to Bethany A. Horsburgh, The Westmead Institute of Medical Research, 176 Hawkesbury Road, Westmead, Australia. Tel: +2145 +61 2 8627 3000; e-mail: bethany.horsburgh@sydney.edu.au Received 12 September, 2019 Revised 14 November, 2019 Accepted 22 November, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2020 Wolters Kluwer Health, Inc.