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Background: Young men who have sex with men and transgender women (YMSM/TGW) have disproportionately high HIV incidence and lower preexposure prophylaxis (PrEP) adherence. Point-of-care (POC) urine tenofovir (TFV) rapid assay (UTRA) testing permits real-time monitoring for nonadherence within clinical settings. We performed UTRA testing among PrEP users to examine the relationship between low PrEP adherence and future PrEP discontinuation, and the accuracy of POC testing compared to gold-standard liquid chromatography tandem mass spectrometry (LC/MS/MS)., Methods: YMSM/TGW participants ( n  = 100) were recruited during a daily PrEP visit. Logistic regression models analyzed the relationship between the primary predictor of urine POC assay results (cutoff 1,500 ng/ml) and the primary outcome of PrEP discontinuation, defined as no PrEP follow-up or prescription within 120 days., Results: Overall, 19% of participants had low urine TFV and 21% discontinued PrEP, while 11% of participants self-reported low PrEP adherence (<4 pills per week), which was only 43% sensitive/84% specific in predicting low TFV levels and was not associated with PrEP discontinuation. Low urine TFV level predicted PrEP discontinuation [adjusted odds ratio (AOR) 6.1; 95% confidence interval (CI): 1.4-11; P  = 0.005] and was 71% sensitive/90% specific for discontinuation after 120 days. Compared to LC/MS/MS, UTRA testing had a 98% positive and 100% negative predictive value., Conclusions: In a sample of YMSM/TGW on daily PrEP, POC UTRA testing predicted PrEP discontinuation more accurately than self-reported adherence, with high predictive values compared to LC/MS/MS. UTRA testing may be a clinical tool for directing preventive interventions towards those likelier to discontinue PrEP despite ongoing HIV vulnerability., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Pre-exposure prophylaxis (PrEP) adherence remains a challenge among young men who have sex with men (MSM). We developed and tested a smartphone application ("app"), "DOT Diary", which combines automated directly observed therapy (DOT) with information about PrEP protection levels, pill-taking reminders, a sexual behavior diary, and a PrEP dosing calendar. To contextualize trial results, we qualitatively explored participants' app experiences. The trial enrolled 100 young MSM in San Francisco and Atlanta. Participants were randomized 2:1 to DOT Diary versus standard-of-care and followed for 24 weeks. Interviews were conducted with 24 intervention participants. Data were analyzed using a memo-writing approach. Most expressed overall satisfaction with the app ("it was good for its purpose"), despite concerns about technical glitches. The most popular app features were the monthly calendar showing days PrEP was taken and information about level of protection based on pills taken. The DOT component helped participants establish PrEP routines. The reminders were "annoying but effective" at motivating dosing. Opinions about the sexual behavior diary varied. Overall, DOT Diary was acceptable; participants were willing to use it daily to record pill-taking. Critical components included the information about PrEP protection levels and calendar, while others may be modified to improve future success. Trial registration: ClinicalTrials.gov identifier: NCT03771638.

At the 2024 Conference on Retroviruses and Opportunistic Infections (CROI), investigators presented updates on the global HIV epidemic, focusing on ongoing disparities by race/ethnicity in the US, the ongoing concentration of new infections among men who have sex with men (MSM) and transgender women in the Americas, and a shift to a greater total number of infections now in low versus high prevalence countries globally. HIV testing, the gateway to prevention and to treatment, has not fully rebounded from the substantial declines seen during the early COVID-19 pandemic in some settings, although innovative strategies including home testing and opt-out testing in clinical settings appear to be reaching populations in need of testing. Several investigators reported on the efficacy and effectiveness of doxycycline used as postexposure prophylaxis (doxy-PEP) to prevent bacterial sexual transmitted infections in MSM and transgender women in clinical trials and clinic settings; citywide rates of chlamydia and syphilis have decreased in San Francisco after the rollout of the first doxy-PEP guidelines in the US. Lack of doxy-PEP efficacy in cisgender women in Kenya appears due to low adherence in that trial. Rollout and persistence on oral HIV preexposure prophylaxis (PrEP) are associated with reduced seroincidence on a population and individual level. The rollout of long-acting injectable cabotegravir (CAB-LA) PrEP is proceeding slowly in the US. New, longer-acting oral and injectable agents are in development, with preclinical and early clinical trial data presented at CROI. Oral PrEP uptake among populations in sub-Saharan Africa remains low in most settings, suggesting the need for more options and more support; point-of-care tenofovir testing appear acceptable in various populations and may improve adherence and identify PrEP users needing more support. Choice of PrEP or PEP including CAB-LA combined with clinical support substantially increased biomedical prevention coverage in East Africa. Novel approaches to PrEP rollout, including delivery using mobile services and in nonclinical settings appear to show promise. HIV PEP continues to be underutilized.

At the 2023 Conference on Retroviruses and Opportunistic Infections (CROI), several investigators used tests of recent HIV infection to track which populations are currently most heavily impacted by HIV and to estimate HIV infection rates in those populations. Assisted partner notification for HIV was successfully applied for spouses of persons with HIV and sexual and injection partners of people who inject drugs; however, delays in linkage to care were seen for non-spousal partners in one study. Lack of awareness of HIV positive status remains an issue in various populations; several presentations focused on novel strategies for improving HIV testing uptake in these populations. Doxycycline administered as 200 mg post sexual exposure significantly reduced the risk of syphilis, chlamydia, and gonorrhea infection in men who have sex with men but did not prevent bacterial sexually transmitted infections (STIs) in cis-gender women; reasons for this discrepancy are currently being explored. Although oral HIV preexposure prophylaxis (PrEP) is increasingly being used in populations in greatest need of prevention tools, PrEP uptake and persistence remain low in a number of key populations, including people who inject drugs. Several innovative delivery models show early promise in addressing gaps along the PrEP continuum. The successful use of injectable cabotegravir PrEP in several populations was presented at this conference, although uptake remains low globally. The pipeline of novel long-acting and rapid-onset PrEP agents appears to be robust, including implants, vaginal rings, and topical inserts, with several presentations focusing on preclinical and early clinical trials.

Background: Interventions to reduce sexually transmitted infections (STIs) among men who have sex with men (MSM) are needed., Methods: We conducted an open-label, randomized study involving MSM and transgender women who were taking preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection (PrEP cohort) or living with HIV infection (persons living with HIV infection [PLWH] cohort) and who had had Neisseria gonorrhoeae (gonorrhea), Chlamydia trachomatis (chlamydia), or syphilis in the past year. Participants were randomly assigned in a 2:1 ratio to take 200 mg of doxycycline within 72 hours after condomless sex (doxycycline postexposure prophylaxis) or receive standard care without doxycycline. STI testing was performed quarterly. The primary end point was the incidence of at least one STI per follow-up quarter., Results: Of 501 participants (327 in the PrEP cohort and 174 in the PLWH cohort), 67% were White, 7% Black, 11% Asian or Pacific Islander, and 30% Hispanic or Latino. In the PrEP cohort, an STI was diagnosed in 61 of 570 quarterly visits (10.7%) in the doxycycline group and 82 of 257 quarterly visits (31.9%) in the standard-care group, for an absolute difference of -21.2 percentage points and a relative risk of 0.34 (95% confidence interval [CI], 0.24 to 0.46; P<0.001). In the PLWH cohort, an STI was diagnosed in 36 of 305 quarterly visits (11.8%) in the doxycycline group and 39 of 128 quarterly visits (30.5%) in the standard-care group, for an absolute difference of -18.7 percentage points and a relative risk of 0.38 (95% CI, 0.24 to 0.60; P<0.001). The incidences of the three evaluated STIs were lower with doxycycline than with standard care; in the PrEP cohort, the relative risks were 0.45 (95% CI, 0.32 to 0.65) for gonorrhea, 0.12 (95% CI, 0.05 to 0.25) for chlamydia, and 0.13 (95% CI, 0.03 to 0.59) for syphilis, and in the PLWH cohort, the relative risks were 0.43 (95% CI, 0.26 to 0.71), 0.26 (95% CI, 0.12 to 0.57), and 0.23 (95% CI, 0.04 to 1.29), respectively. Five grade 3 adverse events and no serious adverse events were attributed to doxycycline. Of the participants with gonorrhea culture available, tetracycline-resistant gonorrhea occurred in 5 of 13 in the doxycycline groups and 2 of 16 in the standard-care groups., Conclusions: The combined incidence of gonorrhea, chlamydia, and syphilis was lower by two thirds with doxycycline postexposure prophylaxis than with standard care, a finding that supports its use among MSM with recent bacterial STIs. (Funded by the National Institutes of Health; DoxyPEP ClinicalTrials.gov number, NCT03980223.)., (Copyright © 2023 Massachusetts Medical Society.)

Measurement of adherence to oral pre-exposure prophylaxis (PrEP) in real-time has been challenging. We developed DOT Diary, a smartphone application that combines automated directly observed therapy with a PrEP adherence visualization toolkit, and tested its ability to measure PrEP adherence and to increase adherence among a diverse cohort of young men who have sex with men (MSM). We enrolled 100 MSM in San Francisco and Atlanta and randomly assigned them 2:1 to DOT Diary versus standard of care. Concordance between DOT Diary measurement and drug levels in dried blood spots was substantial, with 91.0% and 85.3% concordance between DOT Diary and emtricitabine-triphosphate and tenofovir-diphosphate, respectively. There was no significant difference in the proportion of participants with detectable PrEP drug levels at 24 weeks between study arms. These results suggest DOT Diary is substantially better than self-reported measures of adherence, but additional interventions are needed to improve PrEP adherence over time., (© 2022. The Author(s).)

Importance: Recent advances in treatment and prevention of HIV warrant updated recommendations to guide optimal practice., Objective: Based on a critical evaluation of new data, to provide clinicians with recommendations on use of antiretroviral drugs for the treatment and prevention of HIV, laboratory monitoring, care of people aging with HIV, substance use disorder and HIV, and new challenges in people with HIV, including COVID-19 and monkeypox virus infection., Evidence Review: A panel of volunteer expert physician scientists were appointed to update the 2020 consensus recommendations. Relevant evidence in the literature (PubMed and Embase searches, which initially yielded 7891 unique citations, of which 834 were considered relevant) and studies presented at peer-reviewed scientific conferences between January 2020 and October 2022 were considered., Findings: Initiation of antiretroviral therapy (ART) is recommended as soon as possible after diagnosis of HIV. Barriers to care should be addressed, including ensuring access to ART and adherence support. Integrase strand transfer inhibitor-containing regimens remain the mainstay of initial therapy. For people who have achieved viral suppression with a daily oral regimen, long-acting injectable therapy with cabotegravir plus rilpivirine given as infrequently as every 2 months is now an option. Weight gain and metabolic complications have been linked to certain antiretroviral medications; novel strategies to ameliorate these complications are needed. Management of comorbidities throughout the life span is increasingly important, because people with HIV are living longer and confronting the health challenges of aging. In addition, management of substance use disorder in people with HIV requires an evidence-based, integrated approach. Options for preexposure prophylaxis include oral medications (tenofovir disoproxil fumarate or tenofovir alafenamide plus emtricitabine) and, for the first time, a long-acting injectable agent, cabotegravir. Recent global health emergencies, like the SARS-CoV-2 pandemic and monkeypox virus outbreak, continue to have a major effect on people with HIV and the delivery of services. To address these and other challenges, an equity-based approach is essential., Conclusions and Relevance: Advances in treatment and prevention of HIV continue to improve outcomes, but challenges and opportunities remain.

Background: The identification of baseline host determinants that associate with robust HIV-1 vaccine-induced immune responses could aid HIV-1 vaccine development. We aimed to assess both the collective and relative performance of baseline characteristics in classifying individual participants in nine different Phase 1-2 HIV-1 vaccine clinical trials (26 vaccine regimens, conducted in Africa and in the Americas) as High HIV-1 vaccine responders., Methods: This was a meta-analysis of individual participant data, with studies chosen based on participant-level (vs. study-level summary) data availability within the HIV-1 Vaccine Trials Network. We assessed the performance of 25 baseline characteristics (demographics, safety haematological measurements, vital signs, assay background measurements) and estimated the relative importance of each characteristic in classifying 831 participants as High (defined as within the top 25th percentile among positive responders or above the assay upper limit of quantification) versus Non-High responders. Immune response outcomes included HIV-1-specific serum IgG binding antibodies and Env-specific CD4+ T-cell responses assessed two weeks post-last dose, all measured at central HVTN laboratories. Three variable importance approaches based on SuperLearner ensemble machine learning were considered., Findings: Overall, 30.1%, 50.5%, 36.2%, and 13.9% of participants were categorized as High responders for gp120 IgG, gp140 IgG, gp41 IgG, and Env-specific CD4+ T-cell vaccine-induced responses, respectively. When including all baseline characteristics, moderate performance was achieved for the classification of High responder status for the binding antibody responses, with cross-validated areas under the ROC curve (CV-AUC) of 0.72 (95% CI: 0.68, 0.76) for gp120 IgG, 0.73 (0.69, 0.76) for gp140 IgG, and 0.67 (95% CI: 0.63, 0.72) for gp41 IgG. In contrast, the collection of all baseline characteristics yielded little improvement over chance for predicting High Env-specific CD4+ T-cell responses [CV-AUC: 0.53 (0.48, 0.58)]. While estimated variable importance patterns differed across the three approaches, female sex assigned at birth, lower height, and higher total white blood cell count emerged as significant predictors of High responder status across multiple immune response outcomes using Approach 1. Of these three baseline variables, total white blood cell count ranked highly across all three approaches for predicting vaccine-induced gp41 and gp140 High responder status., Interpretation: The identified features should be studied further in pursuit of intervention strategies to improve vaccine responses and may be adjusted for in analyses of immune response data to enhance statistical power., Funding: National Institute of Allergy and Infectious Diseases (UM1AI068635 to YH, UM1AI068614 to GDT, UM1AI068618 to MJM, and UM1 AI069511 to MCK), the Duke CFAR P30 AI064518 to GDT, and National Institute of Dental and Craniofacial Research (R01DE027245 to JJK). This work was also supported by the Bill and Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding sources., Competing Interests: Declaration of interests Y.H. declares contract payments to her institution from the World Health Organization to conduct statistical analysis work (outside the scope of the current work; related to COVID-19 vaccines) and plan to submit the results for publication, within the past 36 months, as well as service to WHV as an SMB (payment directly to her) within the past 36 months. K.E.S. and J.H. declare coverage of travel expenses for attendance at the HVTN Full Group Meeting in 2022 (reimbursement by the HVTN); K.E.S. additionally declares payment of a registration fee for virtual seminar attendance directly to Keystone Symposium by the HVTN. S.D.R. declares contracts awarded to his institution from Battelle and from Janssen, and grants awarded to his institution from the Gates Medical Research Institute and from the Paul G. Allen Family Foundation, within the past 36 months. P.A.G. declares consulting fees received from Johnson and Johnson within the past 36 months, as well as a patent for a COVID-19 monoclonal antibody that is not yet clinically available. K.W.C. declares funding from the Bill and Melinda Gates Foundation in the form of payments to her institution within the last 36 months. B.D.W. declares grant payments made to his institution within the past 36 months from the following entities: Centers for Disease Control and Prevention, Patient-Centered Outcomes Research Institute, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Cancer Institute, and the National Institute of General Medical Studies; an honorarium for delivering an invited webinar to the American Statistical Association: Statistical Learning and Data Science Section; travel support through a grant from the National Institute of Mental Health; and retirement accounts invested in mutual funds operated by Vanguard and by TIAA (he does not choose individual stocks). L.-G.B. declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead Sciences, Janssen, and Merck PTY LTD within the past 36 months, as well as participation on a Data Safety Monitoring Board or Advisory Board for the PrEPVAC study within the past 36 months. G.D.T. declares consulting fees received from Axon and from Janssen (not related to this work), serving as an Advisory Board member for the NIH VRC, UNC CFAR, and Johns Hopkins (not related to this work), and serving as a scientific review member for Gilead (not related to this work), all within the past 36 months, as well as travel as part of research funding (more than 3 years prior, with funding paid to her institution). J.T. declares consulting fees from Vaccitech within the past 36 months., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: After coronavirus disease 2019 (COVID-19) shelter-in-place (SIP) orders, viral suppression (VS) rates initially decreased within a safety-net human immunodeficiency virus (HIV) clinic in San Francisco, particularly among people living with HIV (PLWH) who are experiencing homelessness. We sought to determine if proactive outreach to provide social services, scaling up of in-person visits, and expansion of housing programs could reverse this decline., Methods: We assessed VS 24 months before and 13 months after SIP using mixed-effects logistic regression followed by interrupted time series (ITS) analysis to examine changes in the rate of VS per month. Loss to follow-up (LTFU) was assessed via active clinic tracing., Results: Data from 1816 patients were included; the median age was 51 years, 12% were female, and 14% were experiencing unstable housing/homelessness. The adjusted odds of VS increased 1.34 fold following institution of the multicomponent strategies (95% confidence interval [CI], 1.21-1.46). In the ITS analysis, the odds of VS continuously increased 1.05 fold per month over the post-intervention period (95% CI, 1.01-1.08). Among PLWH who previously experienced homelessness and successfully received housing support, the odds of VS were 1.94-fold higher (95% CI, 1.05-3.59). The 1-year LTFU rate was 2.8 per 100 person-years (95% CI, 2.2-3.5)., Conclusions: The VS rate increased following institution of the multicomponent strategies, with a lower LFTU rate compared with prior years. Maintaining in-person care for underserved patients, with flexible telemedicine options, along with provision of social services and permanent expansion of housing programs, will be needed to support VS among underserved populations during the COVID-19 pandemic., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: In 2010-2014, the San Francisco Department of Public Health (SFDPH) established programs to rapidly link people with human immunodeficiency virus (PWH) to care and offer antiretroviral therapy (ART) at human immunodeficiency virus (HIV) diagnosis. Such programs reduced the number of PWH out of care or with detectable HIV viral load (ie, uncontrolled HIV infection). We investigated the role of social determinants of health (SDH) on uncontrolled HIV., Methods: Cross-sectional data from adult PWH diagnosed and reported to the SFDPH as of December 31, 2019, prescribed ART, and with confirmed San Francisco residency during 2017-2019 were analyzed in conjunction with SDH metrics derived from the American Community Survey 2015-2019. We focused on 5 census tract-level SDH metrics: percentage of residents below the federal poverty level, with less than a high school diploma, or uninsured; median household income; and Gini index. We compared uncontrolled HIV prevalence odds ratios (PORs) across quartiles of each metric independently using logistic regression models., Results: The analysis included 7486 PWH (6889 controlled HIV; 597 uncontrolled HIV). Unadjusted PORs of uncontrolled HIV rose with increasingly marginalized quartiles, compared to the least marginalized quartile for each metric. Adjusting for demographics and transmission category, the POR for uncontrolled HIV for PWH in the most marginalized quartile remained significant across metrics for poverty (POR = 2.0; confidence interval [CI] = 1.5-2.6), education (POR = 2.4; CI = 1.8-3.2), insurance (POR = 1.8; CI = 1.3-2.5), income (POR = 1.8; CI = 1.4-2.3), and income inequality (POR = 1.5; CI = 1.1-2.0)., Conclusions: Beyond demographics, SDH differentially affected the ability of PWH to control HIV. Despite established care programs, PWH experiencing socioeconomic marginalization require additional support to achieve health outcome goals., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

To assess SARS-CoV-2 outcomes, we matched a municipal COVID-19 registry and clinic rosters from a municipal primary care network containing a large HIV clinic and assessed clinical outcomes by HIV status. The risk of severe COVID-19 was higher among people with HIV (PWH, adjusted relative risk = 1.84, 95% confidence interval = 1.05-3.25), while SARS-CoV-2 incidence was lower despite higher testing rates. SARS-CoV-2 vaccination campaigns should prioritize PWH to prevent severe COVID-19 disease given potentially higher risk., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Ending the HIV epidemic in the U.S. holds rapid antiretroviral therapy as a key strategy to improve the health of those with HIV and to decrease transmission. In 2015, Getting to Zero San Francisco, a multisector consortium, expanded rapid antiretroviral therapy citywide., Methods: A Getting to Zero San Francisco Rapid ART Program Initiative for HIV Diagnoses Committee (academic, community, service delivery, health department partners) designed the program, protocol, dissemination plan, and monitoring strategy. Newly diagnosed patients were linked to an HIV medical home or Rapid ART Program Initiative for HIV Diagnoses initiation hub to best deliver rapid antiretroviral therapy across a diverse patient mix, with a goal of ≤5 working days from diagnosis to care and ≤1 day from care to antiretroviral therapy. Stakeholders were trained on rapid antiretroviral therapy via Getting to Zero San Francisco meetings, in-services, public health detailing, and peer-to-peer recruiting, prioritizing HIV clinics serving patients of color, Latinx ethnicity, youth, and the uninsured or publicly insured. Rapid ART Program Initiative for HIV Diagnoses-specific metrics were derived from surveillance data; stratified by sex/gender, age, race/ethnicity, and housing status; and presented at public meetings. Data were analyzed between January and April 2021., Results: From 2014 to 2018, median time from diagnosis to care decreased 71% (7 to 2 days), care to antiretroviral therapy decreased from 19 to 0 days, and diagnosis to virologic suppression decreased 51% (94 to 46 days). Improvements occurred regardless of age, race/ethnicity, sex/gender, exposure, or housing status., Conclusions: During a citywide initiative to optimize antiretroviral therapy initiation, time from HIV diagnosis to care, antiretroviral therapy, and virologic suppression decreased across all affected groups to varying degrees. The Rapid ART Program Initiative for HIV Diagnoses Committee continues to address challenges to retention and expand implementation., (Copyright © 2021 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Inaccuracies in cause-of-death information in death certificates can reduce the validity of national death statistics and result in poor targeting of resources to reduce morbidity and mortality in people with HIV. Our objective was to measure the sensitivity, specificity, and agreement between multiple causes of deaths from death certificates obtained from the National Death Index (NDI) and causes determined by expert physician review., Methods: Physician specialists determined the cause of death using information collected from the medical records of 50 randomly selected HIV-infected people who died in San Francisco from July 1, 2016, through May 31, 2017. Using expert review as the gold standard, we measured sensitivity, specificity, and agreement., Results: The NDI had a sensitivity of 53.9% and a specificity of 66.7% for HIV deaths. The NDI had a moderate sensitivity for non-AIDS-related infectious diseases and non-AIDS-related cancers (70.6% and 75.0%, respectively) and high specificity for these causes (100.0% and 94.7%, respectively). The NDI had low sensitivity and high specificity for substance abuse (27.3% and 100.0%, respectively), heart disease (58.3% and 86.8%, respectively), hepatitis B/C (33.3% and 97.7%, respectively), and mental illness (50.0% and 97.8%, respectively). The measure of agreement between expert review and the NDI was lowest for HIV (κ = 0.20); moderate for heart disease (κ = 0.45) and hepatitis B/C (κ = 0.40); high for non-AIDS-related infectious diseases (κ = 0.76) and non-AIDS-related cancers (κ = 0.72); and low for all other causes of death (κ < 0.35)., Conclusions: Our findings support education and training of health care providers to improve the accuracy of cause-of-death information on death certificates.

Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans ( n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Importance: Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices., Objective: To evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV., Evidence Review: New evidence was collected since the previous International Antiviral (formerly AIDS) Society-USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations., Findings: From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic., Conclusion and Relevance: Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.

PrEP persistence, or PrEP use over time, has been shown to be short, with most PrEP users stopping within 6-12 months. Furthermore, those most vulnerable to HIV often use PrEP for shorter periods. This qualitative study explores patient, provider, and contextual factors that influence PrEP persistence. In interviews with 25 PrEP users and 18 PrEP providers in San Francisco's safety net clinics, we analyze the perceived benefits and difficulties of taking PrEP, including structural barriers. We identify different steps in receipt of PrEP care (clinic visits and lab tests, pharmacy interactions, and medication adherence), and describe barriers and facilitators for providers and patients at each step. Our findings suggest that drop-in visits, streamlined testing, standing orders for labs, and 90-day PrEP prescriptions are highly desirable for many PrEP users. Also important are the proactive provision of adherence support and counseling, and referrals for housing, substance use, and mental health services.

Efficacious HIV-1 vaccination requires elicitation of long-lived antibody responses. However, our understanding of how different vaccine types elicit durable antibody responses is lacking. To assess the impact of vaccine type on antibody responses, we measured IgG isotypes against four consensus HIV antigens from 2 weeks to 10 years post HIV-1 vaccination and used mixed effects models to estimate half-life of responses in four human clinical trials. Compared to protein-boosted regimens, half-lives of gp120-specific antibodies were longer but peak magnitudes were lower in Modified Vaccinia Ankara (MVA)-boosted regimens. Furthermore, gp120-specific B cell transcriptomics from MVA-boosted and protein-boosted vaccines revealed a distinct signature at a peak (2 weeks after last vaccination) including CD19, CD40, and FCRL2-5 activation along with increased B cell receptor signaling. Additional analysis revealed contributions of RIG-I-like receptor pathway and genes such as SMAD5 and IL-32 to antibody durability. Thus, this study provides novel insights into vaccine induced antibody durability and B-cell receptor signaling.

At the 2020 Conference on Retroviruses and Opportunistic Infections, held virtually as a result of the emerging COVID-19 pandemic, trends in the HIV epidemic were highlighted, with decreasing HIV incidence reported across several countries, although key regions remain heavily impacted, including the US South. Adolescent girls and young women, men who have sex with men (MSM), transgender persons, and people who inject drugs continue to experience a high burden of new infections. Sexually transmitted infections during pregnancy can lead to a number of adverse outcomes in infants; novel strategies to detect and treat these infections are needed. Innovative HIV testing strategies, including self-testing and assisted partner services, are expanding the reach of testing; however, linkage to care can be improved. Novel preexposure prophylaxis (PrEP) delivery strategies are increasing uptake of PrEP in different groups, although adherence and persistence remain a challenge. Use of on-demand PrEP is increasing among MSM in the US. Strategies are needed to address barriers to PrEP uptake and persistence among cis- and transgender women. Several novel regimens for postexposure prophylaxis show promise.

Introduction: Pre-exposure prophylaxis (PrEP) is highly effective, although PrEP adherence and persistence has been variable during real world implementation. Little is known about missed opportunities to enhance PrEP adherence among individuals who later HIV seroconverted after using PrEP. The goal of this analysis was to identify all HIV infections among individuals who had accessed PrEP in an integrated health system in San Francisco, and to identify potentially intervenable factors that could have prevented HIV infection through in-depth interviews with people who HIV seroconverted after using PrEP., Methods: We identified individuals who initiated PrEP in an integrated safety-net public health system and performed in-depth chart review to determine person-time on and after stopping PrEP over six years. We identified all PrEP seroconversions using the Centers for Disease Control and Prevention's Enhanced HIV/AIDS Reporting System and then calculated HIV incidence while using PrEP and during gaps in use. We then performed in-depth interviews with those who seroconverted., Results: Overall, 986 initiated PrEP across the San Francisco Department of Public Health from July 2012 to November 2018. Data were gathered from 895 person-years on PrEP and 953 after stopping PrEP. The HIV incidence was 7.5-fold higher after stopping PrEP compared to while on PrEP (95% CI 1 to 336). Of the eight individuals who HIV seroconverted; only one was taking PrEP at the time of seroconversion but was using on-demand PrEP inconsistently. All eight agreed to qualitative interviews. Major barriers to PrEP persistence included substance use, mental health and housing loss; difficulty accessing PrEP due to cost, insurance, and the cost and time of medical visits; difficulty weighing PrEP's benefit versus self-perceived risk; and entering a primary partnership. The individual who developed HIV using on-demand PrEP reported confusion about the dosing regimen and which sexual encounters required accompanying PrEP dosing., Conclusions: HIV incidence during gaps in PrEP use was nearly eight-fold higher than while on PrEP in this large cohort in San Francisco. Many individuals who stop PrEP remain at risk of HIV, and participants reported that proactive outreach could potentially have prevented HIV infections. Individuals using non-daily PrEP may require additional education and support in the United States., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Building on several decades of innovative HIV prevention and treatment programming in San Francisco, in 2014, a small group of academic, civic, and community leaders launched Getting to Zero San Francisco, a city-wide consortium focused on getting to zero HIV infections, zero HIV-related deaths, and zero HIV stigma and discrimination., Setting: San Francisco city and county., Methods: The consortium operates under the principles of collective impact composed of 5 components: a common agenda, shared measurement, mutually reinforcing activities, continuous communication, and organization backbone. Two flagship initiatives are described: citywide scale-up of pre-exposure prophylaxis and rapid antiretroviral therapy upon diagnosis., Results: The number of new HIV diagnoses declined by over 50% from 399 to 197 from 2013 to 2018; the time from diagnosis to viral suppression decreased from 134 to 62 days during that period. However, continued racial/ethnic disparities in new HIV diagnoses and viral suppression rates point to the need for the Getting to Zero San Francisco committees to focus on racial/ethnic equity as a primary focus. Cisgender and transgender women, people who inject drugs, and people who are homeless also have lower viral suppression rates; ongoing initiatives are attempting to address these disparities., Conclusion: A collective impact implementation strategy that operates by unifying municipal organizations toward a common goal was associated with citywide gains in reducing new HIV diagnosis and time to viral suppression in San Francisco. Formal evaluation of this strategy will help elucidate under which conditions this approach is most likely to succeed.

HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four FCGR2C single-nucleotide polymorphism [SNP] sites) (hazard ratio [HR] = 9.79, P  = 0.035) but not among participants without the haplotype (HR = 0.86, P  = 0.67); the interaction of vaccine and haplotype effect was significant ( P  = 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 FCGR3B SNPs) (HR = 2.78, P  = 0.058) but not among participants without the haplotype (HR = 0.73, P  = 0.44); again, the interaction of vaccine and haplotype was significant ( P = 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8 + T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an FCGR2A SNP and two FCGR2B SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination. IMPORTANCE By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines., (Copyright © 2019 American Society for Microbiology.)

Introduction: Developing guidelines to inform the use of antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention in resource-limited settings must necessarily be informed by considering the resources and infrastructure needed for PrEP delivery. We describe an approach that identifies subpopulations of cisgender men who have sex with men (MSM) and transgender women (TGW) to prioritize for the rollout of PrEP in resource-limited settings., Methods: We use data from the iPrEx study, a multi-national phase III study of PrEP for HIV prevention in MSM/TGW, to build statistical models that identify subpopulations at high risk of HIV acquisition without PrEP, and with high expected PrEP benefit. We then evaluate empirically the population impact of policies recommending PrEP to these subpopulations, and contrast these with existing policies., Results: A policy recommending PrEP to a high risk subpopulation of MSM/TGW reporting condomless receptive anal intercourse over the last 3 months (estimated 3.3% 1-year HIV incidence) yields an estimated 1.95% absolute reduction in 1-year HIV incidence at the population level, and 3.83% reduction over 2 years. Importantly, such a policy requires rolling PrEP out to just 59.7% of MSM/TGW in the iPrEx population. We find that this policy is identical to that which prioritizes MSM/TGW with high expected PrEP benefit. It is estimated to achieve nearly the same reduction in HIV incidence as the PrEP guideline put forth by the US Centers for Disease Control, which relies on the measurement of more behavioral risk factors and which would recommend PrEP to a larger subset of the MSM/TGW population (86% vs. 60%)., Conclusions: These findings may be used to focus future mathematical modelling studies of PrEP in resource-limited settings on prioritizing PrEP for high-risk subpopulations of MSM/TGW. The statistical approach we took could be employed to develop PrEP policies for other at-risk populations and resource-limited settings., Competing Interests: SB, DVG, KHM, VM, MS, JG, MC have served as investigators on studies for which Gilead Sciences donated study drug. DG has accepted fees from Gilead Sciences and has served on advisory boards for Gilead Sciences. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Bone mineral density (BMD) declines due to tenofovir-containing pre-exposure prophylaxis (PrEP) have varied among PrEP demonstration projects, potentially related to variable adherence. Characterization of BMD changes in highly adherent individuals, estimated via tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS), can assist clinicians when counseling patients. Cisgender men who have sex with men and transwomen in the optional dual-energy X-ray absorptiometry (DXA) substudy of a large, international, open-label PrEP demonstration project, the iPrEx-open-label extension (OLE) study underwent DXA scans and DBS collection every 24 weeks, with average weekly dosing adherence patterns (2, 4, and 7 doses/week) estimated from validated TFV-DP cut-offs. The mean percent BMD change was estimated in strata of average weekly adherence by using a linear mixed-effects model to calculate the BMD decline in highly adherent individuals on PrEP for the first time. DXA/DBS data were available for 254 individuals over a median of 24 weeks in iPrEx-OLE from June 2011 to December 2013. The percent decline in spine BMD was monotonically associated with strata of increasing average weekly adherence ( p  < .001 trend); the p value for trends using hip BMD measurements was .07. Individuals with estimated daily adherence experienced a 1.2% decrease in spine BMD and a 0.5% drop in hip BMD. In highly adherent PrEP users, we found a lower-than-expected drop in BMD when compared with previous studies. This drop is likely not clinically significant for most PrEP users. However, for those at the highest risk of fracture who plan prolonged PrEP use, alternate PrEP strategies could be considered.

Objective: San Francisco, California, has experienced a 44% reduction in new HIV diagnoses since 2013 supported by its 'Getting to Zero' initiative; however, the age-adjusted mortality rate in people with HIV (PWH) has not decreased. We sought to identify factors associated with death among PWH in San Francisco., Design: Population-based incidence-density case-control study., Methods: Among PWH in the San Francisco HIV surveillance registry, a random sample of 48 decedents from 1 July 2016 to 31 May 2017 were each matched to two to three controls who were alive at the date of death (108 controls matched on age and time since diagnosis). Covariates included demographics, substance use, housing status, medical conditions, and care indicators from the study population. We used matched-pair conditional logistic regression to examine factors associated with mortality., Results: Of the 156 PWH in the study, 14% were African-American, 14% Latino, and 8% female sex. In adjusted analysis, factors associated with higher odds of death included: homelessness at HIV diagnosis [adjusted odds ratio (AOR) = 27.4; 95% confidence interval (CI) = 3.0-552.1], prior-year IDU (AOR = 10.2; 95% CI = 1.7-128.5), prior-year tobacco use (AOR = 7.2; 95% CI = 1.7-46.9), being off antiretroviral therapy at any point in the prior year (AOR = 6.8; 95% CI = 1.1-71.4), and being unpartnered vs. married/partnered (AOR = 4.7; 95% CI = 1.3-22.0)., Conclusion: People homeless at HIV diagnosis had 27-fold higher odds of death compared with those with housing; substance use and retention on antiretroviral therapy in the prior year are other important intervenable factors. New strategies to address these barriers, and continued investment in supportive housing and substance use treatment, are needed.

Background: Objective adherence metrics for tenofovir (TFV) disoproxil fumarate/emtricitabine (FTC)-based pre-exposure prophylaxis (PrEP) were critical for interpretation of efficacy in PrEP clinical trials, and there is increasing interest in using drug levels to tailor interventions for reengagement and adherence. Point-of-care immunoassays for TFV, which examine short-term adherence, are in development. However, the ability of poor short-term and long-term adherence to predict future PrEP nonretention is unknown., Setting: Secondary data analysis of a large, prospective multi-site U.S. PrEP demonstration project., Methods: An adjusted Cox-proportional hazards model examined the relationship of dried blood spot (DBS) levels of FTC-triphosphate (FTC-TP) or TFV-diphosphate (TFV-DP), measures of short-term and long-term PrEP adherence, respectively, with future study nonretention., Results: Overall, 294 individuals (median age 33 years) contributed drug levels within the U.S. PrEP demonstration project. By the end of study, 27% were lost to follow-up, 25% had at least one undetectable FTC-TP level indicating poor short-term adherence, and 29% had a drug level indicating suboptimal long-term adherence (TFV-DP <700 fmol/punch). The strongest factor associated with future study nonretention using a binary drug-level cut-off was an undetectable DBS FTC-TP level (adjusted hazard ratio 6.3; 95% confidence interval 3.8 to 10.2). The suboptimal long-term adherence based on low DBS TFV-DP levels was also associated with nonretention (adjusted hazard ratio 4.3; 95% confidence interval: 2.4 to 7.6)., Conclusions: Both short- and long-term metrics of PrEP adherence are strongly associated with future loss to follow-up in a U.S. demonstration project study. Short-term metrics of adherence, once available at the point-of-care, could be used to direct real-time tailored retention and adherence interventions.

At the 2019 Conference on Retroviruses and Opportunistic Infections (CROI), a plan for ending the HIV epidemic in the United States was presented. More rapid HIV diagnosis and treatment is a key component needed nationwide. In international settings, substantial scale up of HIV testing and treatment has led to substantial declines in HIV incidence. U=U (undetectable equals untransmittable) is a powerful concept that can reduce stigma and encourage engagement in testing and care, but raises a number of clinical questions. HIV testing remains a gateway to HIV prevention and treatment, and innovative testing strategies, including HIV self-testing, show promise. Opioid overdose deaths are on the rise, highlighting the need for comprehensive prevention efforts. Molecular data are being used to identify rapidly growing clusters of infections for intervention. Rates of sexually transmitted infections have increased substantially in recent years. A new preexposure prophylaxis (PrEP) combination, tenofovir alafenamide/emtricitabine (FTC), was demonstrated to be non inferior to tenofovir disoproxil fumarate/FTC, with improved bone and renal safety. PrEP uptake is increasing globally, but use is lower in several populations, including African Americans, cis- and transgender women, and youth. Same-day PrEP initiations are a promising approach to increasing access, but PrEP discontinuations remain a challenge.

Current strategies to prevent sexually transmitted infections (STIs) are not controlling the epidemic. The efficacy of doxycycline STI postexposure prophylaxis shows promise in pilot studies, but wider acceptability is unknown. A majority (84%) of diverse individuals using a gay social networking application were interested in doxycycline STI postexposure prophylaxis. Doxycycline STI postexposure prophylaxis should be examined in larger trials.

Objective: We examined the relationship between urine tenofovir (TFV) levels measured with a novel immunoassay, which permits point-of-care testing, with HIV seroconversion and objective adherence metrics in a large preexposure prophylaxis (PrEP) demonstration project., Design: Secondary analysis of stored specimens from an open-label PrEP cohort study., Methods: We examined the association between undetectable urine TFV levels and HIV seroconversion in iPrEx open-label extension using generalized estimating equations. We examined rank correlations between levels of TFV and emtricitabine in urine, dried blood spots (DBS), and hair and determined the sensitivity and specificity of undetectable urine TFV for predicting dosing cut-offs in DBS., Results: The median urinary TFV level was 15 000 ng/ml in those who remained HIV-negative (n = 105; interquartile range: 1000-45 000); 5500 in those who eventually seroconverted (n = 11; interquartile range: 1000-12 500); and all were undetectable at seroconversion (n = 9; P < 0.001). Decreasing strata of urine TFV levels were associated with future HIV seroconversion (P = 0.03). An undetectable urine TFV was 100% sensitive and 81% specific when compared with an undetectable DBS TFV-diphosphate level and 69% sensitive, but 94% specific when compared with low adherence by DBS (<2 doses/week)., Conclusion: Urine TFV detection by a novel antibody-based assay was associated with protection from HIV acquisition among individuals on PrEP. Urine TFV levels were correlated with hair and DBS levels and undetectable urine TFV was 100% sensitive in detecting nonadherence. By implementing the immunoassay into a point-of-care strip test, PrEP nonadherence could be detected in real-time, allowing rapid intervention.

Background: Maintaining retention in preexposure prophylaxis (PrEP) care among diverse patient populations will be needed to support PrEP's efficacy. We characterized patterns of PrEP care retention in a US municipal primary care health network and examined whether missed visits, a metric of care retention that is easy to evaluate in clinic, are associated with subsequent discontinuation., Methods: We included individuals on PrEP from July 2012 until August 2017 in the San Francisco Primary Care Clinics, a 15-clinic municipal health network. We categorized PrEP usage patterns as follows: early discontinuation (<90 days), later discontinuation (after ≥90 days), and continuing use at the end of follow-up. We first examined early discontinuation using adjusted Poisson regression. In patients who continued PrEP for ≥90 days, we examined factors associated with late discontinuation., Results: Of the 364 individuals who started PrEP, 16% discontinued PrEP before 90 days, 46% discontinued later, and 38% were retained in care over a median 12 months of observation. Transgender women were more likely to discontinue PrEP early (adjusted risk ratio; 2.16; 95% confidence interval, 1.36-3.49), and younger users were more likely to discontinue late (0.82 per 10-year increase in age; .70-.96), as were persons who use illicit drugs (1.59; 1.02-2.47). Missed visits during use of PrEP were associated with future discontinuation (adjusted risk ratio, 1.52; 95% confidence interval, 1.14-2.03). Later year of current PrEP use was associated with both early and late discontinuation., Conclusion: Diverse populations may require differentiated care to continue PrEP. Missed visits should trigger tailored interventions to maximize the impact of PrEP.

Background: Timely pre-exposure prophylaxis (PrEP) initiation is critical in at-risk populations, given that HIV acquisition risk persists during delays. Time to treatment initiation, a key metric in HIV care, has not been explored among PrEP users. Interventions that reduce time to PrEP initiation could prevent HIV infections., Setting: Individuals initiating PrEP in a large primary care health network of 15 clinics, the San Francisco Primary Care Clinics (SFPCC), from July 2012 to July 2017 (N = 411)., Methods: We examined factors associated with time from first PrEP discussion with a provider to PrEP initiation date using an adjusted Cox proportional-hazards model, with hazard ratios (HRs) >1 indicating earlier initiation. We also examined the relationship between delayed PrEP initiation and PrEP persistence (staying on PrEP) in an adjusted Cox proportional-hazards model., Results: PrEP users initiated PrEP after a median of only 7 days. However, there were notable outliers, with 29% waiting >30 days and 12% waiting >90 days. In an adjusted proportional-hazards model, a panel management and patient navigation intervention was associated with earlier PrEP initiation [HR: 1.5; 95% confidence interval (CI): 1.1 to 2.0], whereas only other race/ethnicity compared with white race was associated with delayed PrEP initiation (HR: 0.7; 95% CI: 0.5 to 1.0). Delayed PrEP initiation >30 days was associated with shorter PrEP persistence in an adjusted proportional-hazards model (HR: 1.3; 95% CI: 1.0 to 1.7)., Conclusions: PrEP initiation within a week is feasible in a primary care safety-net health system. Setting a goal of rapid PrEP initiation, with the support of panel management and patient navigation, could address delays in at-risk groups.

Importance: Antiretroviral therapy (ART) is the cornerstone of prevention and management of HIV infection., Objective: To evaluate new data and treatments and incorporate this information into updated recommendations for initiating therapy, monitoring individuals starting therapy, changing regimens, and preventing HIV infection for individuals at risk., Evidence Review: New evidence collected since the International Antiviral Society-USA 2016 recommendations via monthly PubMed and EMBASE literature searches up to April 2018; data presented at peer-reviewed scientific conferences. A volunteer panel of experts in HIV research and patient care considered these data and updated previous recommendations., Findings: ART is recommended for virtually all HIV-infected individuals, as soon as possible after HIV diagnosis. Immediate initiation (eg, rapid start), if clinically appropriate, requires adequate staffing, specialized services, and careful selection of medical therapy. An integrase strand transfer inhibitor (InSTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is generally recommended for initial therapy, with unique patient circumstances (eg, concomitant diseases and conditions, potential for pregnancy, cost) guiding the treatment choice. CD4 cell count, HIV RNA level, genotype, and other laboratory tests for general health and co-infections are recommended at specified points before and during ART. If a regimen switch is indicated, treatment history, tolerability, adherence, and drug resistance history should first be assessed; 2 or 3 active drugs are recommended for a new regimen. HIV testing is recommended at least once for anyone who has ever been sexually active and more often for individuals at ongoing risk for infection. Preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and appropriate monitoring is recommended for individuals at risk for HIV., Conclusions and Relevance: Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.

Background: Antiretroviral drugs have been associated with changes in lipids, fat mass and dat distribution. Tenofovir disoproxil fumarate (TDF) has been shown to have a more favorable metabolic profile than other drugs in its class. However, the metabolic effects of TDF in preexposure prophylaxis (PrEP) are unknown., Methods: We evaluated the effects of TDF/emtricitabine (FTC) on lipids and body composition in a blinded, placebo-controlled PrEP trial. Participants enrolled in a metabolic subcohort (N = 251, TDF/FTC; N = 247, placebo) consented to fasting lipid panels, dual-energy X-ray absorptiometry scans for body composition, and pharmacologic testing of drug metabolites at baseline and every 24 weeks thereafter., Results: Lean body mass was stable and unaffected by TDF/FTC. Body weight increased in both groups but was lower on TDF/FTC through week 72. This difference was explained by lower fat accumulation on TDF/FTC. The net median percent difference (standard error, P value) for TDF/FTC vs placebo at week 24 was -0.8% (0.4%, P = .02), +0.3% (0.4%, P = .46), and -3.8% (1.4%, P = .009) for total, lean, and fat mass, respectively. There was no apparent differential regional fat accumulation on TDF/FTC. Decreases in cholesterol, but not triglycerides, were seen in TDF/FTC participants, with detectable drug levels compared to placebo., Conclusions: TDF/FTC for PrEP showed cholesterol reductions and appeared to transiently suppress the accumulation of weight and body fat compared to placebo. There was no evidence of altered fat distribution or lipodystrophy during daily oral TDF/FTC PrEP., Clinical Trials Registration: NCT00458393.

Insufficient pre-exposure prophylaxis (PrEP) laboratory monitoring could increase HIV resistance and sexually transmitted infections. We examined test-ordering in a primary care network. Providers did not order HIV testing before almost one-quarter of PrEP initiations; panel management was associated with higher testing. Effective monitoring is needed to maximize PrEP's preventive impact.

At the 2018 Conference on Retroviruses and Opportunistic Infections, trends in and risk factors for in HIV infection were highlighted. In the United States, new HIV diagnoses are highest in the South and among African Americans and are increasing in rural areas. Youth remain highly vulnerable to HIV infection globally. The epidemiology of HIV infections among people who inject drugs is changing, with overdose deaths, a major public health concern. Phylogenetics are being used to identify HIV transmission clusters and hotspots, which can inform prevention efforts. Vaginal microbial dysbiosis and proteomic alterations are associated with increased risk of HIV acquisition, as are the pregnancy and postpartum periods. HIV testing is a central first step for the HIV care and treatment continua, and several innovative strategies to expand HIV testing coverage and frequency show promise. Preexposure prophylaxis (PrEP) uptake is rapidly increasing in some cities, with reductions of new infections at the population level, but use is lower among African Americans and Latinos, youth, cis- and transgender women, and people who inject drugs. PrEP continuation remains a challenge. Two open-label extension studies of the dapivirine vaginal ring demonstrated high uptake, adherence, and reduced HIV infections. Several novel systemic and topical prevention agents show promise in non-human primates.

Preexposure prophylaxis (PrEP) with tenofovir/emtricitabine (slash indicates coformulation) is highly effective in preventing new HIV infections. PrEP efficacy is strongly associated with adherence. In clinical trials, PrEP has been more effective in men who have sex with men and HIV-serodiscordant heterosexual couples than in women, likely reflecting pharmacokinetic differences between levels of tenofovir disoproxil fumarate in vaginal and rectal tissues, and poorer adherence in studies in women. Current guidelines recommend daily PrEP for men and women; however, PrEP taken at least 4 days per week for men may be as effective as daily PrEP, and women must take PrEP 6 to 7 days per week to maximize efficacy. Data are accumulating on the effectiveness of pericoital PrEP for men who have sex with men, but it is not yet recommended in the United States. PrEP is underprescribed for younger individuals, black individuals, and Hispanic and Latino individuals. This article summarizes a presentation by Susan P. Buchbinder, MD, at the IAS-USA continuing education program, Improving the Management of HIV Disease, held in Chicago, Illinois, in May 2017.

Preexposure prophylaxis is a highly protective HIV prevention strategy, yet nonadherence can significantly reduce its effectiveness. We conducted a mixed methods evaluation of a mobile health intervention (iText) that utilized weekly bidirectional text or e-mail support messages to encourage preexposure prophylaxis (PrEP) adherence among participants in the multi-site iPrEx open-label extension study. A convenience sample of PrEP users from the San Francisco and Chicago sites participated in a 12-week pilot study. Fifty-six men who have sex with men were enrolled; a quarter of them were less than 30 years of age, 13% were black/African American, 11% were Latino, and most (88%) completed some college. Two-thirds opted for text message delivery. Of the 667 messages sent, only 1 individual requested support; initial nonresponse was observed in 22% and was higher among e-mail compared to text message recipients. Poststudy, a majority of participants would recommend the intervention to others, especially during PrEP initiation. Moreover, younger participants and men of color were more likely to report that they would use the iText strategy if it were available to them. Several participants commented that while they were aware that the messages were automated, they felt supported and encouraged that "someone was always there." Study staff reported that the intervention is feasible to administer and can be incorporated readily into clinic flow. A pre-post intervention regression discontinuity analysis using clinic-based pill counts showed a 50% reduction in missed doses [95% confidence interval (CI) 16-71; p = 0.008] and 77% (95% CI 33-92; p = 0.007) when comparing pill counts at quarterly visits just before and after iText enrollment. A mobile health intervention using weekly bidirectional messaging was highly acceptable and demonstrated promising effects on PrEP adherence warranting further evaluation for efficacy in a randomized controlled trial.

Background: HIV preexposure prophylaxis (PrEP) using daily oral tenofovir-disoproxil-fumarate/emtricitabine (TDF/FTC) is effective for preventing HIV acquisition, but concerns remain about its potential kidney toxicity. This study examined kidney function in individuals using PrEP in real-world clinical settings., Setting: Demonstration project in 2 sexually transmitted infection clinics and a community health center., Methods: We evaluated kidney function among men who have sex with men and transgender women taking tenofovir-disoproxil-fumarate/emtricitabine PrEP for up to 48 weeks. Serum creatinine and urine dipstick for protein were obtained at 12-week intervals. Kidney function was estimated using creatinine clearance (CrCl) (Cockcroft-Gault) and estimated glomerular filtration rate (eGFR) (CKD-EPI)., Results: From October 2012 to January 2014, we enrolled 557 participants (median age 33). Mean creatinine increased from baseline to week 12 by 0.03 mg/dL (4.6%) (P < 0.0001); mean CrCl decreased by 4.8 mL/min (3.0%) (P < 0.0001). These changes remained stable through week 48 (P = 0.81, P = 0.71 respectively). There were 75/478 (15.7%) participants who developed worsening proteinuria at week 12 compared with baseline (P < 0.0001), and this percent remained stable through week 48 (P = 0.73). Twenty-five participants (5.1%) developed new-onset eGFR <70 mL/min/1.73 m; independent predictors of this outcome were age ≥40 years (OR 3.79, 95% CI: 1.43 to 10.03) and baseline eGFR <90 mL/min/1.73 m (OR 9.59, 3.69-24.94)., Conclusions: In a demonstration setting, daily tenofovir-disoproxil-fumarate/emtricitabine PrEP leads to reduced CrCl and eGFR; however, these eGFR changes are based on very small changes in serum creatinine and seem to be nonprogressive after the first 12 weeks. Future studies are needed to understand the prognostic significance of these small changes.

Background: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART., Methods and Findings: Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection., Conclusions: We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

Background: Oral tenofovir disoproxil fumarate (TDF) for HIV prevention and treatment is associated with decreases in bone mineral density (BMD). Previous reports suggest that these changes may be reversible after discontinuation of TDF., Setting: A metabolic substudy of 498 participants in a randomized, placebo-controlled HIV prevention trial of oral coformulated TDF with emtricitabine (TDF/FTC, Truvada) for HIV pre-exposure prophylaxis (PrEP) enrolling a global sample of men who have sex with men and trans women., Methods: Participants underwent dual X-ray absorptiometry to quantify bone mineral density (BMD) in the hip and spine during PrEP and at 2 visits after stopping (median of 23 and 79 weeks post-PrEP, respectively). Results are stratified by pharmacologic measure of TDF/FTC adherence., Results: There was no significant difference in change in hip/spine BMD at any time point between placebo and those with low adherence. Adherent participants had a mean (standard error) BMD change at TDF/FTC discontinuation of -1.02% (0.24) in the hip and -1.84% (0.36) in the spine. After stop, annualized BMD increases of 1.13% per year (0.27) in hip and 1.81% per year (0.36) in spine BMD were observed in adherent participants compared with 0.19% (0.16) and 0.74% (0.21) in the placebo group, respectively (P = 0.003, both comparisons). On average, BMD returned to baseline levels by 1 year after PrEP stop. Recovery was consistent across age, baseline BMD z-score, and treatment duration., Conclusions: Mean BMD returns to baseline levels within 12-18 months after TDF-based PrEP discontinuation in both hip and spine with consistency across participant subgroups., Clinical Trials Registration: clinicaltrials.gov NCT00458393.

Background: A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env., Methods: Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM&#95;M or DgDgMM&#95;M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively. Peak immunogenicity was measured 2 weeks post-last vaccination., Results: All regimens were well tolerated and safe. Full dose DgDgM&#95;M and DgDgMM&#95;M regimens generated Env-specific IgG to HIV-1 Env in >90%, IgG3 in >80%, and IgA in <20% of participants. Responses to gp140 and gp41 targets were more common and of higher magnitude than to gp120 and V1V2. The gp41 antibody included reactivity to the conserved immunodominant region with specificities known to mediate virus capture and phagocytosis and did not cross-react with a panel of intestinal flora antigens. The 3rd dose of MVA increased the avidity of elicited antibody (7.5% to 39%), the ADCC response to Bal gp120 (14% to 64%), and the one-year durability of the IgG3 responses to gp41 by 4-fold (13% vs. 3.5% retention of peak response). The co-expressed GM-CSF did not enhance responses over those in trials testing this vaccine without GM-CSF., Conclusion: This DNA/MVA prime-boost regimen induced durable, functional humoral responses that included ADCC, high antibody avidity, and Env IgG1 and IgG3 binding responses to the immunodominant region of gp41. The third, spaced MVA boost improved the overall quality of the antibody response. These products without co-expressed GM-CSF but combined with protein boosts will be considered for efficacy evaluation., Trial Registration: ClinicalTrials.gov NCT01571960.

At the 2017 Conference on Retroviruses and Opportunistic Infections (CROI), trends in the HIV epidemic were highlighted, with decreasing HIV incidence reported across several countries, although key groups remain underdiagnosed and undertreated. In the United States, men who have sex with men (MSM) continue to comprise the largest number of new and undiagnosed HIV infections, with rising incidence in MSM 25 to 34 years old and Latino MSM. Phylogenetics are being used to identify rapidly growing HIV transmission clusters, which can inform prevention efforts. HIV testing is a crucial first step for accessing HIV prevention and treatment, and several innovative strategies to increase HIV testing show promise. Sexually transmitted infections (STIs) have been on the rise but predate widespread use of HIV preexposure prophylaxis (PrEP); enhanced STI screening and treatment coupled with PrEP could substantially reduce STI incidence in the United States. Several studies indicate increasing PrEP awareness and use, although disparities exist in vulnerable populations. PrEP persistence remains a challenge, and practitioner adherence to prescribing guidelines is suboptimal. Novel PrEP delivery models are being developed to increase PrEP knowledge, access, and support.

Background: It is important to identify vaccine-induced immune responses that predict the preventative efficacy of a human immunodeficiency virus (HIV)-1 vaccine. We assessed T-cell response markers as correlates of risk in the HIV Vaccine Trials Network (HVTN) 505 HIV-1 vaccine efficacy trial., Methods: 2504 participants were randomized to DNA/rAd5 vaccine or placebo, administered at weeks 0, 4, 8, and 24. Peripheral blood mononuclear cells were obtained at week 26 from all 25 primary endpoint vaccine cases and 125 matched vaccine controls, and stimulated with vaccine-insert-matched peptides. Primary variables were total HIV-1-specific CD4+ T-cell magnitude and Env-specific CD4+ polyfunctionality. Four secondary variables were also assessed. Immune responses were evaluated as predictors of HIV-1 infection among vaccinees using Cox proportional hazards models. Machine learning analyses identified immune response combinations best predicting HIV-1 infection., Results: We observed an unexpectedly strong inverse correlation between Env-specific CD8+ immune response magnitude and HIV-1 infection risk (hazard ratio [HR] = 0.18 per SD increment; P = .04) and between Env-specific CD8+ polyfunctionality and infection risk (HR = 0.34 per SD increment; P < .01)., Conclusions: Further research is needed to determine if these immune responses are predictors of vaccine efficacy or markers of natural resistance to HIV-1 infection., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)