Pre-exposure prophylaxis differentially alters circulating and mucosal immune cell activation in HSV-2 seropositive women Objective: Oral tenofovir-based pre-exposure prophylaxis (PrEP) is an important tool for prevention of new HIV infections, which also reduces subclinical HSV-2 shedding and symptomatic lesions in HIV-negative, HSV-2-seropositive individuals. However, the impact of PrEP on mucosal immunity has not been examined in detail. Design: Here we evaluate paired genital tissue and systemic immune profiles to characterize the immunological effects of PrEP in HIV-negative, HSV-2-seropositive African women sexually exposed to HIV. Methods: We compared local and systemic innate and T-cell characteristics in samples collected during PrEP usage and two months after PrEP discontinuation. Results: We found that frequencies of cervical CCR5+CD4+ cells, regulatory T-cells, and tissue macrophages were significantly reduced during PrEP use compared to after PrEP discontinuation. In contrast, peripheral blood CD4+ and CD8+ T-cells expressing markers of activation and trafficking were increased during PrEP usage. Conclusions: Together, our data are consistent with PrEP altering immunity differentially in the female genital tract compared to circulation in HSV-2+ women. Further study including comparison to HSV-2 negative women is needed to define the overall impact and mechanisms underlying these effects. These results point to the critical need to study the human mucosal compartment to characterize immune responses to mucosal infections. Correspondence to Jennifer M. Lund, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, E5-110, Seattle, WA, 98109 USA. Tel: +001 206 667 2217; fax: +001 206 667 7767; e-mail: jlund@fredhutch.org Received 17 September, 2018 Revised 22 May, 2019 Accepted 3 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.

Cross-sectional analysis of cognitive function in the MACS with multivariate normative comparisons Background: Prevalence estimates of cognitive impairment in HIV disease vary widely. Here we used multivariate normative comparison (MNC) to identify individuals with impaired cognition, and to compare the results with those using the Frascati and Gisslén criteria. Methods: This project used data collected before October 2014 from bisexual/gay men from the Multicenter AIDS Cohort Study. 2,904 men (mean age 39.7yr, 52.7% seropositive) had complete data in six cognitive domains at their first neuropsychological evaluation. T-scores were computed for each domain and the MNC was applied to detect impairment among seronegative and seropositive groups. Results: The MNC classified 6.26% of seronegative men as being impaired using a predetermined 5% false discovery rate (FDR). By contrast, the Frascati and the Gisslén criteria identified 24.54% and 11.36% of seronegative men as impaired. For seropositive men, the percent impairment was 7.45%, 25.73%, and 11.69%, respectively, by the MNC, Frascati and Gisslén criteria. When we used seronegative men without medical comorbidities as the control group, the MNC, the Frascati and the Gisslén criteria identified 5.05%, 27.07% and 4.21% of the seronegative men, and 4.34%, 30.95%, and 4.48% of the seropositive men as having cognitive impairment. For each method, serostatus was not associated with cognitive impairment. Conclusions: The MNC controls the FDR and therefore avoids the low specificity that characterizes the Frascati and Gisslén criteria. More research is needed to evaluate the sensitivity of the MNC method in a seropositive population that may be sicker and older than the current study sample and that includes women. Correspondence to James T. Becker, Department of Psychiatry, Neurology, and Psychology, 3501 Forbes Avenue, Suite 830, University of Pittsburgh, Pittsburgh PA 15213. Tel: +412 246 6970; e-mail: beckerjt@upmc.edu Received 30 October, 2018 Revised 26 April, 2019 Accepted 3 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.

How are transgender women acquiring hiv? insights from phylogenetic transmission clusters in San Francisco Objective: We explored potential HIV transmission typologies that involve transgender women to obtain insights on sexual and needle-sharing networks as sources of HIV infection. Design: San Francisco residents diagnosed with HIV in care at public facilities who had available viral pol sequences from June 2001 through January 2016 were included in the analysis. Methods: Viral sequence data were matched to the San Francisco HIV/AIDS Case Registry to obtain demographic and risk classification information. Transmission clusters with ≥2 cases were identified by bootstrap values ≥90% and mean pairwise genetic distances ≤0.025 substitutions per site. Results: Transgender women represented 275 of 5,200 patients; 86 were present in 70 clusters. Four typologies were hypothesized: 1) transgender women in clusters with men who have sex with men (MSM), 2) transgender women who inject drugs in clusters with cisgender women and men who inject drugs, 3) multiple transgender women in clusters with one man, and 4) multiple transgender women who do not inject drugs in clusters with men and cisgender women who inject drugs. Conclusions: Transmission patterns of transgender women may stand apart from MSM epidemics. Transgender women clustered with people who inject drugs, and with men who have sex with transgender women and cisgender women. Aggregation of transgender women into the category of MSM may obscure understanding of how they acquire HIV and to whom they may transmit infection. Phylogenetic insights strengthen the case that HIV prevention programs for MSM may not be applicable to transgender women or their partners. Correspondence to Dr. Hong-Ha M. Truong, 550 16th Street, 3rd Floor, San Francisco, CA 94158; e-mail: Hong-Ha.Truong@ucsf.edu Received 18 December, 2018 Revised 19 April, 2019 Accepted 17 June, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

A 24-week pilot study of dual maintenance therapy with raltegravir plus lamivudine Background: There is an increasing interest in two-drug regimens. We hypothesized that maintenance therapy with raltegravir plus lamivudine would keep HIV-1 suppressed and be well tolerated. Methods: Virally suppressed HIV-1-infected adults without previous viral failures or known resistance mutations to integrase inhibitors or 3TC/FTC or chronic hepatitis B were randomized 2:1 to switch to fixed-dose combination 150 mg lamivudine/300 mg raltegravir twice daily or to continue therapy. Primary outcome was the proportion of patients free of therapeutic failure (defined as viral failure, change in treatment for any reason, consent withdrawal, loss to follow-up or death) at week 24. Secondary outcomes were changes in laboratory, body composition, sleep quality, adherence, and adverse effects. Results: There were 75 patients included: men 78%; median age 50 years; median CD4 622/mm3. At week 24, 7 (9%) patients had therapeutic failure: raltegravir plus lamivudine 2 (4%) vs. control 5 (20%). The difference in proportions of therapeutic failures raltegravir plus lamivudine minus control was -0.159 (95% confidence interval: -0.353; -0.012). There was a trend to more weight gain with raltegravir plus lamivudine, but no significant changes in other secondary outcomes. Sixty four percent of patients in each arm had at least one adverse effect. Two (6%) patients in control arm and 4 (7%) patients in raltegravir plus lamivudine arm had severe adverse effects. Conclusion: This pilot study suggests that switching to raltegravir plus lamivudine in patients with viral suppression maintains efficacy and is well tolerated. A larger study of longer duration is required to confirm these findings. Correspondence to Esteban Martinez, PhD, Senior Consultant & Associate Professor of Medicine, Infectious Diseases Unit, Hospital Clínic & University of Barcelona, 08036 Barcelona, Spain. Tel: +34 93 227 55 74; fax: +34 93 451 44 38; e-mail: estebanm@clinic.cat Received 21 December, 2018 Revised 1 May, 2019 Accepted 26 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.

Contributions of HIV, HCV, and traditional vascular risk factors to peripheral artery disease in women Objectives: Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have been associated with cardiovascular disease (CVD), but it is unclear whether HIV and HCV are also associated with peripheral artery disease (PAD). We examined the association of HIV, HCV, and traditional CVD risk factors with PAD in the Women's Interagency HIV Study (WIHS), a multicenter U.S. cohort. Methods: In this cross-sectional study, ankle-brachial index (ABI) was estimated using Doppler ultrasound and manual sphygmomanometer in 1,899 participants aged >40 years with HIV/HCV coinfection, HCV or HIV monoinfection, or neither infection. Multivariable logistic regression was used to estimate the odds of PAD (ABI≤0.9) after controlling for demographic, behavioral, and CVD risk factors. Results: Over two-thirds were African-American, median age was 50 years, and PAD prevalence was 7.7% with little difference by infection status. After multivariable adjustment, neither HIV nor HCV infection was associated with greater odds of PAD. Factors associated with PAD included older age [adjusted(a) OR:2.15 for age>61-70 vs 40-50 years;95%CI:1.13,4.11)], Black race (aOR:2.24;95%CI:1.12,4.47), smoking (aOR:1.25 per 10-pack-year increment;95%CI:1.07,1.45), and higher systolic blood pressure (aOR:1.14 per 10mmHg;95%CI:1.02,1.29). Conclusions: The high PAD prevalence in this nationally representative cohort of women with or at risk for HIV is on par with general population studies in individuals a decade older than our study's median age. HIV and HCV infection are not associated with greater PAD risk relative to uninfected women with similar risk factors. Modifiable traditional CVD risk factors may be important early intervention targets in women with and at risk for HIV. Correspondence to Phyllis C. Tien, University of California, San Francisco, VAMC, Infectious Disease Section, 111W, 4150 Clement Street, San Francisco, CA 94121. Tel: +415 221 4810; ext 22577; fax: +415 379 5523; (e-mail: Phyllis.tien@ucsf.edu), Emily R. Cedarbaum, MD, MPH, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, Tel: +360 480 9600; fax: +415 379 5523; (e-mail: emily.cedarbaum@ucsf.edu). Received 27 February, 2019 Revised 28 May, 2019 Accepted 16 June, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Uptake and effectiveness of two-drug compared to three-drug antiretroviral Regimens among HIV-positive Individuals in Europe Objective: To assess the use of two-drug antiretroviral regimens (2DR) and virologic and immunologic outcomes compared to three-drug regimens (3DR) in the EuroSIDA cohort. Design: Multicentre, prospective cohort study. Methods: Logistic regression was used to analyse the uptake and outcomes among HIV-positive individuals who started or switched to a 2DR compared to those on a 3DR. Virologic outcomes were assessed on-treatment as the proportion of individuals with controlled viral load (VL, <400 copies/mL), or with a composite modified FDA snapshot endpoint (mFDA), with mFDA success defined as controlled VL at 6- or 12-months for individuals with a known VL, no regimen changes, AIDS or death. Immunologic response was defined as a 100 cells/μL or a 25% increase in CD4 counts from baseline. Results: Between 1/7/2010-31/12/2016, 423 individuals started or switched to a 2DR (8 antiretroviral-naïve) and 4347 started a 3DR (566 naïve). Individuals on 2DR tended to have suppressed VL, higher CD4 cell counts and more comorbidities at baseline compared to those on 3DR. There were no differences in the proportions of individuals who obtained on-treatment or mFDA success, and no significant differences in the adjusted odds ratios for mFDA success or immunologic responses between the 2DR and 3DR groups at 6- or 12-months. Conclusion: In routine clinical practice, 2DR were largely used for virologically suppressed individuals with higher cumulative exposure to ARVs and comorbidities. Virologic and immunologic outcomes were similar among those on 2DR or 3DR, although confounding by indication cannot be fully excluded due to the observational nature of the study. Correspondence to Bastian Neesgaard, MD, CHIP, Department of Infectious Diseases, Section 2100, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. Tel: +45 35 45 57 70; fax: +45 35 45 57 58; e-mail: Bastian.neesgaard@regionh.dk Received 15 March, 2019 Revised 9 June, 2019 Accepted 16 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.

Association between zidovudine-containing antiretroviral therapy exposure in utero and leukocyte telomere length at birth Objectives: Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor that could cause telomere shortening through inhibition of telomerase. We examined the association between in utero exposure to ZDV and telomere length (TL) at birth in HIV-exposed uninfected (HEU) newborns. Methods: We selected 94 ZDV-exposed HEU children and 85 antiretroviral therapy (ART)-unexposed HEU children from the Surveillance Monitoring for ART Toxicities Study and the Women and Infants Transmission Study. We assessed relative TL in stored peripheral blood mononuclear cells taken in the first 7 days of life using quantitative polymerase chain reaction. We used linear regression to compare relative TL between ZDV-exposed and ART-unexposed children. We additionally evaluated relative TL according to maternal and infant characteristics. Results: Relative TL was longer in ZDV-exposed children compared to ART-unexposed individuals (adjusted mean ratio difference 0.21, 95%CI 0.15–0.28, p < 0.001). We found an inverse correlation between maternal HIV RNA levels and infant relative TL (-0.06 per log10 copies, 95%CI -0.08 to -0.03, p < 0.001). Relative TL was not associated with maternal CD4 count, maternal age, gestational age, sex, sample storage time, or maternal substance use (p > 0.05). Conclusion: Relative TL was longer in ZDV-exposed infants. This difference may reflect beneficial health effects of antiretroviral therapy during pregnancy, since we observed an inverse association with maternal HIV RNA levels. Correspondence to Youjin Wang, PhD, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD 20850; e-mail: youjin.wang@nih.gov Received 10 April, 2019 Revised 12 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.

The association of provider and practice factors with HIV ART adherence Objective: While Anti-Retroviral Therapy (ART) is essential to patients with HIV, there is substantial variation in adherence nationally. We assess how provider and practice factors contribute to successful HIV ART adherence. Design: We used Medicaid Analytic Extract claims from 2008–2012. We attributed patients with HIV to the provider that provided the plurality of HIV-related services or primary care in a given year and assigned these providers to a medical practice based on the National Provider Identifier registry file. We fit successive linear hierarchical models with patient, provider, and practice characteristics to partition the variation in adherence driven by each factor. Our unit of analysis was the patient-year. Setting: 14 US states with the highest HIV prevalence Participants: 111,013 patient-years representing 60,496 Medicaid enrollees living with HIV attributed to 4,930 providers and 1,960 practices Main outcome measure: Percent of year individual patients were adherent to an ART regimen Results: Provider and practice random effects jointly explained 6.8% of variation in adherence with patient differences accounted for 45.2% of the variation. Patients seen by generalists and other specialists had a 1.6 (95%CI: 0.6–2.5) and 5.1 (95%CI: 4.1–6.1) percentage point greater adherence than those seen by infectious disease specialists (p < 0.001). Every additional year a patient saw the same provider was associated with a 6% increase in adherence (95%CI:5.7–6.3). Conclusions: There is substantial variation in ART adherence attributable to providers and practices and between provider specialties. To improve ART adherence for patients living with HIV, structural aspects of care should be considered. Correspondence to David J. Meyers, Brown University School of Public Health, Providence, RI United States. e-mail: david_meyers@brown.edu Received 24 April, 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.

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.