AIDS

Long-term safety and vaccine-induced seropositivity in healthy volunteers from HIV vaccine trials: a French cohort study Background: The ANRS COV1-COHVAC cohort was a long-term safety cohort of healthy volunteers who received preventive HIV-vaccine candidates in 17 phase I/II clinical trials. Methods: Data collected from the first vaccine candidate administration and annually after inclusion in the cohort included grade 3/4 adverse events and all grade adverse events suggestive of neurological, ophthalmological and immune disorders, self-administered questionnaires on behaviors and HIV ELISA results. Age-and-sex-standardized mortality rates (SMRs) were calculated with respect to the French population. The cohort was early terminated in 2016 due to the absence of safety signal. Results: Of 496 volunteers, 488 were included: 355 in the 7-year prospective follow-up and 133 in the retrospective data collection only. The total follow-up after the first vaccination was 4934 person-years (median: 10 years) and 270 (76%) volunteers completed their follow-up. No relevant adverse event possibly related to the vaccine was reported. Breast cancer incidence and woman mortality did not differ from those of the French general population (standardized incidence ratio = 1.47, P = 0.45 and SMR = 0.65, P = 0.28, respectively) while man mortality was significantly lower (SMR = 0.26, P = 0.0003). At the last visit, 21/29 (72%) volunteers who received the recombinant HIV gp160 protein still showed vaccine-induced seropositivity after a median follow-up of 23 years. Only a few volunteers reported risky sexual practices (men: 20/192, women: 2/162). Conclusion: Volunteers showed a sustained high commitment. No long-term safety alert was identified during the postvaccine follow-up. Participating in vaccine trials did not increase risky behaviors for HIV infection. Vaccine-induced seropositivity may persist for more than 23 years after receiving rgp160. Correspondence to Christine Durier, INSERM SC10-US019, Paris, France. E-mail: christine.durier@inserm.fr Received 14 January, 2019 Revised 31 May, 2019 Accepted 6 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.

Delays in fast track ART initiation and reasons for not starting treatment among eligible children in Eastern Cape, South Africa We report data from an observational cohort of South African children living with HIV <12 years of age eligible for fast track ART (rapid) initiation. We found that less than half those eligible for rapid ART initiation based on immunologic and disease status started treatment within one week. Correspondence to Chloe A. Teasdale, ICAP-Columbia University, MSPH, 722 W168th Street, Room 1319, New York, NY 10032. Tel: +212 304 7920; fax: +212 342 1824; e-mail: ct116@columbia.edu Received 25 April, 2019 Revised 30 May, 2019 Accepted 6 June, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

A pharmacokinetic and pharmacogenetic evaluation of contraceptive implants and antiretroviral therapy among women in Kenya and Uganda Objectives: To evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz- or nevirapine-containing antiretroviral therapy (ART). Design: We analyzed stored samples from women self-reporting implant use in the Partners PrEP Study. Methods: Plasma samples collected every six months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared to pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on efavirenz and nevirapine to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on efavirenz, nevirapine, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations. Results: Our analysis included 11 women who initiated efavirenz, 13 who initiated nevirapine, and 36 who remained ART-naïve. In the efavirenz group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 (90% confidence intervals (0.31, 0.49); p < 0.001) and the etonogestrel aGMR was 0.51 (0.34, 0.76); p = 0.006) compared to the control group. No difference was observed in the nevirapine group compared to controls (levonorgestrel 0.93 (0.74, 1.18); p = 0.64; etonogestrel 1.07 (0.77, 1.50); p = 0.73). Possession of four allele variants were found to result in further reductions in progestin concentrations among those receiving efavirenz. Conclusions: Concomitant use of efavirenz significantly reduces levonorgestrel or etonogestrel concentrations by 61% and 49%, respectively, compared to no ART use. We also report allelic variants in hepatic enzymes that influenced the extent of the observed drug-interaction between progestins and efavirenz. Correspondence to Rena C. Patel, UW Box 359927, 325 Ninth Avenue, Seattle, WA, 98104. Tel: +206 520 3800; e-mail: rcpatel@uw.edu Received 27 March, 2019 Revised 28 May, 2019 Accepted 31 May, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Viro-immunological outcomes after thirteen-valent pneumococcal vaccination in HIV-1 infected subjects on stable virological suppression Background: Very limited data are available on the immunovirological outcomes after 13-valent pneumococcal conjugate vaccine (PCV13) in ART-treated patients. The aim of this study was to assess the immune-virological outcomes in HIV-1 infected ART-treated patients on stable virological suppression who underwent pneumococcal conjugate vaccination. Methods: Retrospective, cohort study on ART-treated HIV-1 infected subjects, age ≥18 years, with 3 consecutive determinations of HIV-RNA <50 copies/mL before the administration of PCV13 (baseline BL) at San Raffaele Hospital and with ≥2 HIV-RNA values after vaccination. Results: Overall 1197 patients underwent PCV13 vaccination. During 6-month of follow-up (594 person-years of follow-up, PYFU), 12 CVF and 35 VB were observed; the overall incidence rate (IR) of CVF was 2.02 (95%CI: 0.88–3.16) per 100-PYFU and the IR of VB was 5.89 (95%CI: 3.94–7.84) per 100-PYFU. Median CD4 change from BL at six months was +10 cells/μL [IQR -67, +111; p = 0.0002]. Median change in CD4/CD8 ratio was +0.02 [IQR -0.06, +0.11; P < 0.001]. Conclusions: Viral blips and confirmed virological failures were rarely observed in patients on stable virological suppression in the first 6 months following vaccination with PCV13. Additionally, no decrease of CD4 and CD4/CD8 ratio was recorded. Correspondence to Silvia Nozza, Via Stamira d’Ancona 20, 20127 Milano (Italy). Tel: +390226437961; fax: +390226437030; e-mail: nozza.silvia@hsr.it Received 13 March, 2019 Revised 15 May, 2019 Accepted 28 May, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Low level viremia and virologic failure in persons with HIV infection treated with antiretroviral therapy Background: The clinical management of low level viremia (LLV) remains unclear. The objective of this study was to investigate the association of blips and LLV with virologic failure. Methods: We enlisted patients who newly enrolled into the HIV Research Network between 2005-2015, had HIV-1 RNA >200 c/mL, and were either ART-naïve or ART-experienced and not on ART. Patients were included who achieved virologic suppression (≤ 50 on two consecutive viral loads) and had ≥ 2 viral loads following suppression. Blips and LLV (≥ 2 consecutive > 51 c/mL) were categorized separately into 3 categories: no blips/LLV, 51-200, 201-500. Cox proportional hazards regression was used to assess association between rates of blips/LLV and virologic failure (two consecutive >500). Results: The 2795 patients were mostly male (75.4%), black (50.3%), and MSM (52.9%). Median age was 38 years old (IQR 29-48). Most patients (88.8%) were ART-naïve at study entry. Overall, 283 (10.1%) patients experienced virologic failure. A total of 152 (5.4%) patients experienced LLV to 51-200 and 110 (3.9%) patients experienced LLV to 201-500. Both LLV 51-200 (aHR 1.83 [1.10,3.04]) and LLV 201-500 (aHR 4.26 [2.65,6.86]) were associated with virologic failure. In sensitivity analysis excluding ART experienced patients, the association between LLV51-200 and virologic failure was not statistically significant. Conclusions: LLV between 201-500 was associated with virologic failure, as was LLV between 51-200, particularly among ART experienced patients. Patients with LLV below the current DHHS threshold for virologic failure (persistent viremia ≥ 200) may require more intensive monitoring because of increased risk for virologic failure. Correspondence to Julia Fleming, Johns Hopkins University School of Medicine, Baltimore, Maryland UNITED STATES; e-mail: julia.green.fleming@gmail.com Received 4 January, 2019 Revised 10 April, 2019 Accepted 11 April, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

A modeling framework to inform PrEP initiation and retention scale-up in the context of Getting to Zero Initiatives Objective(s): “Getting to Zero” (GTZ) initiatives aim to eliminate new HIV infections over a projected time frame. Increased PrEP uptake among populations with the highest HIV incidence, such as young black men who have sex with men (YBMSM), is necessary to accomplish this aim. Agent-based network models (ABNMs) can help guide policymakers on strategies to increase PrEP uptake. Design: Effective PrEP implementation requires a model that incorporates the dynamics of interventions and dynamic feedbacks across multiple levels including virus, host, behavior, networks and population. ABNMs are a powerful tool to incorporate these processes. Methods: An ABNM, designed for and parameterized using data for YBMSM in Illinois, was used to compare the impact of PrEP initiation and retention interventions on HIV incidence after 10 years, consistent with GTZ timelines. Initiation interventions selected individuals in serodiscordant partnerships, or in critical sexual network positions, and compared to a controlled setting where PrEP initiators were randomly selected. Retention interventions increased the mean duration of PrEP use. A combination intervention modeled concurrent increases in PrEP initiation and retention. Results: Selecting HIV negative individuals for PrEP initiation in serodiscordant partnerships resulted in the largest HIV incidence declines, relative to other interventions. For a given PrEP uptake level, distributing effort between increasing PrEP initiation and retention in combination was approximately as effective as increasing only one exclusively. Conclusions: Simulation results indicate that expanded PrEP interventions alone may not accomplish GTZ goals within a decade, and integrated scale-up of PrEP, ART and other interventions might be necessary. Correspondence to Aditya S. Khanna, 5837 S Maryland Ave, MC 5065, Chicago IL 60637. Tel: +773 834 5635; fax: +773 702 8998; e-mail: akhanna@medicine.bsd.uchicago.edu Received 4 December, 2018 Revised 13 March, 2019 Accepted 15 March, 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.

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand Objective: To describe growth during puberty in young people with vertically acquired HIV. Design: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. Methods: 1094 children initiating an NNRTI- or boosted PI-based regimen aged 1 to 10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using 3 parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (World Health Organisation references) at ART initiation. Multivariate regression explored characteristics associated with these 3 parameters. Results: At ART initiation median age and HAZ was 6.4[IQR:2.8,9.0] years and -1.2[-2.3,-0.2], respectively. Median follow-up was 9.1[6.9,11.4] years. In females, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% CI 0.20,0.62) years later in children starting ART age 6-<11 years compared to 1-<3 years and 1.50 (1.21,1.78) years later in those starting with HAZ<-3 compared to HAZ≥-1. Later growth spurts in females resulted in continued height growth into later adolescence. In males starting ART with HAZ<-1, growth spurts were later in children starting ART in the oldest age group, but for HAZ≥-1 there was no association with age. Males and females who initiated ART with HAZ≥-1 maintained a similar height to the WHO reference mean. Conclusions: Stunting at ART initiation was associated with later growth spurts in females. Children with HAZ≥-1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age. Correspondence to Siobhan Crichton, PhD, MRC Clinical Trials Unit at UCL, 90 High Holborn, London WC1 V 6LJ. Tel: +44 0 20 7670 4913; e-mail: s.crichton@ucl.ac.uk Received 6 November, 2018 Revised 15 May, 2019 Accepted 17 May, 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.

Growth curve modelling to determine distinct body mass index trajectory groups in HIV-positive adults on ART in South Africa Objective: Obesity is a major long-term concern in HIV-positive patients due to the pathogenic link between obesity and non-communicable chronic diseases (NCD). We aim to characterize changes in body mass index (BMI) over time on antiretroviral therapy (ART) and investigate the association between weight gain and survival in South Africa. Design & Methods: Prospective cohort study among HIV-positive adults on first-line ART between April 2004-2015 in Johannesburg, South Africa. We used latent-class growth modelling (adjusted for age, gender, and CD4 count) to identify groups of individuals with similar patterns of change in BMI over time. Results: 11,263 patients were included. The best fit model involved two linear and two quadratic trajectories. 35% of patients categorized into group one (mean BMI at ART initiation, 20.4 kg/m2; mean BMI after 8 years of follow-up, 20.9 kg/m2), 38% into group two (24.5 to 26.2 kg/m2), 21% into group three (29.5 to 32.6 kg/m2)and 6% into group four (36.5 to 40.0 kg/m2). Over the 8 years of follow-up, 6% of our cohort went down in BMI standard category, while 45% went up. The largest increase occurred in the first 12 months on ART. In years two through eight, we saw a more gradual increase in BMI. Conclusion: The largest gain in BMI in HIV patients occurred in the first year on ART. During follow-up, over 50% of our population changed BMI categories putting them at increased risk for NCDs. Consistent counselling on nutritional and lifestyle changes could help improve ART patients’ long term health outcomes. Correspondence to Kaitlyn M. Berry, Department of Global Health, Boston University School of Public Health Crosstown Center, 3rd Floor, 801 Massachusetts Ave, Boston, MA 02118. Tel: +617 358 2156; e-mail: berrykm1@bu.edu Received 9 January, 2019 Revised 20 May, 2019 Accepted 24 May, 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.

Performance of cepheid GeneXpert HIV-1 viral load plasma assay to accurately detect treatment failure: a clinical meta-analysis Background: Coverage of viral load testing remains low with only half of the patients in need having adequate access. Alternative technologies to high throughput centralized machines can be used to support viral load scale-up; however, clinical performance data are lacking. We conducted a meta-analysis comparing the Cepheid Xpert HIV-1 viral load plasma assay to traditional laboratory-based technologies. Methods: Cepheid Xpert HIV-1 and comparator laboratory technology plasma viral load results were provided from 13 of the 19 eligible studies, which accounted for a total of 3790 paired data points. We used random effects models to determine the accuracy and misclassification at various treatment failure thresholds (detectable, 200, 400, 500, 600, 800 and 1000 copies/ml). Results: Thirty percent of viral load test results were undetectable, while 45% were between detectable and 10 000 copies/ml and the remaining 25% were above 10 000 copies/ml. The median Xpert viral load was 119 copies/ml and the median comparator viral load was 157 copies/ml, while the log10 bias was 0.04 (0.02–0.07). The sensitivity and specificity to detect treatment failure were above 95% at all treatment failure thresholds, except for detectable, at which the sensitivity was 93.33% (95% confidence interval: 88.2–96.3) and specificity was 80.56% (95% CI: 64.6–90.4). Conclusion: The Cepheid Xpert HIV-1 viral load plasma assay results were highly comparable to laboratory-based technologies with limited bias and high sensitivity and specificity to detect treatment failure. Alternative specimen types and technologies that enable decentralized testing services can be considered to expand access to viral load. Correspondence to Lara Vojnov, PhD, World Health Organization. Tel: +1 617 774 0110; e-mail: vojnovl@who.int Received 28 March, 2019 Revised 7 May, 2019 Accepted 17 May, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Nonadherence and unsuppressed viral load across adolescence among US youth with perinatally acquired HIV Objective: To identify factors associated with nonadherence and unsuppressed viral load across adolescence among youth with perinatally-acquired HIV (PHIV). Design: Longitudinal study at 15 US clinical sites Methods: Self-reported antiretroviral medication nonadherence (any missed dose, past week) and unsuppressed VL (HIV RNA>400 copies/mL) were assessed annually. Individual, caregiver, social and structural factors associated with nonadherence and unsuppressed VL were identified by age (years): 8–11 (“pre-adolescence”), 12–14 (“early adolescence”), 15–17 (“middle adolescence”), and 18–22 (“late adolescence/young adulthood”), utilizing multivariable generalized linear mixed effects models. Results: During a median 3.3-year follow-up, 381 youth with PHIV contributed VL measurements and 379 completed 1190 adherence evaluations. From pre-adolescence to late adolescence/young adulthood, prevalence of nonadherence increased from 31% to 50% (p < 0.001); prevalence of unsuppressed VL increased from 16% to 40% (p < 0.001). In adjusted analyses, in pre-, middle-, and late adolescence/young adulthood, perceived antiretroviral side effects were associated with nonadherence. Additional factors associated with nonadherence included: in pre-adolescence, using a buddy system (as an adherence reminder); in early adolescence, identifying as black, using buddy system; in middle adolescence, CD4% < 15%, unmarried caregiver, indirect exposure to violence, stigma/fear of inadvertent disclosure, stressful life events. Associations with unsuppressed VL included: in early adolescence, youth unawareness of HIV status, lower income; in middle adolescence, perceived antiretroviral side effects, lower income; in late adolescence/young adulthood, distressing physical symptoms and perceived antiretroviral side effects. Conclusion: Prevalence of nonadherence and unsuppressed VL increased with age. Associated factors varied across adolescence. Recognition of age-specific factors is important when considering strategies to support adherence. Correspondence to Deborah Kacanek, Sc.D., Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, 665 Huntington Ave. FXB 505, Boston, MA 02115. Tel: +617 432 2833; fax: +617 432 3163; e-mail: dkacanek@sdac.harvard.edu Received 18 March, 2019 Revised 9 June, 2019 Accepted 17 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.