Time to rethink endpoints for new antiretroviral regimen registration? HIV RNA re-suppression in the ADVANCE trial In the ADVANCE study of first-line treatment, there were 48 participants with HIV RNA ≥50 copies/mL in the week 48 window who had subsequent follow-up data available with no change in randomised treatment. More participants achieved virological re-suppression in the TAF/FTC/DTG and TDF/FTC/DTG arms (26/34, 76%) than on TDF/FTC/EFV (6/14 = 43%) (p = 0.0421). It is unclear whether participants with HIV RNA ≥50 copies/mL at week 48 should be termed ‘virological failures’ on integrase inhibitor-based treatment. Correspondence to Toby Pepperrell, Imperial College London Faculty of Medicine, London, United Kingdom. Tel: +447930853428; e-mail: tp1615@ic.ac.uk Received 1 September, 2019 Revised 1 October, 2019 Accepted 5 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Serum extracellular vesicles expressing bone activity markers associate with bone loss after HIV antiretroviral therapy Objective: We tested whether bone-related extracellular vesicle phenotypes changed after initiating antiretroviral therapy (ART) and determined whether changes in levels of extracellular vesicles correlated with changes in bone mineral density (BMD). Design: Extracellular vesicle phenotypes were measured in blinded serum samples from 15 adults with HIV at baseline, 1, 3, 6 and 12 months after ART initiation. Not all samples were available at each time point so we averaged early (TP1, 1–3 months) and late (TP2, 6–12 months) time points. Methods: Extracellular vesicles were stained for osteocalcin (OC), RANKL (CD254), RANK (CD265), M-CSF (macrophage colony stimulating factor), and CD34+. Serum OC, procollagen type I N-terminal propeptide (P1NP), and C-terminal telopeptide of type 1 collagen (CTx) were also measured. Results: BMD significantly decreased from baseline to 12 months. Levels of OC+EVs, serum OC, serum P1NP, and CTx were significantly higher at early and late time points compared with baseline. Increases in EVs expressing OC, RANKL, RANK, and CD34+ from baseline to TP1 were associated with decreases in total hip BMD from baseline to 12 months. Change in serum OC, P1NP, and CTx from baseline to TP1 or TP2 did not correlate with change in BMD. Conclusion: Early changes in extracellular vesicles as expressing markers of bone activity were associated with total hip bone loss 12 months after ART initiation. These data suggest that serum extracellular vesicles may serve as novel biomarkers of bone remodeling. Future studies are required to determine if extracellular vesicles contribute to the effects of ART on changes in bone turnover markers and BMD. Correspondence to Philip J. Norris, Vitalant Research Institute, 270 Masonic Avenue, San Francisco, CA 94118, USA. E-mail: PNorris@vitalant.org Received 4 July, 2019 Revised 28 September, 2019 Accepted 11 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Cognitive impairment severity in relation to signs of subclinical Wernicke's encephalopathy in HIV and alcoholism comorbidity Objectives: The comorbidity of Human Immunodeficiency Virus (HIV) infection and alcoholism (ALC) is prevalent. Wernicke's encephalopathy (WE), a neurological disorder resulting from thiamine depletion, has been generally associated with alcoholism but has also been reported in HIV infection. This study examined whether subclinical WE signs could contribute to the heterogeneity of cognitive and motor deficits observed in individuals with both disease conditions (HIV+ALC). Design: 61 HIV+ALC individuals and 59 controls were assessed on attention and working memory, production, immediate and delayed episodic memory, visuospatial abilities, and upper limb motor function. Methods: Using Caine criteria (dietary deficiency, oculomotor abnormality, cerebellar dysfunction, and altered mental state), HIV+ALC individuals were classified by subclinical WE risk factors. Results: Signs of subclinical WE were present in 20% of the HIV+ALC participants. For attention/working memory, delayed memory, and upper limb motor function, HIV+ALC Caine 2+ (i.e., meeting two or three criteria) demonstrated the most severe deficits, scoring lower than HIV+ALC Caine 1 (i.e., meeting one criterion), HIV+ALC Caine 0 (i.e., meeting no criteria), and controls. Conclusions: The high prevalence of subclinical signs of WE and relevance to performance indicate that this condition should be considered in assessment of HIV-infected individuals, especially when alcoholism comorbidity is known or suspected. Above and beyond clinical factors such as depression, alcoholism and HIV disease-related variables, AIDS, hepatitis C and drug history known to mediate neuropsychological performance, subclinical WE signs could partly explain the heterogeneity in patterns and severity of cognitive and motor impairments in HIV-infected individuals with alcoholism comorbidity. Correspondence to Anne-Pascale Le Berre, PhD, Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, 401 Quarry Road, Stanford, CA 94305-5723, USA. Tel: +650 859 2155; e-mail: aleberre@stanford.edu Received 18 July, 2019 Revised 22 October, 2019 Accepted 23 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 alcohol use and HIV care cascade outcomes among adults undergoing population-based HIV testing in East Africa Objective: To assess the impact of alcohol use on HIV care cascade outcomes. Design: Cross-sectional analyses. Methods: We evaluated HIV care cascade outcomes and alcohol use in adults (≥15 years) during baseline (2013--2014) population-based HIV testing in 28 Kenyan and Ugandan communities. ‘Alcohol use’ included any current use and was stratified by Alcohol Use Disorders Identification Test-Concise (AUDIT-C) scores: nonhazardous/low (1--3 men/1--2 women), hazardous/medium (4--5 men/3--5 women), hazardous/high (6--7), hazardous/very-high (8--12). We estimated cascade outcomes and relative risks associated with each drinking level using targeted maximum likelihood estimation, adjusting for confounding and missing measures. Results: Among 118 923 adults, 10 268 (9%) tested HIV-positive. Of those, 10 067 (98%) completed alcohol screening: 1626 (16%) reported drinking, representing 7% of women (467/6499) and 33% of men (1 159/3568). Drinking levels were: low (48%), medium (34%), high (11%), very high (7%). Drinkers were less likely to be previously HIV diagnosed (58% [95% CI: 55--61%]) than nondrinkers [66% (95% CI: 65–67%); RR: 0.87 (95% CI: 0.83–0.92)]. If previously diagnosed, drinkers were less likely to be on ART [77% (95% CI: 73–80%)] than nondrinkers [83% (95% CI 82–84%); RR: 0.93 (95% CI: 0.89–0.97)]. If on ART, there was no association between alcohol use and viral suppression; however, very-high-level users were less likely to be suppressed [RR: 0.80 (95% CI: 0.68–0.94)] versus nondrinkers. On a population level, viral suppression was 38% (95% CI: 36–41%) among drinkers and 44% (95% CI: 43–45%) among nondrinkers [RR: 0.87 (95% CI 0.82–0.94)], an association seen at all drinking levels. Conclusion: Alcohol use was associated with lower viral suppression; this may be because of decreased HIV diagnosis and ART use. Correspondence to Sarah B. Puryear, MD, MPH, Division of HIV, Infectious Diseases and Global Medicine, University of California San Francisco, 995 Potrero Avenue, Ward 84, San Francisco, CA 94110, USA. Tel: +1 415 476 4082 x445; e-mail: sarah.puryear@ucsf.edu Received 24 July, 2019 Revised 17 October, 2019 Accepted 19 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Regional brain volumetric changes despite two years of treatment initiated during acute HIV infection Objective: To assess changes in regional brain volumes after 24 months among individuals who initiated combination antiretroviral therapy (cART) within weeks of HIV exposure. Design: Prospective cohort study of Thai participants in the earliest stages of HIV-1 infection. Methods: Thirty-four acutely HIV-infected individuals (AHI; Fiebig I-V) underwent brain magnetic resonance (MR) imaging and MR spectroscopy at 1.5T and immediately initiated cART. Imaging was repeated at 24 months. Regional brain volumes were quantified using FreeSurfer's longitudinal pipeline. Voxel-wise analyses using tensor-based morphometry (TBM) were conducted to verify regional assessments. Baseline brain metabolite levels, blood and cerebrospinal fluid biomarkers assessed by ELISA, and peripheral blood monocyte phenotypes measured by flow cytometry were examined as predictors of significant volumetric change. Results: Participants were 31 ± 8 years old. The estimated mean duration of infection at cART initiation was 15 days. Longitudinal analyses revealed reductions in volumes of putamen (p < 0.001) and caudate (p = 0.006). TBM confirmed significant atrophy in the putamen and caudate, as well as in thalamic and hippocampal regions. In exploratory post-hoc analyses, higher baseline frequency of P-selectin glycoprotein ligand-1 (PSGL-1)-expressing total monocytes correlated with greater caudate volumetric decrease (ρ = 0.67, p = 0.017), while the baseline density of PSGL-1-expressing inflammatory (CD14+CD16+) monocytes correlated with putamen atrophy (ρ = 0.65, p = 0.022). Conclusion: Suppressive cART initiated during AHI may not prevent brain atrophy. Volumetric decrease appears greater than expected age-related decline, although examination of longitudinal change in demographically similar HIV-uninfected Thai individuals is needed. Mechanisms underlying progressive HIV-related atrophy may include early activation and enhanced adhesive and migratory capacity of circulating monocyte populations. Correspondence to Kalpana J. Kallianpur, John A. Burns School of Medicine, 651 Ilalo Street, BSB 231-C, Honolulu, HI 96813, USA. E-mail: kalpana@hawaii.edu Received 3 April, 2019 Revised 3 October, 2019 Accepted 12 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Summarizing the results and methods of the 2019 UNAIDS HIV estimates No abstract available

EPP-ASM and the r-hybrid model: new tools for estimating HIV incidence trends in sub-Saharan Africa Objectives: Improve models for estimating HIV epidemic trends in sub-Saharan Africa (SSA). Design: Mathematical epidemic model fit to national HIV survey and ANC sentinel surveillance (ANC-SS) data. Methods: We modified EPP to incorporate age and sex stratification (EPP-ASM) to more accurately capture the shifting demographics of maturing HIV epidemics. Secondly, we developed a new functional form, termed ‘r-hybrid’, for the HIV transmission rate which combines a four-parameter logistic function for the initial epidemic growth, peak, and decline followed by a first-order random walk for recent trends after epidemic stabilization. We fitted the r-hybrid model along with previously developed r-spline and r-trend models to HIV prevalence data from household surveys and ANC-SS in 177 regions in 34 SSA countries. We used leave-one-out cross validation with household survey HIV prevalence to compare model predictions. Results: The r-hybrid and r-spline models typically provided similar HIV prevalence trends, but sometimes qualitatively different assessments of recent incidence trends due to different structural assumptions about the HIV transmission rate. The r-hybrid model had the lowest average continuous ranked probability score, indicating the best model predictions. Coverage of 95% posterior predictive intervals was 91.5% for the r-hybrid model, versus 87.2% and 85.5% for r-spline and r-trend, respectively. Conclusions: The EPP-ASM and r-hybrid models improve consistency of EPP and Spectrum, improve the epidemiological assumptions underpinning recent HIV incidence estimates, and improve estimates and short-term projections of HIV prevalence trends. Countries that use general population survey and ANC-SS data to estimate HIV epidemic trends should consider using these tools. Correspondence to Jeffrey W. Eaton, Department of Infectious Disease Epidemiology, Imperial College London, St Mary's Hospital Campus, London W2 1PG, United Kingdom. E-mail: jeffrey.eaton@imperial.ac.uk Received 25 April, 2019 Revised 31 October, 2019 Accepted 31 October, 2019 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.

Potential health gains among key populations in West and Central Africa through savings from lower-cost HIV treatment Objective: Prices of antiretroviral (ARV) drugs in lower-income countries have decreased substantially over the past two decades, helping facilitate greatly expanded access to antiretroviral therapy (ART). However, ART coverage in many parts of the world remains low. We investigate the extent of epidemiological benefits that might be expected if ARV drug prices declined further. Design: A modeling study using data from seven countries in West and Central Africa (Cameroon, Democratic Republic of the Congo, Côte d’Ivoire, Niger, Nigeria, Senegal, and Togo). Methods: We investigated how the timing of ARV cost reductions could affect the impact and compared three different possible investment strategies: reinvesting in ART, reinvesting in the HIV response according to historical allocations, and reinvesting with the aim of minimizing HIV incidence and mortality. Results: If ARV prices fell by 37% relative to 2018 levels (i.e., following continued trend declines), we calculate ART unit costs could decrease by ∼20% (holding other cost components constant). If this could be achieved by 2020 and the savings were reinvested into ART, we estimate that an additional 8% of HIV infections and 11% of HIV-related deaths could be averted over 2020–2030 across the 7 countries. Slightly greater gains could be attained if funds were reinvested in ART in combination with primary prevention. Delays in the year of introduction of ARV price reductions would reduce the impact by about 1% per year. Conclusion: ARV price reductions could free up funds that – if strategically invested – would help countries move closer toward the elimination of HIV. Correspondence to Robyn M. Stuart, Universitetsparken 5, København Ø, 2300, Denmark. Tel: +45 2878 5222; e-mail: robyn@math.ku.dk Received 19 March, 2019 Revised 2 October, 2019 Accepted 7 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.

Association between quality of care indicators for HIV infection and healthcare resource utilization and costs Objectives: Multiple care quality indicators for HIV infection exist but few studies examine their impact on health outcomes. This study assessed, which HIV quality indicators were associated with healthcare resource utilization and costs. Design: Retrospective analysis of Texas Medicaid claims data (01 January 2012 to 31 September 2016). Methods: Included patients had at least two HIV-related medical claims during the identification period (01 July 2012 to 31 August 2014) (index = date of first HIV claim), were 18–62 years at index, and were continuously enrolled in the 6-month pre-index and 1-year post-index periods. Dependent variables included emergency department (ED) visits, inpatient hospitalizations, prescription count, and all-cause healthcare costs. Independent variables included CD4+ cell count monitoring, syphilis, chlamydia, gonorrhea, hepatitis B, hepatitis C, and tuberculosis screenings, influenza and pneumococcal vaccinations, retention in care, and HAART initiation. Covariates included age, chronic hepatitis C virus infection, AIDS diagnosis, sex, and baseline healthcare cost. The study objective was addressed using generalized linear modeling. Results: CD4+ cell count monitoring and HAART initiation were significantly associated with reduced emergency department visits (P < 0.0001 for each). Influenza vaccination was significantly associated with reduced inpatient hospitalization (P < 0.0001). CD4+ cell count monitoring (P < 0.0001), TB screening (P = 0.0006), influenza vaccination (P < 0.0001), and HAART initiation (P < 0.0001) were significantly associated with increase prescription claims. CD4+ cell count monitoring, TB screening, and HAART initiation (P < 0.0001 for each) were significantly associated with all-cause healthcare costs. Conclusion: HAART may reduce use of emergency care services as early as 1 year following initiation. Correspondence to Jamie C. Barner, Health Outcomes Division, The University of Texas at Austin College of Pharmacy, 2409 University Avenue MC A1930, Austin, TX 78712, USA. E-mail: jbarner@austin.utexas.edu Received 10 May, 2019 Revised 27 September, 2019 Accepted 7 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.

Lifetime alcohol use among persons living with hiv is associated with frailty Background: The average lifespan of persons living with HIV (PLWH) on antiretroviral therapy approximates the general population. However, PLWH are susceptible to early aging and frailty. Behaviors such as alcohol consumption may contribute to frailty among PLWH. Objective: To determine the relationships between recent and lifetime alcohol use and frailty among PLWH. Design: Cross-sectional, prospective cohort study of in-care PLWH (n = 365) participating in the New Orleans Alcohol Use in HIV Study. Methods: Recent alcohol exposure was measured by the 30-day alcohol timeline follow-back (TLFB) assessment and by whole-blood-spot phosphatidylethanol (PEth) quantitation. Lifetime alcohol exposure (LAE) was estimated by a modified lifetime drinking history instrument. Frailty was assessed by a 58-item deficit index (DI58) and the phenotypic frailty index (PFI). The Veterans Aging Cohort Study Risk Index 2.0 was calculated. Results: Using generalized linear regression, LAE was positively associated with the DI58 [95%CI:(0.001,0.006)] and PFI severity [95%CI:(0.004,0.023)] after adjustment for age and other factors. Conversely, recent alcohol exposure was negatively associated with the DI58 [TLFB 95% CI: (−0.126, −0.034), PEth: (−0.163, −0.058)] and PFI severity [TLFB 95% CI: (−0.404, −0.015), PEth: (−0.406, 0.034)]. The VACS was not associated with alcohol use. Median per-decade alcohol exposure peaked in the second decade and tapered with aging thereafter. Increasing LAE and decreasing TLFB were co-associated with a specific subset of health deficits. Conclusion: Lifetime alcohol use is positively associated with frailty among PLWH. Specific health deficits may discourage alcohol consumption in some PLWH. Correspondence to David A. Welsh, MD, New Orleans, United States. Tel: +504 568 4634; fax: +504 568 4295; e-mail: dwelsh@lsuhsc.edu Received 15 May, 2019 Revised 13 October, 2019 Accepted 14 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.