Early cardiac dysfunction in children and young adults with perinatally acquired HIV Objective: To define the prevalence of early cardiac dysfunction in children and young adults with perinatally acquired HIV and predictors of cardiac function. Design: Cross-sectional design. Methods: Early cardiac dysfunction was defined as left ventricular (LV) global longitudinal strain z-score less than −2 or myocardial performance index at least 0.5 with normal LV ejection fraction. Regression models were fitted to assess the relationship between measures of cardiac function and HIV RNA levels, clinical variables, and markers of inflammation. Results: Six-hundred and forty-three individuals (mean age 14.1 ± 5.2 years) were enrolled. The average time on combination antiretroviral treatment was 6.8 ± 3.6 years. Nearly 28% of individuals met criteria for early cardiac dysfunction. Individuals with early cardiac dysfunction were older (15.3 vs. 13.5 years, P < 0.001), had more frequently detectable HIV RNA (52.5 vs. 41.7%, P = 0.018), were more likely exposed to azidothymidine or zidoudine (55.6 vs. 41.2%, P = 0.002), and had higher median level of plasma IL-6 concentrations (1.00 vs. 0.88 pg/ml, P = 0.011). Multivariable models show LV ejection fraction negatively associated with HIV RNA levels [β −0.18; 95% confidence interval (CI) −0.33, −0.03] and azidothymidine or zidoudine exposure (β −1.75; 95% CI −2.62, −0.88) and positively associated with proportion of life on combination antiretroviral treatment (β 2.65; 95% CI 0.90, 4.41). Higher myocardial performance index was positively associated with serum inflammation marker (IL-6 β 0.01; 95% CI 0.0001, 0.001). Left ventricular global longitudinal strain was not significantly associated with clinical and laboratory variables of interest. Conclusion: Over one-quarter of children and young adults living with HIV demonstrated evidence of cardiac dysfunction, which may be associated with increasing levels of systemic inflammation. Correspondence to Andrew W. McCrary, MD, MSc, Division of Pediatric Cardiology, Duke University Medical Center, 7506 Hospital North, DUMC Box 3090, Durham, NC 27710, USA. Tel: +1 919 681 5166; fax: +1 919 681 7892; e-mail: andrew.mccrary@duke.edu Received 3 September, 2019 Revised 17 October, 2019 Accepted 25 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Challenges to achieving and maintaining viral suppression among Canadian children living with perinatal HIV infection in the Early Pediatric Initiation Canada Child Cure Cohort Objectives: The objective of this study was to determine the time to, and durability of, viral suppression, among Canadian children living with HIV after initiation of combination antiretroviral therapy (cART). Design: Prospective, multicenter Canadian cohort study (Early Pediatric Initiation Canada Child Cure Cohort), using both prospective and retrospectively collected data. Methods: Kaplan–Meir survival estimates with Cox regression were used to determine the time to and risk factors for viral suppression, defined as two consecutive undetectable viral loads (<50 copies/ml) at least 30 days apart after initiation of cART. Results: A total of 228 children were enrolled between December 2014 and December 2018. The time to viral suppression was significantly shorter among children initiating cART after 5 vs. 5 years or less of age [adjusted hazard ratio (aHR) 1.57, 95% confidence interval (CI) 1.13–2.20], among those born after 2010 vs. prior (aHR 1.71, 95% CI 1.04–2.79), and among those without child protection services involvement (aHR 1.44, 95% CI 1.03–2.01). Overall, 27% of children had a viral rebound within 3 years of achieving viral suppression; the risk of viral rebound was significantly lower among children initiating cART after 5 vs. 5 years or less of age [adjusted odds ratio (aOR): 0.32, 95% CI 0.13–0.81], those whose families had not received social assistance (aOR 0.16, 95% CI 0.06–0.46), and females vs. males (aOR 0.51, 95% CI 0.26–0.99). Conclusion: Only 73% of the children in the Early Pediatric Initiation Canada Child Cure Cohort had maintained viral suppression 3 years after it was first achieved. Age at cART initiation, and socioeconomic factors were predictors of both time to viral suppression and risk of viral rebound in this cohort. Correspondence to Dr Fatima Kakkar, Pediatric Infectious Diseases Department, CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec, Canada. Tel: +1 514 345 4931x6885; e-mail: fatima.kakkar@umontreal.ca Received 15 July, 2019 Revised 11 November, 2019 Accepted 13 November, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Use of viral load to improve survey estimates of known HIV-positive status and antiretroviral treatment coverage Objective: To compare alternative methods of adjusting self-reported knowledge of HIV-positive status and antiretroviral (ARV) therapy use based on undetectable viral load (UVL) and ARV detection in blood. Design: Post hoc analysis of nationally representative household survey to compare alternative biomarker-based adjustments to population HIV indicators. Methods: We reclassified HIV-positive participants aged 15–64 years in the 2012 Kenya AIDS Indicator Survey (KAIS) that were unaware of their HIV-positive status by self-report as aware and on antiretroviral treatment if either ARVs were detected or viral load was undetectable (<550 copies/ml) on dried blood spots. We compared self-report to adjustments for ARV measurement, UVL, or both. Results: Treatment coverage among all HIV-positive respondents increased from 31.8% for self-report to 42.5% [95% confidence interval (CI) 37.4–47.8] based on ARV detection alone, to 42.8% (95% CI 37.9–47.8) when ARV-adjusted, 46.2% (95% CI 41.3–51.1) when UVL-adjusted and 48.8% (95% CI 43.9–53.8) when adjusted for either ARV or UVL. Awareness of positive status increased from 46.9% for self-report to 56.2% (95% CI 50.7–61.6) when ARV-adjusted, 57.5% (95% CI 51.9–63.0) when UVL-adjusted, and 59.8% (95% CI 54.2–65.1) when adjusted for either ARV or UVL. Conclusion: Undetectable viral load, which is routinely measured in surveys, may be a useful adjunct or alternative to ARV detection for adjusting survey estimates of knowledge of HIV status and antiretroviral treatment coverage. Correspondence to Peter W. Young, PO Box 606, Village Market, Nairobi 00601, Kenya. Tel: +254 728608673; e-mail: Pyoung1@cdc.gov Received 7 August, 2019 Revised 2 November, 2019 Accepted 11 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). Copyright © 2019 Wolters Kluwer Health, Inc.

The impact of localized implementation: determining the cost-effectiveness of HIV prevention and care interventions across six United States cities Objective: Effective interventions to reduce the public health burden of HIV/AIDS can vary in their ability to deliver value at different levels of scale and in different epidemiological contexts. Our objective was to determine the cost-effectiveness of HIV treatment and prevention interventions implemented at previously documented scales of delivery in six US cities with diverse HIV microepidemics. Design: Dynamic HIV transmission model-based cost-effectiveness analysis. Methods: We identified and estimated previously documented scale of delivery and costs for 16 evidence-based interventions from the US CDC's Compendium of Evidence-Based Interventions and Best Practices for HIV Prevention. Using a model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City and Seattle, we estimated averted HIV infections, quality-adjusted life years (QALY) gained and incremental cost-effectiveness ratios (healthcare perspective; 3% discount rate, 2018$US), for each intervention and city (10-year implementation) compared with the status quo over a 20-year time horizon. Results: Increased HIV testing was cost-saving or cost-effective across cities. Targeted preexposure prophylaxis for high-risk MSM was cost-saving in Miami and cost-effective in Atlanta ($6123/QALY), Baltimore ($18 333/QALY) and Los Angeles ($86 117/QALY). Interventions designed to improve antiretroviral therapy initiation provided greater value than other treatment engagement interventions. No single intervention was projected to reduce HIV incidence by more than 10.1% in any city. Conclusion: Combination implementation strategies should be tailored to local epidemiological contexts to provide the most value. Complementary strategies addressing factors hindering access to HIV care will be necessary to meet targets for HIV elimination in the United States. Corresponding to: Bohdan Nosyk, PhD, BC Centre for Excellence in HIV/AIDS, St. Paul's Hospital, 613-1081 Burrard Street. Vancouver, BC, Canada V6Z 1Y6. Tel: +1 604 806 8649; e-mail: bnosyk@cfenet.ubc.ca Received 28 August, 2019 Revised 12 November, 2019 Accepted 15 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). Copyright © 2019 Wolters Kluwer Health, Inc.

Use of molecular HIV surveillance data and predictive modeling to prioritize persons for transmission-reduction interventions Background: To develop a predictive model to prioritize persons with a transmissible HIV viral load for transmission-reduction interventions. Methods: New York City (NYC) HIV molecular surveillance data from 2010 to 2013 were used to build a model to predict the probability that the partial pol gene of the virus of a person with a transmissible HIV viral load (>1500 copies/ml) would be genetically similar to that of a person with a new HIV infection (diagnosis at stage 0 or 1 according to the revised Centers for Disease Control and Prevention classification system). Data from 2013 to 2016 were then used to validate the model and compare it with five other selection strategies that can be used to prioritize persons for transmission-reduction interventions. Results: A total of 10 609 persons living with HIV (PLWH) were included in the development dataset, and 8257 were included in the validation dataset. Among the six selection strategies, the predictive model had the highest area under the receiver operating characteristic curve (AUC) [0.86, 95% confidence interval (CI) 0.84--0.88), followed by the ‘Young MSM’ (0.79, 95% CI 0.77--0.82), ‘MSM with high viral loads’ (0.74, 95% CI 0.72--0.76), ‘Random sample of MSM’ (0.73, 95% CI 0.71--0.76), ‘Persons with high viral loads’ (0.56, 95% CI 0.54--0.59), and ‘Random sample’ (0.50, 95% CI 0.48--0.53) strategies. Conclusions: Jurisdictions should consider applying predictive modeling to prioritize persons with a transmissible viral load for transmission-reduction interventions and to evaluate its feasibility and effectiveness. Correspondence to Qiang Xia, MD, MPH, HIV Epidemiology and Field Services Program, Bureau of HIV Prevention and Control, New York City Department of Health and Mental Hygiene, 42-09 28th Street, Queens, NY 11101, USA. E-mail: qxia@health.nyc.gov Received 29 August, 2019 Revised 30 October, 2019 Accepted 31 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

HIV pre-exposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health Objective: To evaluate the effects of HIV preexposure prophylaxis (PrEP) with tenofovir disoproxial fumurate (TDF)/emtricitabine (FTC) on kidney function and kidney tubular health. Design: The Iniciativa Profilaxis Pre-Exposicion open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. This study included 123 iPrEx-OLE participants who demonstrated PrEP adherence. Methods: We compared estimated glomerular filtration rate calculated using serum creatinine (eGFRcr), serum cystatin C (eGFRcys), and in combination (eGFRcr-cys), and a panel of 14 urine biomarkers reflecting kidney tubular health before and 6 months after PrEP initiation. Results: At baseline, mean eGFRcr, eGFRcys, and eGFRcr-cys were 108.3, 107.0, and 111.1 ml/min/1.73 m2, respectively. Six months after PrEP initiation, eGFRcr declined by −4% (95% CI: −5.7 to −2.4%), eGFRcys declined by −3.3% (95% CI: −8.3 to 1.9%), and eGFRcr-cys declined by −4.1% (95% CI: −7.5 to −0.7%). From the urine biomarker panel, α1-microglobulin and β2-microglobulin increased by 22.7% (95% CI: 11.8--34.7%) and 14.1% (95% CI: −6.1 to 38.6%), whereas chitinase-3-like 1 protein and monocyte chemoattractant protein-1 decreased by −37.7% (95% CI: −53.0 to −17.3%) and −15.6% (95% CI: −31.6 to 4.2%), respectively. Ten of the 14 urine biomarkers, including albumin, had estimated changes of less than 12% with wide confidence intervals. Conclusion: Six months of PrEP with TDF/FTC was associated with decreases in eGFRcr and eGFRcys. We also observed for the first time changes in 4 of 14 urine biomarkers reflecting kidney tubular health. These findings demonstrate that PrEP has direct effects on eGFR and the proximal tubule. Correspondence to Vasantha Jotwani, MD, 4150 Clement Street, Bldg 2, Rm 145, San Francisco, CA 94121, USA. E-mail: Vasantha.Jotwani@ucsf.edu Received 20 August, 2019 Revised 17 October, 2019 Accepted 25 October, 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.

Associations between recent thymic emigrants and CD4+ T cell recovery after short-term antiretroviral therapy initiation Objective: Around 20–30% of HIV-infected subjects (HIV+) on successful antiretroviral therapy (ART) fail to normalize their CD4+ T cell counts. Various factors could contribute to the lack of immune reconstitution (IR), one of them being thymic insufficiency. We aimed to explore associations between recent thymic emigrants (RTEs) and CD4+ T cell recovery. Design: ART-naïve HIV+ subjects who started ART with advanced AIDS were selected. Good versus poor IR was defined by CD4 gains above or below 100 CD4+ T cells/mm3. The follow-up period was 6 months. Methods: Peripheral blood mononuclear cells were isolated and flow cytometry was used to characterize RTEs as the fraction of naïve CD4+ T cells expressing CD31, the platelet endothelial cell adhesion molecule. Markers of cellular activation, senescence, exhaustion and cycling were also assessed. Results: After 6 months on ART, HIV+ subjects with good IR had higher absolute numbers of RTEs, compared to those with poor IR, and these strongly correlated with CD4 gains in those subjects with good IR but not with poor IR. We also found CD8+ T cell immune activation decreased as early as 2 months-post ART initiation in subjects with good IR, but only at month 6 post-ART in subjects with poor IR. Levels of immune activation were inversely correlated with the absolute numbers of RTEs in both groups, but more strongly so in subjects with poor IR. Conclusions: We show that RTEs are linked to CD4+ T cell recovery and that the degree of IR is not directly linked to persistent immune activation. Correspondence to Sandra Pinto-Cardoso, PhD, Departamento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Col Sección XVI, 14080 Mexico City, Mexico; e-mail: sandra.pinto@cieni.org.mx Received 6 May, 2019 Revised 13 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). Thisis 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.

National HIV testing and diagnosis coverage in sub-Saharan Africa: a new modeling tool for estimating the “first 90” from program and survey data Objective: HIV testing services (HTS) are a crucial component of national HIV responses. Learning one's HIV diagnosis is the entry point to accessing life-saving antiretroviral treatment and care. Recognizing the critical role of HTS, the Joint United Nations Programme on HIV/AIDS (UNAIDS) launched the 90-90-90 targets stipulating that by 2020, 90% of people living with HIV know their status, 90% of those who know their status receive antiretroviral therapy, and 90% of those on treatment have a suppressed viral load. Countries will need to regularly monitor progress on these three indicators. Estimating the proportion of people living with HIV who know their status (i.e., the “first 90”), however, is difficult. Methods: We developed a mathematical model (henceforth referred to as “F90”) that formally synthesizes population-based survey and HTS program data to estimate HIV status awareness over time. The proposed model uses country-specific HIV epidemic parameters from the standard UNAIDS Spectrum model to produce outputs that are consistent with other national HIV estimates. The F90 model provides estimates of HIV testing history, diagnosis rates, and knowledge of HIV status by age and sex. We validate the F90 model using both in-sample comparisons and out-of-sample predictions using data from three countries: Côte d’Ivoire, Malawi, and Mozambique. Results: In-sample comparisons suggest that the F90 model can accurately reproduce longitudinal sex-specific trends in HIV testing. Out-of-sample predictions of the fraction of PLHIV ever tested over a 4-to-6-year time horizon are also in good agreement with empirical survey estimates. Importantly, out-of-sample predictions of HIV knowledge are consistent (i.e., within 4% points) with those of the fully calibrated model in the three countries when HTS program data are included. The F90 model's predictions of knowledge of status are higher than available self-reported HIV awareness estimates, however, suggesting –in line with previous studies– that these self-reports could be affected by non-disclosure of HIV status awareness. Conclusion: Knowledge of HIV status is a key indicator to monitor progress, identify bottlenecks, and target HIV responses. The F90 model can help countries track progress towards their “first 90” by leveraging surveys of HIV testing behaviors and annual HTS program data. Correspondence to Mathieu Maheu-Giroux, ScD, McGill University, Montreal, CANADA. E-mail: mathieu.maheu-giroux@mcgill.ca Received 27 January, 2019 Revised 20 May, 2019 Accepted 19 September, 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 © 2019 Wolters Kluwer Health, Inc.

Parameter estimates for trends and patterns of excess mortality among persons on ART in high-income european settings Introduction: HIV cohort data from high-income European countries were compared to the UNAIDS Spectrum modelling parameters for these same countries to validate mortality rates and excess mortality estimates for people living with HIV (PLHIV) on antiretroviral therapy (ART). Methods: Data from 2000–2015 were analysed from the Antiretroviral Therapy Cohort Collaboration (ART-CC) for Austria, Denmark, France, Italy, the Netherlands, Spain, and Switzerland. Flexible parametric models were used to compare All-cause mortality rates in the ART-CC and Spectrum. The percentage of AIDS-related deaths and excess mortality (both are the same within Spectrum) were compared, with excess mortality defined as that in excess of the general population mortality. Results: Analyses included 94026 PLHIV with 585784 person-years of follow-up, from which there were 5515 deaths. All-cause annual mortality rates in Spectrum for 2000–2003 were 0.0121, reducing to 0.0078 in 2012–2015, whilst the ART-CC's corresponding annual mortality rates were 0.0151 (95% confidence interval [95%CI]: 0.0130–0.0171) reducing to 0.0049 (95%CI: 0.0039–0.0060). The percentage of AIDS-related deaths in Spectrum was 74.7% in 2000–2003, dropping to 43.6% in 2012–15. In the ART-CC, AIDS-related mortality comprised 45.3% (95%CI: 38.4%-52.9%) of mortality in 2000–2003 and 26.7% (95%CI: 19.0%, 46.0%) between 2012–2015. Excess mortality in the ART-CC was broadly similar to the Spectrum estimates, dropping from 75.3% (95%CI: 60.3%-95.2%) in 2000–2003 to 30.7% (95%CI: 25.5%-63.7%) in 2012-2015. Conclusions: All-cause mortality assumptions for PLHIV on ART in high-income European settings should be adjusted in Spectrum to be higher in 2000–2003 and decline more quickly to levels currently captured for recent years. Correspondence to Adam Trickey, Oakfield House, Population Health Sciences, University of Bristol, Bristol, UK, BS8 2BN. E-mail: adam.trickey@bristol.ac.uk Received 28 January, 2019 Accepted 24 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 Creative Commons Attribution License 4.0, 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.

Use of the dapivirine vaginal ring and effect on cervical cytology abnormalities Objective: We aimed to determine if the dapivirine vaginal ring and the ring device alone (flexible silicone matrix polymer) was associated with the development of cervical cytology abnormalities. Design: Secondary analysis comparing cervical cytology results between two randomized controlled microbicide trials (ASPIRE and VOICE) Methods: Data from the MTN-020/ASPIRE, a phase III, placebo-controlled trial of the dapivirine vaginal ring, were used in this analysis. Cervical cytology smears were evaluated at baseline and at the final visit with product use. We compared cytology results between women randomized to dapivirine versus placebo vaginal ring. We further assessed for the effect of the vaginal ring device on cervical cytology by comparing results with data from the oral placebo arm of MTN-003/VOICE, a prior HIV-1 prevention trial conducted in a similar population. Results: Cervical cytology results for 2394 women from ASPIRE (1197 per study arm) were used in this analysis; median time between baseline and final visit with product use was 22.1 months. Cytology smear findings were comparable between dapivirine and placebo vaginal ring arms: at final visit, normal: 90.6% vs. 91.5%, ASC-US//LSIL: 7.8% vs. 7.4%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 1.7% vs. 1.1%, p = 0.44. Cytology data from VOICE had findings (normal: 87.8%, ASC-US/LSIL: 9.8%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 2.4%) comparable to that of both dapivirine (p = 0.93) and placebo vaginal ring arms (p = 0.24). Conclusions: These findings indicate that neither use of the dapivirine vaginal ring nor the vaginal ring device alone, over a period of two years, is associated with development of cervical cytology abnormalities that could lead to pre-cancerous or cancerous lesions. Correspondence to Krishnaveni Reddy, Wits RHI Research Center, 7 Esselen Street, Hillbrow, Johannesburg, South Africa, 2038. E-mail: kreddy@wrhi.ac.za Received 31 July, 2019 Revised 31 October, 2019 Accepted 31 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.