Cannabinoids and inflammation: Implications for People Living with HIV Thanks to the success of modern antiretroviral therapy (ART), people living with HIV (PLWH) have life expectancies which approach that of persons in the general population. However, despite the ability of ART to suppress viral replication, PLWH have high levels of chronic systemic inflammation which drives the development of comorbidities such as cardiovascular disease, diabetes and non-AIDS associated malignancies. Historically, cannabis has played an important role in alleviating many symptoms experienced by persons with advanced HIV infection in the pre-ART era and continues to be used by many PLWH in the ART era, though for different reasons. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the phytocannabinoids which have received most attention for their medicinal properties. Due to their ability to suppress lymphocyte proliferation and inflammatory cytokine production, there is interest in examining their therapeutic potential as immunomodulators. CB2 receptor activation has been shown in vitro to reduce CD4 T-cell infection by CXCR4-tropic HIV and to reduce HIV replication. Studies involving SIV-infected macaques have shown that Δ9-THC can reduce morbidity and mortality and has favourable effects on the gut mucosal immunity. Furthermore, Δ9-THC administration was associated with reduced lymph node fibrosis and diminished levels of SIV proviral DNA in spleens of rhesus macaques compared with placebo-treated macaques. In humans, cannabis use does not induce a reduction in peripheral CD4 T-cell count or loss of HIV virological control in cross-sectional studies. Rather, cannabis use in ART-treated PLWH was associated with decreased levels of T-cell activation, inflammatory monocytes and pro-inflammatory cytokines secretion, all of which are related to HIV disease progression and co-morbidities. Randomized clinical trials should provide further insights into the ability of cannabis and cannabinoid-based medicines to attenuate HIV-associated inflammation. In turn, these findings may provide a novel means to reduce morbidity and mortality in PLWH as adjunctive agents to ART. Correspondence to Cecilia T. Costiniuk, Dr, Chronic Viral Illnesses Service, McGill University Health Centre, Montreal, Quebec Canada, Royal Victoria Hospital: Glen Site; 1001 boulevard Decarie, Montreal, Quebec, H4A 3J1. Tel: +14-843-2090; fax: +514-843-2092; e-mail: cecilia.costiniuk@mcgill.ca Received 6 August, 2019 Accepted 8 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Social Harms in Female-INITIATED hiv prevention method RESEARCH: state of the evidence Objectives: Assessment of safety is an integral part of real-time monitoring in clinical trials. In HIV prevention research, safety of investigational products and trial participation has been expanded to include monitoring for “social harms” (SH), generally defined as negative consequences of trial participation that may manifest in social, psychological, or physical ways. Further research on SH within HIV prevention research is needed to understand the potential safety risks for women and advance the implementation of prevention methods in real-world contexts. Methods: Secondary analysis of quantitative data from three randomized, double-blind, placebo-controlled trials of microbicide candidates in sub-Saharan Africa was conducted. Additionally, we assessed data from two prospective cohort studies that included participants who became HIV-positive or pregnant during parent trials. Results: SH reporting was low across the largest and most recent microbicide studies. SH incidence per 100 person-years ranged from 1.10 (95% CI: 0.78–1.52) to 3.25 (95% CI: 2.83–3.74) in the phased trials. Reporting differed by dosing mechanism (e.g. vaginal gel, oral tablet, ring) and study, most likely as a function of measurement differences. SH were most frequently associated with male partners, rather than, for example, experiences of stigma in the community. Conclusions: Measurement and screening for SH is an important component of conducting ethical research of novel HIV prevention methods. To date SH incidence reported in microbicide trials has been relatively low (<4% per 100py), and the majority have been partner-related events. However, any incidence of SH within the context of HIV prevention is important to capture and understand for the safety of individual women, and for the successful impact of prevention methods in a real-world context. Correspondence to Elizabeth T. Montgomery, E-mail: emontgomery@rti.org Received 28 February, 2019 Revised 12 July, 2019 Accepted 19 July, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Serious clinical events in HIV-positive persons with chronic kidney disease (CKD) Objectives: Predictors of chronic kidney disease (CKD) amongst HIV-positive persons are well established, but insights into the prognosis after CKD including the role of modifiable risk factors are limited. Design: Prospective cohort study Methods: D:A:D participants developing CKD (confirmed, >3 months apart, eGFR ≤ 60 mL/min/1.73 m2 or 25% eGFR decrease when eGFR ≤ 60) were followed to incident serious clinical events (SCE); end stage renal (ESRD) and liver disease, cardiovascular disease (CVD), AIDS- and non-AIDS defining malignancies (NADM), other AIDS or death, 6 months after last visit or 02.01.2016. Poisson regression models considered associations between SCE and modifiable risk factors. Results: During 2.7 (IQR 1.1–5.1) years median follow-up 595 persons with CKD (24.1%) developed a SCE (incidence rate 68.9/1000 PYFU [95%CI 63.4–74.4]) with 8.3% [6.9–9.0] estimated to experience any SCE at one year. The most common SCE was death (12.7%), followed by NADM (5.8%), CVD (5.6%), other AIDS (5.0%) and ESRD (2.9%). Crude SCE ratios were significantly higher in those with vs. without CKD, strongest for ESRD (65.9 [43.8–100.9]) and death (4.8 [4.3–5.3]). Smoking was consistently associated with all CKD-related SCE. Diabetes predicted CVD, NADM and death, while dyslipidaemia was only significantly associated with CVD. Poor HIV-status predicted other AIDS and death, eGFR < 30 mL/min/1.73m2 predicted CVD and death and low BMI predicted other AIDS and death. Conclusion: In an era where many HIV-positive persons require less monitoring due to efficient antiretroviral treatment, persons with CKD carry a high burden of SCE. Several potentially modifiable risk factors play a central role for CKD-related morbidity and mortality. Correspondence to Lene Ryom, Department of Infectious Diseases, CHIP, Section 2100, Rigshospitalet, Finsencentret, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen O. Tel: +45 35 45 57 65; fax: +45 35 45 57 57; e-mail: Lene.ryom.nielsen@regionh.dk Received 16 April, 2019 Revised 23 June, 2019 Accepted 24 June, 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 © 2019 Wolters Kluwer Health, Inc.

Mycoplasma genitalium infection among HIV-infected pregnant African women and implications for mother-to-child transmission of HIV Objective: Many sexually transmitted infections (STIs) increase risk of mother-to-child transmission (MTCT) of HIV, but the effect of Mycoplasma genitalium (MG) is not known. We hypothesized that MG infection would be common among HIV-infected pregnant women and could be associated with in utero and intrapartum MTCT. Design: Observational case-cohort study Methods: This study used specimens from a Kenyan perinatal MTCT cohort (1999–2005) involving HIV-infected women and their infants, who received short-course zidovudine for prevention of MTCT. Vaginal swabs collected at 32 weeks gestation were tested for MG using a transcription-mediated amplification assay. Infant perinatal HIV infection was determined at birth and 4 weeks of age by DNA PCR. Using a case-cohort design, a random sample was generated with 3:1 control: case ratio; prevalence and correlates of MG were assessed with Chi-squared and t-tests; predictors of infant outcomes were analyzed using logistic regression. Results: Among 220 HIV-infected pregnant women evaluated, 47 women (21.4%) had MG. Antenatal MG infection was associated with higher HIV RNA in plasma (5.0 vs. 4.6 log10 copies/ml in MG-positive vs. MG-negative women, p = 0.02) at 32 weeks. Women with MG were less likely to report prior STIs and genital ulcers (both p = 0.05). There was no association found between exposure to MG and perinatal MTCT (OR = 0.72, 95% CI 0.35, 1.51, p = 0.39). Conclusions: Vaginal MG infection was frequently detected among Kenyan HIV-infected pregnant women and was associated with higher plasma HIV levels, but was not associated with perinatal transmission of HIV. Correspondence to Alison C. Roxby, MD, MSc, Departments of Medicine and Global Health, University of Washington, PO Box 359909, Seattle, WA 98104. Tel: +206 543 4278; fax: +206 543 4818; e-mail: aroxby@uw.edu Received 10 April, 2019 Revised 20 June, 2019 Accepted 27 June, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

The proportion of CD57+ cells among effector CD8+ T cells is lower HIV controllers compared to ART treated patients Background: HIV infection has often been linked to faster immune aging. We sought to determine whether or not treatment-naïve spontaneous HIV-1 controllers (HICs) and ART-exposed patients differ with regard to the expression of cell senescence markers. Methods: Eighty-eight chronically infected HICs and ART-exposed patients (median time since infection: 15 years) with an undetectable plasma HIV RNA load (for at least the previous two years) were included. We used flow cytometry to measure immunosenescence markers (KLRG-1 and CD57) expression in fresh blood samples collected from patients and healthy donors. Results: For the CD8+ T cell population as a whole, the ART-exposed but not the HIC patients exhibited a much higher proportion of KLRG-1+ and CD57+ CD8+ T cells than HDs. For the CD8+ T cell subsets, HICs had a lower proportion of CD57+ effector CD8+ T cells than ART patients or HDs, whereas the proportions of KLRG-1+ effector were similar. A similar trend was observed for terminal effectors. No impact of age, gender or standard parameters of infection (CD4 percentage, protective HLA allele, viral blips) was observed. The difference in the proportion of CD57+ cells between HIC and ART was observed more specifically in long-term infected patients (>20 years). However, when considering the CD57- effector memory and effector subsets, the cytotoxic granule content was greater in HICs than in ART. Conclusion: The proportion of CD57+ effector CD8+ T cells is lower in HICs than in ART-exposed patients. This profile may be beneficial by ensuring limited senescence associated with consistent cytotoxic potential. Correspondence to Christine Bourgeois, INSERM U1184, Faculté de Médecine Du Kremlin-Bicêtre, 63 avenue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France; e-mail: christine.bourgeois@u-psud.fr Received 23 February, 2019 Revised 31 July, 2019 Accepted 31 July, 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 © 2019 Wolters Kluwer Health, Inc.

Estimating and projecting the number of new HIV diagnoses and incidence in Spectrum's case surveillance and vital registration tool Objective: The United Nations Program on HIV/AIDS-supported Spectrum software package is used by most countries worldwide to monitor the HIV epidemic. In Spectrum, HIV incidence trends among adults (aged 15–49 years) are derived by either fitting to seroprevalence surveillance and survey data or generating curves consistent with case surveillance and vital registration data, such as historical trends in the number of newly diagnosed infections or AIDS-related deaths. This article describes development and application of the case surveillance and vital registration (CSAVR) tool for United Nations Program on HIV/AIDS’ 2019 estimate round. Methods: Incidence in CSAVR is either estimated directly using single logistic, double logistic, or spline functions, or indirectly via the ‘r-logistic’ model, which represents the (log-transformed) per-capita transmission rate using a logistic function. The propensity to get diagnosed is assumed to be monotonic, following a Gamma cumulative distribution function and proportional to mortality as a function of time since infection. Model parameters are estimated from a combination of historical surveillance data on newly reported HIV cases, mean CD4+ at HIV diagnosis and estimates of AIDS-related deaths from vital registration systems. Bayesian calibration is used to identify the best fitting incidence trend and uncertainty bounds. Results: We used CSAVR to estimate HIV incidence, number of new diagnoses, mean CD4+ at diagnosis and the proportion undiagnosed in 31 European, Latin American, Middle Eastern, and Asian-Pacific countries. The spline model appeared to provide the best fit in most countries (45%), followed by the r-logistic (25%), double logistic (25%), and single logistic models. The proportion of HIV-positive people who knew their status increased from about 0.31 [interquartile range (IQR): 0.10–0.45] in 1990 to about 0.77 (IQR: 0.50–0.89) in 2017. The mean CD4+ at diagnosis appeared to be stable, decreasing from 410 cells/μl (IQR: 224–567) in 1990 to 373 cells/μl (IQR: 174–475) by 2017. Conclusion: Robust case surveillance and vital registration data are routinely available in many middle-income and high-income countries while HIV seroprevalence surveillance and survey data may be scarce. In these countries, the CSAVR offers a simpler, improved approach to estimating and projecting trends in both HIV incidence and knowledge of HIV status. Correspondence to Severin G. Mahiane, Center for Modeling and Analysis, Avenir Health, 655 Winding Brook Dr Suite 4040, Glastonbury, Connecticut, USA. E-mail: GMahiane@avenirhealth.org Received 14 April, 2019 Accepted 25 July, 2019 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0 Copyright © 2019 Wolters Kluwer Health, Inc.

The use of molecular markers for cervical screening of women living with hiv in South Africa Objective: To determine the performance of molecular screening strategies for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in comparison with cytology screening in women living with HIV (WLHIV). Design: post-hoc analysis using data from a South African study cohort. Methods: Cytology and human papillomavirus (HPV) based strategies were evaluated, including single test and FAM19A4/miR124-2 methylation triage strategies. Participants underwent cytology screening and a colposcopy-directed biopsy. Valid results on cytology, HPV status, 16/18 genotyping, and histology were available for 318 women. Detection of HPV and FAM19A4/miR124-2 hypermethylation was performed on DNA from cervical scrapes. Histological diagnosis of CIN3+ was used as outcome. Results: Cytology provided highest specificity (91.6%), but lowest sensitivity (59.3%), whereas a single HPV test provided highest sensitivity (83.1%), but lowest specificity (66.4%). Combining cytology with methylation did not improve the performance compared with cytology alone: a slight increase in sensitivity was seen, at the cost of a decrease in specificity. Triage of high-risk HPV positive women with methylation increased specificity (76.1%) compared with a single HPV or cytology test, while maintaining acceptable sensitivity (72.9%). Similar performance was observed for HPV16/18 with methylation triage (sensitivity 79.7%, specificity 74.8%). The number of women needed to refer to detect one CIN3+ ranged from 1.5 (cytology) to 2.6 (single HPV test). Conclusions: Molecular screening strategies using HPV, with or without HPV16/18 genotyping, and FAM19A4/miR124-2 methylation have higher sensitivity with an acceptable loss in specificity compared with current cytology screening and are efficient for the detection of CIN3+ in South African WLHIV. Correspondence to Wieke W. Kremer, Amsterdam UMC, location VU University Medical Center, department of Pathology, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands. Tel: +31 20 444 51 02; e-mail: w.kremer@amsterdamumc.nl Received 27 May, 2019 Revised 16 July, 2019 Accepted 25 July, 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/4.0 Copyright © 2019 Wolters Kluwer Health, Inc.

Antibody-mediated control of HIV-1 infection through an alternative pathway It remains unclear if therapeutic enhancement of IgG antibody responses against HIV-1 envelope glycoproteins might contribute to depletion of HIV-1 cellular reservoirs and/or long-term control of HIV-1 infection without antiretroviral therapy. Here, it is proposed that enhancement of an alternative pathway of antibody-mediated control of HIV-1 infection might achieve these aims. The main components of this pathway are IgG1 and probably IgG2 antibody responses against HIV-1 p17 and/or p24, generated at least in part by stimulation of IgM+ memory B cells, that mediate an opsonophagocytic antibody response against virion- and cell-free HIV-1 capsids (containing HIV RNA) resulting in formation of capsid/antibody complexes, which are phagocytosed by plasmacytoid dendritic cells via FcγRIIa and augment IFN-α production, via TLR7, that suppresses HIV-1 replication in CD4+ T cells. Substantiation of this hypothesis would support the development of therapeutic vaccination strategies that enhance both T cell and antibody responses against HIV-1 Gag-encoded antigens. Correspondence to Martyn French, The University of Western Australia (M574), 35 Stirling Highway, Crawley, WA 6009, Australia. E-mail: martyn.french@uwa.edu.au Received 22 January, 2019 Revised 6 April, 2019 Accepted 3 June, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Interventions to reduce gender-based violence among young people living with or affected by HIV/AIDS in low- and middle- income countries Objective(s): This study explored the effectiveness of gender-based violence (GBV) interventions on young people living with or affected by HIV in low- and middle-income countries (LMICs). Design: Systematic review and meta-analysis. Methods: We pre-registered a protocol, then searched thirteen databases and grey literature. We screened randomised and quasi-experimental studies (n = 2199) of young people (aged 10–24) living with or affected by HIV in LMICs. Outcomes were GBV and/or GBV-related attitudes. We appraised the data for risk of bias and quality of evidence. Narrative syntheses and multi-level random effects meta-analyses were conducted. Results: We included 18 studies evaluating 21 interventions. Intervention arms were categorised as: a) sexual health and social empowerment (SHSE) (n = 7); b) SHSE plus economic strengthening (n = 4); c) self-defence (n = 3); d) safer schools (n = 2); e) economic strengthening only (n = 2); f) GBV sensitisation (n = 2) and g) safer schools plus parenting (n = 1). Risk of bias was moderate/high and quality of evidence low. Narrative syntheses indicated promising effects on GBV exposure, but no or mixed effects on GBV perpetration and attitudes for self-defence and GBV sensitisation interventions. Safer schools interventions showed no effects. For SHSE interventions and SHSE plus economic strengthening, meta-analysis showed a small reduction in GBV exposure but not perpetration. Economic-only interventions had no overall effect. Conclusions: SHSE, SHSE plus and self-defence and gender sensitisation interventions may be effective for GBV exposure and GBV-related attitudes but not for GBV perpetration. However, the quality of evidence is poor. Future intervention research must include both boys and girls, adolescents living with HIV and key populations. Correspondence to Franziska Meinck, Department of Social Policy and Intervention, Oxford University, Oxford, OX1 2ER. E-mail: Franziska.Meinck@spi.ox.ac.uk Received 13 March, 2019 Revised 3 July, 2019 Accepted 5 July, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Prevalence and risk factors of prolonged QT interval and electrocardiographic abnormalities in persons living with HIV Abnormal electrocardiograms (ECG) are associated with increased risk of arrhythmias and sudden cardiac death. We aimed to investigate the prevalence and associated risk factors of prolonged QTc and major ECG abnormalities, in persons living with HIV (PLWH) and uninfected controls. Design: PLWH aged ≥40 were recruited from the Copenhagen comorbidity in HIV infection (COCOMO) study and matched on sex and age to uninfected controls from the Copenhagen General Population Study. Methods: ECGs were categorized according to Minnesota Code Manual of ECG Findings definition of major abnormalities. A QT interval corrected for heart rate (QTc) >440ms in males and >460ms in females was considered prolonged. Pathologic Q-waves were defined as presence of major Q-wave abnormalities. Results: ECGs were available for 745 PLWH and 2,977 controls. Prolonged QTc was prevalent in 9% of PLWH and 6% of controls, p = .052. Pathologic Q-waves were more common in PLWH (6%) than in controls (4%), p = .028. There was no difference in prevalence of major ECG abnormalities between PLWH and controls, p = .987. In adjusted analyses, HIV was associated with a 3.6ms[1.8–5.4] longer QTc interval, p < .001, and HIV was independently associated with prolonged QTc (adjusted odds ratio: 1.59 [1.14–2.19]), p = .005. HIV was borderline associated to pathologic Q-waves after adjusting, p = .051. Conclusion: HIV was associated with higher odds ratio of prolonged QTc after adjustment for cardiovascular risk factors, but analyses were not adjusted for QT-prolonging medication. Although evidence indicated more pathologic Q-waves in PLWH, the risk seemed to be associated mainly with an adverse risk profile. Correspondence to Susanne Dam Nielsen, MD, DMSc, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark. E-mail: sdn@dadlnet.dk Received 20 March, 2019 Revised 12 June, 2019 Accepted 16 June, 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 © 2019 Wolters Kluwer Health, Inc.