Oral pre-exposure prophylaxis (PrEP) continuation, measurement, and reporting: a systematic review and meta-analysis Objective: To appropriately plan for rollout and monitor impact of oral pre-exposure prophylaxis (PrEP) it is important to understand PrEP continuation and come to a consensus on how best to measure PrEP continuation. This study reviews data on PrEP continuation to document how it is reported, and to compare continuation over time and across populations. Design: Systematic review and meta-analysis. Methods: We searched MEDLINE, Embase, and Global Health and reviewed abstracts from HIV conferences from 2017–2018 for studies reporting primary data on PrEP continuation. Findings were summarized along a PrEP cascade and continuation was presented by population at months 1, 6, and 12, with random-effects meta-analysis. Results: Of 2,578 articles and 596 abstracts identified, 41 studies were eligible covering 22,034 individuals. Continuation data were measured and reported inconsistently. Results showed high discontinuation at month 1 and persistent discontinuation at later time points in many studies. Pooled continuation estimates were 66% at month 1 (n = 5,348; 95% CI: 48%-82%), 63% at month 6 (n = 13,629; 95% CI: 48%-77%), and 71% at month 12 (n = 14,933; 95% CI: 60%-81%; higher estimate than previous timepoints due to inclusion of different studies). Adequate data were not available to reliably compare estimates across populations. Conclusions: This review found that discontinuation at 1 was high, suggesting PrEP initiations may be a poor measure of effectiveness. Continuation declined further over time in many studies, indicating existing cross-sectional indicators may not be adequate to understand PrEP use patterns. Studies do not measure continuation consistently, and consensus is needed. Correspondence to Kayla Stankevitz, MSc, FHI 360, 359 Blackwell Street, Suite 200, Durham, NC 27701 USA; e-mail: kstankevitz@fhi360.org Received 24 March, 2020 Revised 18 May, 2020 Accepted 26 May, 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.

Managing amphetamine use is critical to achieving HIV control No abstract available

First-line HIV treatment outcomes following the introduction of integrase inhibitors in UK guidelines: a cohort study Objective: To investigate the characteristics and outcomes of people who initiated different antiretroviral therapy (ART) regimens during the era of integrase strand transfer inhibitors (INSTIs). Design: UK-based observational cohort study. Methods: UK Collaborative HIV Cohort study participants were included if they had started ART between 1st January 2012 and 30th June 2017. Virological failure (VF) was defined as the first of two consecutive plasma HIV RNA > 50 copies/mL, at least six months after starting ART. Follow-up was censored at ART discontinuation, class switch or death. The risk of VF among those on INSTI, protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens was compared using Kaplan-Meier and Cox regression methods. Results: Of 12,585 participants, 45.6% started a NNRTI, 29.0% a PI and 25.4% an INSTI regimen. Over a median follow-up of 20.3 months (interquartile range 7.9–389), 7.5% of participants experienced VF. Compared to those starting an NNRTI regimen, people receiving INSTIs or PIs were more likely to experience VF: INSTI group adjusted hazard ratio [aHR] 1.52, 95% confidence interval [CI] 1.19–1.95, p = 0.0009; PI group aHR 2.70, 95% CI 2.27–3.21, p < 0.0001, likelihood ratio test p < 0.0001. Conclusions: First-line INSTI regimens were associated with a lower risk of VF than PI regimens but both groups were more likely to experience VF than those initiating treatment with a NNRTI. There is likely to be residual channelling bias resulting from selected use of INSTIs and PIs in specific clinical contexts, including in those with a perceived risk of poor adherence. Correspondence to Kate E.L. Bouzidi, Research Department of Infection & Population Health, Institute for Global Health, UCL Royal Free Campus, Rowland Hill Street, London NW3 2PF. Tel: +44 207 794 0500 ext 36762; e-mail: k.elbouzidi@ucl.ac.uk Received 15 January, 2020 Revised 5 May, 2020 Accepted 14 May, 2020 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 © 2020 Wolters Kluwer Health, Inc.

Sterol metabolism modulates susceptibility to HIV-1 Infection Background: 25-hydroxylase (CH25H) is an Interferon stimulated gene (ISG), which catalyzes the synthesis of 25-Hydroxycholesterol (25HC). 25HC intervenes in metabolic and infectious processes as controls cholesterol homeostasis and influences viral entry into host cells. We verified whether natural resistance to HIV-1 infection in HIV-1-exposed seronegative (HESN) individuals is at least partially mediated by particularities in sterol biosynthesis. Methods: Peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) isolated from 15 sexually-exposed HESN and 15 healthy controls (HC) were in vitro HIV-1-infected and analyzed for: 1) percentage of IFNα-producing plasmacytoid Dendritic Cells (pDCs); 2) Cholesterol signaling and inflammatory response RNA expression; 3) resistance to HIV-1 infection. MDMs from 5 HC were in vitro HIV-1-infected in the absence/presence of exogenously added 25HC. Results: IFNα-producing pDCs were augmented in HESN compared to HCs both in unstimulated and in in vitro HIV-1-infected PBMCs (p<0.001). An increased expression of CH25H and of a number of genes involved in cholesterol metabolism (ABCA1, ABCG1, CYP7B1, LXRα, OSBP, PPARγ, SCARB1) was observed as well; this, was associated with a reduced susceptibility to in vitro HIV-1-infection of PBMCs and MDMs (p<0.01). Notably, addition of 25HC to MDMs resulted in increased cholesterol efflux and augmented resistance to in vitro HIV-1-infection. Conclusions: Results herein show that in HESN sterol metabolism might be particularly efficient. This could be related to the activation of the IFNα pathway and results into a reduced susceptibility to in vitro HIV-1 infection. These results suggest a possible basis for therapeutic interventions to modulate HIV-1 infection. Correspondence to Irma Saulle, PhD, Chair of Immunology, Department of Biomedical and Clinical Sciences- L. Sacco, University of Milan, Via G.B.Grassi 74, 20157 Milan, Italy. Tel: +39 0250319679; e-mail: irma.saulle@unimi.it Received 17 March, 2020 Revised 6 May, 2020 Accepted 19 May, 2020 This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives 4.0 License, 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.

HIV-1-induced changes in HLA-C*03: 04-presented peptide repertoires lead to reduced engagement of inhibitory NK cell receptors Objective: Viral infections influence intracellular peptide repertoires available for presentation by HLA-I. Alterations in HLA-I/peptide complexes can modulate binding of KIRs and thereby the function of NK cells. While multiple studies have provided evidence that HLA-I/KIR interactions play a role in HIV-1 disease progression, the consequence of HIV-1 infection for HLA-I/KIR interactions remain largely unknown. Design: We determined changes in HLA-I-presented peptides resulting from HIV-1 infection of primary human CD4+ T-cells and assessed the impact of changes in peptide repertoires on HLA-I/KIR interactions. Methods: Liquid chromatography-coupled tandem mass spectrometry to identify HLA-I presented peptides, cell-based in vitro assays to evaluate functional consequences of alterations in immunopeptidome and atomistic molecular dynamics simulations to confirm experimental data. Results: A total of 583 peptides exclusively presented on HIV-1-infected cells were identified, of which only 1.4% represented HIV-1-derived peptides. Focusing on HLA-C*03:04/KIR2DL3 interactions, we observed that HLA-C*03:04-presented peptides derived from non-infected CD4+ T-cells mediated stronger binding of inhibitory KIR2DL3 than peptides derived from HIV-1-infected cells. Furthermore, the most abundant peptide presented by HLA-C*03:04 on non-infected CD4+ T-cells (VIYPARISL) mediated the strongest KIR2DL3-binding, while the most abundant peptide presented on HIV-1-infected cells (YAIQATETL) did not mediate KIR2DL3-binding. Molecular dynamics simulations of HLA-C*03:04/KIR2DL3 interactions in the context of these two peptides revealed that VIYPARISL significantly enhanced the HLA-C*03:04/peptide contact area to KIR2DL3 compared to YAIQATETL. Conclusions: These data demonstrate that HIV-1 infection-induced changes in HLA-I-presented peptides can reduce engagement of inhibitory KIRs, providing a mechanism for enhanced activation of NK cells by virus-infected cells. Correspondence to Marcus Altfeld, Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Martinistraße 52, 20251 Hamburg. E-mail: marcus.altfeld@leibniz-hpi.de; Ruhong Zhou, Computational Biology Center IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA. E-mail: ruhongz@us.ibm.com Received 28 January, 2020 Revised 8 May, 2020 Accepted 19 May, 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 4.0 License, 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.

Incidence and risk factors for tuberculosis among people with HIV on antiretroviral therapy in the UK Objective: The UK has a low tuberculosis incidence and earlier combination antiretroviral therapy (cART) is expected to have reduced incidence among people with HIV. Epidemiological patterns and risk factors for active tuberculosis were analysed over a 20 year period among people accessing HIV care at sites participating in the UK CHIC observational study. Design: Cohort analysis. Methods: Data were included for individuals over 15 years old attending for HIV care between 1996 and 2017 inclusive, with at least three months follow up recorded. Incidence rates of new tuberculosis events were calculated and stratified by ethnicity (white/black/other) as a proxy for tuberculosis exposure. Poisson regression models were used to determine the associations of calendar year, ethnicity and other potential risk factors after cART initiation. Results: 58,776 participants (26.3% female; 54.5% white, 32.0% black, 13.5% other/unknown ethnicity; median (interquartile range) age 34 (29–42) years) were followed for 546,617 person-years. 704 were treated for active tuberculosis (rate 1.3 [95% confidence interval (CI) 1.2–1.4]/1000 person-years). Tuberculosis incidence decreased from 1.3 [1.2–1.5] to 0.6 [0.4–0.9]/1000 person-years from pre-2004 to 2011–2017. The decline among people of black ethnicity was less steep than among those of white/other ethnicities, with incidence remaining high among black participants in the latest period (2.1 [1.4–3.1]/1000 person-years). 283 participants (191 (67%) black African) had tuberculosis with viral load < 50 copies/ml. Conclusions: Despite the known protective effect of cART against tuberculosis, a continuing disproportionately high incidence is seen among black African people. Results support further interventions to prevent tuberculosis in this group. Correspondence to Clare L. van Halsema, Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Delaunays Road, Manchester M8 5RB, UK. E-mail: clarevh@doctors.org.uk Received 30 March, 2020 Revised 19 May, 2020 Accepted 26 May, 2020 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 © 2020 Wolters Kluwer Health, Inc.

Population-level viral suppression among pregnant and postpartum women in a universal test and treat trial Objective(s): We sought to determine whether universal ‘test and treat’ (UTT) can achieve gains in viral suppression beyond universal antiretroviral treatment (ART) eligibility during pregnancy and postpartum, among women living with HIV. Design: A community cluster randomized trial. Methods: The SEARCH UTT trial compared an intervention of annual population testing and universal ART with a control of baseline population testing with ART by country standard, including ART eligibility for all pregnant/postpartum women, in 32 communities in Kenya and Uganda. When testing, women were asked about current pregnancy and live births over the prior year and, if HIV-infected, had their viral load measured. Between arms, we compared population-level viral suppression (HIV RNA <500 copies/ml) among all pregnant/postpartum HIV-infected women at study close (year 3). We also compared year-3 population-level viral suppression and predictors of viral suppression among all 15 to 45-year-old women by arm. Results: At baseline, 92 and 93% of 15 to 45-year-old women tested for HIV: HIV prevalence was 12.6 and 12.3%, in intervention and control communities, respectively. Among HIV-infected women self-reporting pregnancy/live birth, prevalence of viral suppression was 42 and 44% at baseline, and 81 and 76% (P = 0.02) at year 3, respectively. Among all 15 to 45-year-old HIV-infected women, year-3 population-level viral suppression was higher in intervention (77%) versus control (68%; P < 0.001). Pregnancy/live birth was a predictor of year-3 viral suppression in control (P = 0.016) but not intervention (P = 0.43). Younger age was a risk factor for nonsuppression in both arms. Conclusion: The SEARCH intervention resulted in higher population viral suppression among pregnant/postpartum women than a control of baseline universal testing with ART eligibility for pregnant/postpartum women. Correspondence to Jane Kabami, MPH, Clinical Epidemiology and Biostatistics Unit, School of Medicine, College of Health Sciences, Makerere University, P.O Box 7062, Kampala, Uganda. Tel: +256 776 411 044; e-mail: kabajane@yahoo.com Received 25 November, 2019 Revised 13 March, 2020 Accepted 26 March, 2020 Copyright © 2020 Wolters Kluwer Health, Inc.

High levels of resistance to nucleoside/nucleotide reverse transcriptase inhibitors in newly-diagnosed antiretroviral treatment naive children in sub-Saharan Africa Exposure of infants to antiretroviral drugs for prevention of mother-to-child transmission can induce resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). Data from nine national surveys of pretreatment drug resistance in children newly diagnosed with HIV show high levels of resistance to NRTIs included in first-line antiretroviral treatment (ART) regimens (dual abacavir-lamivudine/emtricitabine resistance). Additional research is needed to determine the impact of NRTI resistance on treatment response and optimize infant ART. Correspondence to Silvia Bertagnolio, Avenue Appia 20, Department of HIV, Hepatitis, and STI, World Health Organization, Geneva, Switzerland. Tel: +41 79 7288078; e-mail: bertagnolios@who.int Received 17 January, 2020 Revised 30 March, 2020 Accepted 7 April, 2020 Copyright © 2020 Wolters Kluwer Health, Inc.

Risk of HIV infection among adolescent girls and young women in age-disparate relationships in sub-Saharan Africa: a systematic review and meta-analysis Objective: To determine the association between age-disparate relationships and risk of Human Immunodeficiency Virus (HIV) infection among adolescent girls and young women (AGYW) aged 15–24 years. Design: Systematic review and meta-analysis of published studies until January 5, 2020 in sub Saharan Africa (SSA). Methods: We searched several electronic databases, grey literature, and hand searched reference list of included studies to identify eligible studies for data abstraction. We assessed the quality of included studies using Newcastle-Ottawa Scale for non-randomized studies. The DerSimonian-Laird random effects model was used to pool the overall results using risk ratios (RR), presented in a forest plot with 95% confidence interval (CI) and predictive interval (PI). Heterogeneity was assessed with Cochrane's Q-test and quantified with I-squared values. Publication bias was checked with funnel plots and Egger's test. Results: We included 24 studies with an overall sample size of 33,390. Data show that age-disparate relationships were significantly associated with unprotected sexual intercourse (pooled RR, 1.57; 95% CI, 1.34–1.83; 95% PI, 1.22–2.02), and higher risk for HIV infection (pooled RR, 1.39; 95 CI, 1.21–1.60; 95% PI, 0.80–2.42). Studies included in pooling risk of unprotected sexual intercourse were largely homogeneous (I-squared value= 0.0, p = 0.79) while those for HIV infection were heterogeneous (I-squared value = 89.0%, p < 0.01). We found no publication bias and no study influenced the meta-analytic results. Conclusions: Age-disparate relationships among AGYW are associated with increased risk of unprotected sexual intercourse and HIV infection in SSA. HIV prevention interventions should target this sub-population. Correspondence to Francis Bajunirwe, Department of Community Health, Faculty of Medicine, Mbarara University of Science and Technology, P.O. Box, 1410, Mbarara, Uganda; e-mail: fbaj@must.ac.ug Received 7 February, 2020 Revised 26 April, 2020 Accepted 5 May, 2020 Copyright © 2020 Wolters Kluwer Health, Inc.

Determining standardized causes of death of infants, children, and adolescents living with HIV in Asia Objective: To implement a standardized cause of death (CoDe) reporting and review process in order to systematically disaggregate causes of HIV-related deaths in a cohort of Asian children and adolescents. Design: Death-related data were retrospectively and prospectively assessed in a longitudinal regional cohort study. Methods: Children under routine HIV care at sites in Cambodia, India, Indonesia, Malaysia, Thailand, and Vietnam between 2008–2017 were followed. Causes of death were reported and then independently and centrally reviewed. Predictors were compared using competing risks survival regression analyses. Results: Among 5918 children, 5523 (93%; 52% male) had ever been on combination antiretroviral therapy (cART). Of 371 (6.3%) deaths, 312 (84%) occurred in those with a history of cART (crude all-cause mortality 9.6 per 1000 person-years; total follow-up time 32,361 person-years). In this group, median age at death was 7.0 (2.9–13) years; median CD4 count was 73 (16–325) cells/mm3. The most common underlying causes of death were pneumonia due to unspecified pathogens (17%), tuberculosis (16%), sepsis (8.0%), and AIDS (6.7%); 12% of causes were unknown. These clinical diagnoses were further grouped into AIDS-related infections (22%) and non-infections (5.8%), and non-AIDS-related infections (47%) and non-infections (11%); with 12% unknown, 2.2% not reviewed. Higher CD4 count and better weight-for-age z-score were protective against death. Conclusions: Our standardized cause of death assessment provides robust data to inform regional resource allocation for pediatric diagnostic evaluations and prioritization of clinical interventions, and highlight the continued importance of opportunistic and non-opportunistic infections as causes of death in our cohort. Correspondence to Annette H. Sohn, MD TREAT Asia/amfAR, Exchange Tower, 388 Sukhuvmit Road, Suite 2104, Klongtoey, Bangkok, Thailand 10110. Tel: +66 2 663 7561; e-mail: annette.sohn@treatasia.org Received 12 February, 2020 Revised 21 April, 2020 Accepted 27 April, 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.