Altered monocyte phenotype and dysregulated innate cytokine responses among people living with HIV and opioid-use disorder Background: Opioid-use disorders (OUD) and hepatitis C or B co-infection (HEP) are common among people living with HIV (PLHIV). The impact of OUD on innate and adaptive immunity among PLHIV with and without HEP is unknown. Objectives: To investigate the impact of OUD on monocyte and T-cell phenotypes, cytokine responses to lipopolysaccharide (LPS) and phytohemagglutinin (PHA), and plasma inflammatory markers, among PLHIV with and without HEP. Methods: Cross-sectional study enrolling PLHIV receiving ART, with and without OUD. Flow cytometry determined monocyte and T-cell phenotypes; LPS and PHA-induced cytokine production was assessed following LPS and PHA stimulation by multiplex cytokine array; plasma IL-6, soluble CD163, and soluble CD14+ were measured by ELISA. Results: Twenty-two PLHIV with OUD and 37 PLHIV without OUD were included. PLHIV with OUD exhibited higher frequencies of intermediate (CD14++CD16+) and nonclassical (CD14dimCD16+) monocytes when compared with PLHIV without OUD (P = 0.0025; P = 0.0001, respectively), regardless of HEP co-infection. Soluble CD163 and monocyte cell surface CD163 expression was increased among PLHIV with OUD and HEP, specifically. Regardless of HEP co-infection, PLHIV with OUD exhibited reduced production of IL-10, IL-8, IL-6, IL-1alpha, and TNF-alpha in response to LPS when compared with PLHIV without OUD; PHA-induced production of IL-10, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were also reduced among individuals with OUD. Conclusion: OUD among PLHIV are associated with altered monocyte phenotypes and a dysregulated innate cytokine response. Defining underlying mechanisms of opioid-associated innate immune dysregulation among PLHIV should be prioritized to identify optimal OUD treatment strategies. Correspondence to Christina L. Lancioni, MD, Department of Pediatrics, Oregon Health & Science University, 707 SW Gaines Street, CDRC-P, Portland, OR 97239, USA. Tel: +1 503 418 1484; fax: +1 503 494 1542; e-mail: Lancioni@ohsu.edu Received 7 June, 2019 Revised 13 September, 2019 Accepted 3 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). 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.

Clinical outcomes post transition to adult services in young adults with perinatally acquired HIV infection: mortality, retention in care, and viral suppression Objective: Adolescence is the only age group globally where HIV associated mortality is rising, with poorer outcomes at all stages of the care cascade compared to adults. We examined post-transition outcomes for young adults living with perinatal HIV (YAPaHIV). Design: Retrospective cohort analysis. Setting: A tertiary Youth Friendly Service (YFS) London, UK. Participants: 180 YAPaHIV registered between 01.01.06 and 31.12.17 contributed 921 person-years of follow up post-transition to adult services. Intervention: YFS with multidisciplinary care and walk-in access. Main outcome measures: mortality, morbidity, retention in care, antiretroviral (ART) uptake and HIV-viral load (HIV-VL) suppression. Crude incidence rates (CIR) are reported per 1000 person-years. Results: Of 180 youth registered; 4 (2.2%) died, 14 (7.8%) transferred care and 4 (2.2%) were lost to follow up. For the 158 retained in care the median age was 22.9 years (IQR 20.3–25.4), 56% were female, 85% Black African, with a median length of follow up in adult care of 5.5 years (IQR 2.9–7.3). 157 (99.4%) ever received an ART prescription, 127/157 (81%) with a latest HIV-VL < 200 copies RNA/ml, median CD4 count of 626 cells/ul (IQR 441–820). The all-cause mortality was 4.3/1000 person-years (95% CI 1.2 – 11.1), ten fold the aged-matched UK HIV-negative population (0.43/1000 person-years (95% CI 0.41 – 0.44). Post-transition, 17/180 (9.4%) developed a new AIDS diagnosis; CIR 18.5/1000 person-years (95% CI 10.8 – 29.6). Conclusion: Whilst this youth-friendly multi-disciplinary service achieved high engagement and coverage of suppressive ART, mortality remains markedly increased compared to the general UK population. Correspondence to Caroline Foster, The 900 Clinic, Imperial College Healthcare NHS Trust, London W2 1NY. Tel: +02033126411; Mob: 07949009448; e-mail: caroline.foster5@nhs.net Received 11 March, 2019 Revised 11 August, 2019 Accepted 12 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Timing of and factors associated with HIV disclosure among perinatally infected children in rural Zambia Objective: This study was conducted to understand the process of disclosure among HIV-infected children receiving care in rural Zambia. Design: Cross-sectional and longitudinal analyses were conducted within an ongoing clinical cohort study of HIV-infected children receiving care in Macha, Zambia from 2007–2016. Methods: Children receiving HIV care were enrolled into the cohort study and assessed every three months. At each study visit, disclosure status was ascertained through questionnaire. Disclosure was categorized as none (child did not know they were chronically ill), partial (child knew they were chronically ill but not of their HIV infection status), or full (child knew they had HIV infection). Barriers to disclosure, and the timing of and factors associated with disclosure, were evaluated among children 5–15 years of age. Results: At study entry, the prevalence of full disclosure increased with age, from 2.1% to 76.2% among children 5–6 and 13–15 years of age, respectively. Reasons provided by caregivers for not disclosing the child's status included they felt the child was too young, they were afraid to, or they did not know how to tell the child. During follow-up, the median age at full disclosure was 9.0 years. Among children with full disclosure, 89.5% first had partial disclosure at a median age of 7.4 years. Factors associated with disclosure included being female, sharing responsibility for taking their own medication, and low weight-for-age z-score. Conclusions: Given the complexity of the disclosure process and potential for health benefits, interventions and protocols are needed to support caregivers through the disclosure process. Correspondence to Catherine G. Sutcliffe, 615 N. Wolfe Street, Rm E6535, Baltimore, MD 21205. Tel: +410 614 5248; e-mail: csutcli1@jhu.edu Received 17 May, 2019 Revised 25 September, 2019 Accepted 30 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). Copyright © 2019 Wolters Kluwer Health, Inc.

Vitamin E is an effective treatment for nonalcoholic steatohepatitis in HIV mono-infected patients Objective: Human immunodeficiency virus (HIV)-infected patients are at increased risk of nonalcoholic steatohepatitis (NASH). Vitamin E is recommended for treatment of NASH in the general population. However, its safety and efficacy among HIV-infected patients remain unknown. Design: Single centre, phase IV, open-label, single arm clinical trial. Methods: HIV mono-infected patients without significant alcohol intake or viral hepatitis coinfection were included. The diagnosis of NASH was based on the co-existence of fatty liver, diagnosed by controlled attenuation parameter (CAP) ≥ 248 dB/m, and significant hepatocyte apoptosis, defined by the serum biomarker cytokeratin 18 (CK-18) >130.5 U/L. Participants were treated with 800 IU daily of oral vitamin E (alpha-tocopherol) for 24 weeks, and followed for an additional 24 weeks post-discontinuation. Generalized linear mixed effects models were used to evaluate changes in ALT, CAP and CK-18 at the completion of treatment and end of follow-up, controlling for pre-treatment trends. Results: A total of 27 patients were included. Four (15%) had a pretreatment liver biopsy, which confirmed the diagnosis of NASH in all cases. Compared to baseline, 24 weeks of vitamin E treatment improved ALT (−27 units/L; 95% confidence interval [CI] −37, -−17), CAP scores (−22 dB/m; 95% CI −42, −1) and CK-18 (−123 units/L; 95% CI −201, −46). Conversely, there was no change in BMI. No serious adverse event was reported and no patient was lost to follow-up. Conclusion: In this first clinical trial, we showed that vitamin E is an effective and well-tolerated treatment for NASH in HIV-infected patients. Correspondence to Dr Giada Sebastiani, MD, Chronic Viral Illness Service, Royal Victoria Hospital, MUHC, 1001 Boulevard Décarie, Montreal, QC H4A 3J1, Canada. E-mail: giada.sebastiani@mcgill.ca Received 9 August, 2019 Revised 12 September, 2019 Accepted 3 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.

Decreased growth among antiretroviral drug and HIV exposed uninfected versus unexposed children in Malawi and Uganda Objective: To compare growth among antiretroviral drug and maternal-HIV exposed uninfected (AHEU) versus age-and-sex-matched HIV unexposed uninfected (HUU) children. Design: Prospective cohort of AHEU children identified from the PROMISE trial (NCT01061151: clinicaltrials.gov registry) and age-and-sex-matched HUU controls from child-wellness clinics, enrolled (09/2013–10/2014) in Malawi and Uganda. Methods: Weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head-circumference-for-age (HCAZ) z-scores were derived at 12 and 24 months-of-age. Wilcoxon Rank-Sum and Fischer's exact tests were used for unadjusted exposure group comparisons. Generalized-Estimating-Equations models estimated adjusted relative risks (aRR) for poor growth outcomes. Results: Overall, 471 (50.5%) AHEU and 462 (49.5%) HUU children were assessed. Ugandan AHEU compared to HUU children had significantly lower mean LAZ (p < 0.001) and WAZ (p < 0.001) at 12 and 24 months-of-age and HCAZ (p = 0.016) at 24 months, with similar but not significant differences among Malawian AHEU and HUU children. The risk of stunting (more than two standard deviations below the WHO-population LAZ median) was increased among AHEU versus HUU children: aRR = 2.13 (95% confidence interval (CI): 1.36, 3.33), p = 0.001 at 12-months, and aRR = 1.67 (95% CI: 1.16, 2.41), p = 0.006 at 24-months-of-age in Uganda; and aRR = 1.32 (95% CI: 1.10, 1.66), p = 0.018, at 24-months-of-age in Malawi. The risk of HCAZ below WHO median was increased among AHEU versus HUU children at 24-months-of-age, aRR = 1.35 (95% CI: 1.02, 1.79), p = 0.038 in Uganda; and aRR = 1.35 (95% CI: 0.91, 2.02), p = 0.139 in Malawi. Conclusions: Perinatal exposures to maternal-HIV and antiretroviral drugs were associated with lower LAZ (including stunting), WAZ and HCAZ at 24 months-of-age compared HUU children. Correspondence to Jim Aizire, MBCHB, MHS, PhD, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe St., E7132B. Tel: +10-502-8988; e-mail: jaizire1@jhu.edu Received 5 May, 2019 Revised 31 August, 2019 Accepted 2 September, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Genetic Clustering Analysis for HIV Infection among Men Who Have Sex with Men in Nigeria: implications for intervention Background: The HIV epidemic continues to grow among MSM in countries across sub-Saharan Africa including Nigeria. To inform prevention efforts, we used a phylogenetic cluster method to characterize HIV genetic clusters and factors associated with cluster formation among MSM living with HIV in Nigeria. Methods: We analyzed HIV-1 pol sequences from 417 MSM living with HIV enrolled in the TRUST/RV368 cohort between 2013 and 2017 in Abuja and Lagos, Nigeria. A genetically linked cluster was defined among participants whose sequences had pairwise genetic distance of 1.5% or less. Binary and multinomial logistic regressions were used to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for factors associated with HIV genetic cluster membership and size. Results: Among 417 MSM living with HIV, 153 (36.7%) were genetically linked. Participants with higher viral load (AOR = 1.72 95% CI: 1.04–2.86), no female partners (AOR = 3.66; 95% CI: 1.97–6.08), and self-identified as male sex (compared with self-identified as bigender) (AOR = 3.42; 95% CI: 1.08–10.78) had higher odds of being in a genetic cluster. Compared with unlinked participants, MSM who had high school education (AOR = 23.84; 95% CI: 2.66–213.49), were employed (AOR = 3.41; 95% CI: 1.89–10.70), had bacterial sexually transmitted infections (AOR = 3.98; 95% CI: 0.89–17.22) and were not taking antiretroviral therapy (AOR = 6.61; 95% CI: 2.25–19.37) had higher odds of being in a large cluster (size > 4). Conclusion: Comprehensive HIV prevention packages should include behavioral and biological components, including early diagnosis and treatment of both HIV and bacterial sexually transmitted infections to optimally reduce the risk of HIV transmission and acquisition. Correspondence to Yuruo Li, Department of Epidemiology, University of Maryland School of Public Health, 6100 Westchester Park Drive, Apt 520, College Park, MD 20740, USA. Tel: +1 404 539 6249; e-mail: yuruo.li12@gmail.com Received 6 June, 2019 Revised 24 September, 2019 Accepted 25 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). Copyright © 2019 Wolters Kluwer Health, Inc.

Comparison of guidelines for HIV viral load monitoring among pregnant and breastfeeding women in sub-Saharan Africa: a simulation study Background: Intensified viral load (VL) monitoring for pregnant and breastfeeding women has been proposed to help address concerns around antiretroviral therapy (ART) adherence, viraemia and transmission risk, but there have been no systematic evaluations of existing policies. Methods: We used an individual Monte Carlo simulation to describe longitudinal ART adherence and VL from conception until two years postpartum. We applied national and international guidelines for VL monitoring to the simulated data. We compared guidelines on the percentage of women receiving VL monitoring and the percentage of women monitored at the time of elevated VL. Results: Coverage of VL monitoring in pregnancy and breastfeeding varied markedly, with between 14–100% of women monitored antenatally and 38–98% monitored during breastfeeding. Specific recommendations for testing at either a fixed gestation or a short, fixed period after ART initiation achieved >95% testing in pregnancy but this was much lower (14–83%) among guidelines with no special stipulations. By the end of breastfeeding, only a small proportion of simulated episodes of elevated VL > 1000 copies/mL were successfully detected by monitoring (range, 20–50%). Discussion: While further research is needed to understand optimal VL frequency and timing in this population, these results suggest that current policies yield suboptimal detection of elevated VL in pregnant and breastfeeding women. Correspondence to Maia Lesosky, Division of Epidemiology & Biostatistics, School of Public Health & Family Medicine, University of Cape Town Faculty of Health Sciences, Anzio Road, Observatory 7925, South Africa. Tel: +27(0)216504532; e-mail: lesosky@gmail.com Received 17 June, 2019 Revised 30 August, 2019 Accepted 13 September, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

All-cause mortality after ART initiation in HIV-positive women from Europe, Sub-Saharan Africa and the Americas Background: Women account for over half of persons living with HIV/AIDS globally. We examined geographic variation in all-cause mortality after antiretroviral therapy (ART) for women living with HIV (WLWH) worldwide. Methods: We pooled data from WLWH at least 18 years initiating ART 2000–2014 within COHERE (Europe) and IeDEA regions (East Africa, West Africa, South Africa, North America, Latin America/Caribbean). Mortality rates were calculated at 0–3, 3–6, 6–12, 12–24 and 24–48 months after ART, and mortality rate ratios were compared with European rates with piecewise exponential parametric survival models based on Poisson regression. Findings: Nineteen thousand, one hundred and seventy-five WLWH (16% Europe, 47% East Africa, 13% West Africa, 19% South Africa, 1% South America, 3% North America and 2% Central America/Caribbean) were included. The highest death rates occurred 0–3 months after ART [1.51 (95% CI 1.25–1.82) per 100 person-years in Europe, 12.45 (11.30–13.73), 14.03 (13.12–15.02) and 9.44 (8.80–10.11) in East, West and South Africa, and 1.53 (0.97–2.43), 7.83 (5.44–11.27) and 17.02 (14.62–19.81) in North, South America and Central America/Caribbean, respectively] and declined thereafter. Mortality in Europe was the lowest, with regional differences greatest in the first 3 months and smaller at longer ART durations [adjusted rate ratios 24–48 months after ART: 3.63 (95% CI 3.04–4.33), 5.61 (4.84–6.51) and 3.47 (2.97–4.06) for East, West and South Africa; 2.86 (2.26–3.62), 2.42 (1.65–3.55) and 2.50 (1.92–3.26) for North, South America and Central America/Caribbean, respectively]. Conclusion: Global variations in short-term and long-term mortality among WLWH initiating ART may inform context-specific interventions. Correspondence to Julia del Amo, National Plan on HIV/AIDS/STIs, Ministry of Health, Consumer Affairs and Social Well being, Madrid, Spain. E-mail: jamo@mscbs.es Received 17 June, 2019 Revised 3 September, 2019 Accepted 13 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). Copyright © 2019 Wolters Kluwer Health, Inc.

Development and Validation of the First Point-of-Care Assay to Objectively Monitor Adherence to HIV Treatment and Prevention in Real-Time in Routine Settings Objective: HIV prevention and treatment studies demonstrate that pharmacologic adherence metrics are more accurate than self-report. Currently-available metrics use liquid-chromatography/tandem-mass-spectrometry (LC-MS/MS), which is expensive and laboratory-based. We developed a specific and sensitive antibody against tenofovir, the backbone of treatment and prevention, but conversion to a lateral flow assay (LFA) –analogous to a urine pregnancy test- is required for point-of-care testing. We describe the development of the first LFA to measure antiretroviral adherence in real-time. Methods: Previous work in a directly-observed therapy study of providing tenofovir-disoproxil fumarate (TDF) to HIV-noninfected volunteers at various simulated adherence patterns defined the appropriate cut-off for the LFA (1500ng tenofovir/ml urine). We developed the LFA using a sample pad for urine; a conjugate pad coated with TFV-specific antibodies conjugated to colloidal gold nanoparticles; a nitrocellulose membrane striped with tenofovir-antigen (test line) and a control line; with an absorbent pad to draw urine across the reaction membrane. Results: We tested 300 urine samples collected from the directly-observed therapy study by this LFA and the gold-standard method of LC-MS/MS. The LFA demonstrated 97% specificity (95% CI: 93% to 99%) and 99% sensitivity (94% to 100%) compared to LC-MS/MS. The LFA accurately classified 98% of patients who took a dose within 24 hours as adherent. Conclusion: We describe the development and validation of the first point-of-care assay to measure short-term adherence to HIV prevention and treatment in routine settings. The assay is low-cost, easy-to-perform and measures the breakdown product (tenofovir) of both TDF and tenofovir alafenamide (TAF). This assay has the potential to improve HIV and PrEP outcomes worldwide by triggering differentiated service delivery with further study merited. Correspondence to Monica Gandhi,MD, MPH, Professor of Medicine, Division of HIV, Infectious Diseases, and Global Medicine, 995 Potrero Avenue, 4th floor, Room 423D, San Francisco, CA 94110. Tel: +415 476 4082 ext 138; fax: +415 476 9653; e-mail: monica.gandhi@ucsf.edu Received 19 July, 2019 Revised 28 August, 2019 Accepted 29 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

CD4 count stratification to guide tuberculosis preventive therapy for people living with HIV Objectives: In 2018, Brazilian guidelines changed to recommend tuberculosis (TB) preventive therapy for all people with HIV and a CD4≤350 cells/μL, but only for those with a positive tuberculin skin test (TST) if CD4> 350 cells/μL. We determined the potential effectiveness of CD4-based guidelines for TB testing and preventive therapy. Design: Secondary analysis of the stepped-wedge, cluster-randomized THRio trial for isoniazid preventive therapy (IPT). Methods: We analyzed data from 4,114 newly-registered patients with HIV in 29 clinics followed until TB diagnosis, death, or administrative censoring. We compared incidence rates of TB and TB/death between CD4, TST, IPT, and antiretroviral therapy (ART) categories. Results: Initial CD4 count was ≤350 in 2,138 (52%) and > 350 in 1,976 (48%) patients. TST was performed for 2,922 (71%), of whom 657 (16%) were TST-positive (278 [13%] CD4≤350 vs. 379 [19%] CD4> 350). A total of 619 (15%) received IPT and 2,806 (68%) received ART. For patients with CD4≤350 who did not receive IPT, the incidence rate of TB was 1.79/100 person-years (pys) and TB/death was 3.89/100pys. For patients with CD4> 350 who did not receive IPT, the incidence rates of TB and TB/death were 0.57/100pys and 1.49/100pys for TST-negatives, and 1.05/100pys and 1.64/100pys for TST-unknowns. Conclusions: TB incidence was high among all patients who did not receive IPT, including those with CD4> 350 and negative or unknown TST results. TB preventive therapy should be provided to all PLWH in medium burden settings, regardless of CD4 count and TST status. Correspondence to Jonathan Golub, PhD, Johns Hopkins University Center for Tuberculosis Research, 1550 Orleans Street, Cancer Research Building-2, Baltimore, MD 21287. Tel: +43-287-2969; e-mail: jgolub@jhmi.edu Received 13 August, 2019 Revised 3 September, 2019 Accepted 13 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). Copyright © 2019 Wolters Kluwer Health, Inc.