Co-morbidities of HIV infection: role of Nef-induced impairment of cholesterol metabolism and lipid raft functionality Combination anti-retroviral therapy (cART) has dramatically changed the outcome of HIV infection, turning it from a death sentence to a manageable chronic disease. However, co-morbidities accompanying HIV infection, such as metabolic and cardio-vascular diseases, as well as cognitive impairment, persist despite successful virus control by cART and pose considerable challenges to clinical management of people living with HIV (PLWH). These co-morbidities involve a number of pathological processes affecting a variety of different tissues and cells, making it challenging to identify a common cause(s) that would link these different diseases to HIV infection. In this article, we will present evidence that impairment of cellular cholesterol metabolism may be a common factor driving pathogenesis of HIV-associated co-morbidities. Potential implications for therapeutic approaches are discussed. Correspondence to Dr. Michael Bukrinsky, GWU SMHS, 2300 Eye St. NW, Washington, DC 20037, USA. E-mail: mbukrins@gwu.edu Received 24 June, 2019 Revised 9 August, 2019 Accepted 9 September, 2019 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 © 2019 Wolters Kluwer Health, Inc.

Brexit and UK citizens with HIV residing in Spain: A matter of public health Objective: Explore the implications of Brexit from the perspectives of British citizens with HIV residing in Spain (BHIV-RS). Design: UK is due to leave the EU on 31st October 2019, creating uncertainty on the rights enjoyed by EU citizens abroad. Spain is one of the main concerns because almost 30% of the British citizens living in others EU countries live there. Several legal consultations of BHIV-RS have come to the HIV Legal Clinic of the University of Alcalá asking about the right of access to ART after Brexit. Methods: We have studied the healthcare regulatory framework at the European and Spanish levels. This regulatory framework guarantees the right to healthcare in any country of the EU on equal terms with the citizens of the hosting country. Results: If the Withdrawal Agreement is agreed, then reciprocal healthcare rights of BHIV-RS will continue. Without Withdrawal Agreement BHIV-RS will have to rely on any rights which they may be able to claim under the Spanish system unless there is a bilateral agreement. In Spain, access to ART is free and granted by NHS but, constitutionally, who is entitled and their healthcare benefits can be limited, as happened in 2012 with migrants. Conclusions: The events documented in relation to migrants provide a cautionary tale. While some BHIV-RS may have access to ART through private health insurance for the most part of them obtaining ART can be difficult and expensive particularly if they have related co-morbidities. A likely consequence would be the worsening of individual health (late presentations for HIV diagnosis increases the risk of dying) and public health (increases the transmission rate). Correspondence to Miguel A. Ramiro Avilés, University of Alcalá, Faculty of Law, 27 Libreros St, 28801 Alcalá de Henares (Madrid), Spain. E-mail: miguelangel.ramiro@uah.es Received 21 August, 2019 Revised 13 September, 2019 Accepted 16 September, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Switching from efavirenz to rilpivirine improves sleep quality and self-perceived cognition but has no impact on neurocognitive performances: Results from a randomized controlled trial Background: Efavirenz (EFV) association with neurocognitive (NC) impairment is debated. Whether switching away from EFV improves NC performances is still controversial. Methods: In a randomized open-label controlled trial, patients under effective treatment with tenofovir disoproxil-fumarate (TDF), emtricitabine (FTC) and EFV, who had altered NC assessment (Z-transformed score below −1 in ≥1 cognitive domains), depression, anxiety or low sleep-quality, were randomized 1:1 to immediate or delayed (24-weeks) switch to TDF/FTC/rilpivirine (RPV). Treatment efficacy, NC function, symptoms and quality of life were evaluated 12, 24 and 48 weeks after randomization. Findings: 74 patients were randomized to immediate (36 patients) or delayed switch (38 patients). At baseline, 63% and 25% of patients had z-scores below −1 in ≥1 NC or 2 domains, 31.1%, 17.6% and 44.6% had significant depression or anxiety symptoms or low sleep-quality. At week 24 (primary end-point), overall NC improvement was observed, with no statistically significant differences between arms, neither considering the global z-score (between arms difference +0.1; P=0.458), nor domain-specific z-scores. Patients switching away from EFV had significant greater improvement of sleep quality index (between arms difference −1.5; P = 0.011), self-reported cognitive failures (−6.2; P = 0.001) and CNS symptoms score (−5; P = 0.002), but not of anxiety or depression. No protocol defined virological failure, grade ≥3 lab abnormalities or drug-related serious adverse events were reported. Conclusions: Our results do not support the hypothesis that switching to RPV improves cognitive function in patient under stable treatment with EFV. Nonetheless, improvements in neuropsychiatric symptoms, sleep quality and self-perceived cognition were observed. Correspondence to Giuseppe Lapadula, M.D., Ph.D., San Gerardo Hospital, Monza, MB Italy. Tel: +g.lapadula@hsgerardo.org Received 19 May, 2019 Revised 4 August, 2019 Accepted 10 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

High soluble CD163 levels correlate with disease progression and inflammation in kenyan children with perinatal hiv-infection Objectives: CD163 is a hemoglobin scavenger receptor on monocytes and macrophages, cleaved to soluble CD163 (sCD163) in the plasma following activation. In HIV+ adults, sCD163 is linked to non-AIDS morbidity and predicts mortality, but there is limited data in children. We investigated sCD163 levels in HIV+ children and their correlations with disease progression, immune activation and gut mucosal damage. Design and Methods: We quantified sCD163 levels in Kenyan children aged 0-20 years with perinatal HIV infection, including 74 ART-naive (ART-) and 64 virally suppressed on ART (ART+), and 79 HIV unexposed-uninfected controls (HIV-). The cohort was divided into age groups 0–5 (younger) and 5–20 (older) years. Correlations between sCD163 and HIV viral load, %CD8, CD4:CD8 ratio, markers of T cell activation and proliferation, and gut mucosal damage were also assessed. Results: ART- children have higher sCD163 levels compared to HIV- and ART+ children (p ≤ 0.01); ART+ have equivalent sCD163 levels to HIV- children. In a prospective analysis, sCD163 levels decreased in older ART- children after 12 months of treatment (p < 0.0001). Regardless of age, sCD163 levels correlate with clinical disease progression measured by %CD4 T cells, CD4:CD8 T cell ratios and HIV viral load. Soluble CD163 levels directly correlate with T cell activation markers CD38, HLA-DR, and Ki67 (p ≤ 0.01). Conclusions: High plasma sCD163 levels in HIV+ children correlate with advancing disease and T cell activation. ART initiation normalizes sCD163 levels and may alleviate HIV-related morbidities and improve long-term pediatric outcomes. Correspondence to Alka Khaitan, Indiana University School of Medicine, Ryan White Center for Pediatric Infectious Diseases & Global Health; 705 Riley Hospital Drive, Suite 3032, Phase 3; Indianapolis, IN 46202. Tel: +317 944 3698; e-mail: akhaita@iu.edu Received 12 April, 2019 Revised 30 July, 2019 Accepted 8 August, 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.

No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV Objective: Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically-suppressed adults with HIV who switched from non-INSTI regimens to raltegravir- or dolutegravir-containing antiretroviral therapy. Design: Retrospective single-centre cohort. Methods: Adults who switched to raltegravir or dolutegravir before or between January-2015 and October-2017 were identified. Virologically-suppressed, treatment-experienced (≥2 years) individuals, ≥6 months on INSTI, with weight measurements ≤2years pre- and post-switch were included. Our analysis used a random effects model with linear slope pre- and post-INSTI with adjustment for age, gender, ethnicity, pre-switch-regimen (protease inhibitor vs. non-protease inhibitor), and raltegravir vs. dolutegravir use. Results: 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and body mass index (BMI) at switch, of 76.6 kg, and 25.3 kg/m2 respectively were included. Weight increased by an average of 0.63 kg/year (95% CI 0.17–1.09) pre-switch with no overall change in rate of weight gain post-switch [+0.05 kg/year (−0.61–0.71, p = 0.88)]. In our adjusted model, a transition from minimal weight change to weight gain post-switch was isolated to older individuals though this lacked statistical significance [e.g. +1.59 kg/year (−0.26–3.45) if aged 65 years]. Our findings did not differ by gender, ethnicity, pre-switch regimen, or raltegravir vs. dolutegravir. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone. Conclusion: We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically-suppressed individuals. Correspondence to James Edward Burns, MBBS, MSc, University College London Institute for Global Health, London, United Kingdom. E-mail: james.burns@ucl.ac.uk Received 21 June, 2019 Revised 20 August, 2019 Accepted 22 August, 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.

Adherence to tuberculosis preventive therapy measured by urine metabolite testing among people with HIV Objectives: Tuberculosis preventive therapy for people living with HIV is effective, widely recommended, and increasingly prescribed, but completion rates are less than ideal, and adherence is not typically monitored. We sought to quantify adherence to isoniazid preventive therapy using a urine metabolite assay. Design: Two cross-sectional surveys Setting: Rio de Janeiro, Brazil, 2008–2009; and Northwest Province, South Africa, 2018-2019 Participants: 203 Brazilian and 93 South African patients attending HIV clinics with active prescriptions for isoniazid preventive therapy Main outcome measures: Self-reported isoniazid adherence, paired with semiquantitative measurement of urine isoniazid metabolites. Results: By self-report, 90% of patients (95% confidence interval [CI] 86–93%) reported having taken a dose of isoniazid on the day of enrollment or the preceding day, and 91% (95% CI 87–94%) reported missing an average of one dose or fewer per week. By urine testing, only 65% (95% CI 59–70%) of all patients, and 69% (95% CI 63–74%) of those who reported having taken isoniazid on the current or preceding day, had detectable urine metabolites (expected in 95% of patients at 24 hours). Longer time since starting preventive therapy was independently associated with a negative urine test for isoniazid metabolites (adjusted prevalence ratio 1.11 per month of isoniazid, 95% CI 1.05–1.18). Conclusions: Adherence to isoniazid preventive therapy among patients with HIV in Brazil and South Africa is inadequate, is overestimated by self-report, and declines with time on treatment. Shorter regimens for TB preventive therapy may improve adherence and completion, but adherence support for all patients may be necessary. Correspondence to Emily A. Kendall, Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. E-mail: ekendall@jhmi.edu Received 4 July, 2019 Revised 19 August, 2019 Accepted 22 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Human papillomavirus infection and cervical dysplasia in HIV-positive women: potential role of the vaginal microbiota Objectives: To assess the associations between microbiological markers of vaginal dysbiosis and 1) incident/cleared/type-swap/persistent high-risk human papillomavirus (hrHPV) infection; and 2) incident/cured/cleared/persistent high-grade cervical intraepithelial neoplasia (CIN2+) while controlling for persistent hrHPV infection. Design: Two nested case-control studies (N = 304 and 236) within a prospective cohort of HIV-positive women in Johannesburg, South Africa. Methods: Participants were examined for hrHPV type (InnoLipA), cervical dysplasia (histology), and vaginal microbiota (VMB) composition (V3-V4 Illumina HiSeq 2x300 bp) at baseline and endline, a median of 16 months later. Results: Women with incident hrHPV compared to those who remained hrHPV-negative were less likely to have an optimal Lactobacillus crispatus/jensenii-dominated VMB type at endline (relative risk ratio (RRR) = 0.125, p = 0.019) but not at baseline. Having different hrHPV types at both visits was associated with multiple anaerobic dysbiosis markers at baseline (e.g. increased BV-anaerobes relative abundance: RRR = 3.246, p = 0.026). Compared to women without CIN2+ but with hrHPV at both visits, women with incident CIN2+ had increased Simpson diversity (RRR = 7.352, p = 0.028) and non-significant trends in other anaerobic dysbiosis markers at endline but not baseline. These associations persisted after controlling for age, hormonal contraception, and CD4+ count. Current hormonal contraceptive use (predominantly progestin-only injectables) was associated with increased CIN2+ risk over-and-above persistent hrHPV infection and independent of VMB composition. Conclusions: hrHPV infection (and/or increased sexual risk-taking) may cause anaerobic vaginal dysbiosis, but a bidirectional relationship is also possible. In this population, dysbiosis did not increase CIN2+ risk, but CIN2+ increased dysbiosis risk. The CIN2+ risk associated with progestin-only injectable use requires further evaluation. Correspondence to Janneke H.H.M. van de Wijgert, Institute of Infection and Global Health, University of Liverpool, Ronald Ross building, 8 West Derby Street, Liverpool L69 7BE, United Kingdom. Tel: +44 7557195108; E-mail: j.vandewijgert@liverpool.ac.uk Received 27 June, 2019 Revised 25 August, 2019 Accepted 28 August, 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.

Antiretroviral therapy adherence among treatment-naive HIV-infected patients: A retrospective cohort study Objective: To determine the incidence of antiretroviral therapy (ART) adherence among treatment-naive HIV infected patients and to evaluate the impact of single-tablet regimen (STR) on ART adherence among this population. Design: Retrospective cohort study. Methods: We used a nationally representative sample of IQVIA LRx Lifelink individual level pharmacy claims database during 2011–16, and defined adult patients with index date (first complete ART regimen prescription fill date) after June 30, 2011 as treatment-naive. We estimated ART adherence, measured as the proportion of days covered (PDC) during one year following the index date. We conducted multivariable analysis to identify the factors associated with optimum adherence (≥90% PDC). We also compared adherence between patients prescribed STR and multiple-tablet regimens (MTR) among those prescribed integrase strand transfer inhibitor (INSTI)- or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Results: Overall 42.9% of the patients were optimally adherent. Adherence was significantly lower among blacks, Hispanics and patients in low income communities. Adjusting for the covariates, patients on STR had higher incidence of optimum adherence compared to those on MTR among patients on INSTI-based regimens [49% vs 24%, Relative Risk (RR), 2.16 (95% CI: 1.96–2.26)], but no significant difference was observed among those on NNRTI-based regimen [45% vs 45%, RR, 1.12 (95% CI: 0.99–1.26)]. Conclusion: Low ART adherence observed among treatment naïve patients in this nationally representative study suggests the need for public health interventions to improve adherence among this population. Correspondence to Apurba Chakraborty, 1603W. Taylor St. MC 923, Chicago, IL 60612. Tel: +312 375 9292; e-mail: apurba.dr@gmail.com Received 20 April, 2019 Revised 28 August, 2019 Accepted 30 August, 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.

Pharmacokinetics and safety of a raltegravir containing regimen in HIV-infected children aged 2 to 12 years on rifampicin for tuberculosis Objectives: Drug-drug interactions limit current antiretroviral (ARV) treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and safe dose of RAL when administered with RIF to HIV and TB co-infected children. Design: P1101 is a Phase I/II open-label dose-finding study of RAL with RIF for children 2 to < 12 years of age beginning treatment for HIV and active TB. Setting: Four sites in South Africa. Methods: Chewable RAL was given at 12 mg/kg per dose twice daily (twice the usual pediatric dose) with two nucleoside reverse transcriptase inhibitors. Intensive RAL pharmacokinetic sampling was conducted 5 to 8 days after ARV therapy was initiated; a fourth ARV agent was then added. Results: Children were recruited into two age-defined groups: Cohort 1 (2 to <6 years old) and Cohort 2 (6 to <12 years old). Pharmacological targets (geometric mean (GM) AUC12 h of 14–45 μM-h and GM C12 h ≥75 nM) were reached in both Cohort 1 (28.8 μM-h and 229 nM) and Cohort 2 (38.8 μM-h and 228 nM). The RAL-based ART was well tolerated by most participants: one participant discontinued treatment due to Grade 4 hepatitis that was possibly treatment-related. At Week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/mL; 19 of 24 (79%) were below 50 copies/mL. Conclusions: Giving 12 mg/kg twice daily of the chewable RAL formulation achieved PK targets safely in HIV-infected children receiving RIF for TB. Correspondence to Paul Krogstad, MD, Departments of Pediatrics and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA Los Angeles, CA 90095;. e-mail: prkogstad@mednet.ucla.edu Received 18 March, 2019 Revised 15 August, 2019 Accepted 16 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Updates to the Spectrum/AIM model for estimating key HIV indicators at national and subnational levels Background: The Spectrum/AIM model is used by national programs and UNAIDS to prepare annual estimates of the status of the HIV epidemic in 170 countries. The model and assumptions are updated regularly under the guidance of the UNAIDS Reference Group on Estimates, Modelling and Projections in response to new data, studies and program needs. This article describes the most recent updates for the 2018 round of estimates. Methods: New data on AIDS-related mortality from Europe and Brazil have been used to update mortality rates of those not on antiretroviral therapy (ART). Household survey data and new studies of pregnant women, mothers, and children have been used to improve estimates of the number of HIV-positive pregnant and breastfeeding women and pediatric ART initiation. New tools to estimate geographic variation in HIV prevalence have been used to prepare district estimates of key indicators. Results: The 2018 version of Spectrum includes: new estimates of non-ART AIDS-related mortality by CD4+ count that depend on ART coverage; a procedure to estimate country-specific patterns of HIV incidence by age by fitting to prevalence by age from household surveys; an updated estimate of postpartum transmission with ART started before pregnancy of 0.023% per month; an updated estimate of retention on treatment at delivery of 80% for all women on ART; a somewhat older pattern of ART initiation by age that has 26% of new pediatric patients initiating ART at 10–14 years of age, 18% at 2–4 years of age, and 26% at 5–9 years of age; and a new tool for estimating key HIV indicators at the district level. Conclusion: The new methods and data implemented in the 2018 version of Spectrum allow national programs more flexibility in describing their programs and are intended to improve the estimates of adult mortality and pediatric HIV indicators. Correspondence to John Stover, Avenir Heath, Glastonbury, CT, 06033, USA. E-mail: JStover@avenirhealth.org Received 8 February, 2019 Accepted 22 August, 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 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.