Implementation of an intravenous sotalol initiation protocol: Implications for feasibility, safety, and length of stay.

INTRODUCTION: Oral sotalol initiation requires a multiple-day, inpatient admission to monitor for QT prolongation during loading. A 1-day intravenous (IV) sotalol loading protocol was approved by the United States Food and Drug Administration in March 2020, but limited data on clinical use and administration currently exists. This study describes implementation of an IV sotalol protocol within an integrated health system, provides initial efficacy and safety outcomes, and examines length of stay (LOS) compared with oral sotalol initiation. METHODS: IV sotalol was administered according to a prespecified initiation protocol to adult patients with refractory atrial or ventricular arrhythmias. Baseline characteristics, safety and feasibility outcomes, and LOS were compared with patients receiving oral sotalol over a similar time period. RESULTS: From January 2021 to June 2022, a total of 29 patients (average age 66.0 ± 8.6 years, 27.6% women) underwent IV sotalol load and 20 patients (average age 60.4 ± 13.9 years, 65.0% women) underwent oral sotalol load. The load was successfully completed in 22/29 (75.9%) patients receiving IV sotalol and 20/20 (100%) of patients receiving oral sotalol, although 7/20 of the oral sotalol patients (35.0%) required dose reduction. Adverse events interrupting IV sotalol infusion included bradycardia (seven patients, 24.1%) and QT prolongation (three patients, 10.3%). No patients receiving IV or oral sotalol developed sustained ventricular arrhythmias before discharge. LOS for patients completing IV load was 2.6 days shorter (mean 1.0 vs. 3.6, p < .001) compared with LOS with oral load. CONCLUSION: IV sotalol loading has a safety profile that is similar to oral sotalol. It significantly shortens hospital LOS, potentially leading to large cost savings.

Randomized Controlled Trial of Automated Directly Observed Therapy for Measurement and Support of PrEP Adherence Among Young Men Who have Sex with Men.

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.

RESUMEN: La medición de la adherencia a la profilaxis oral previa a la exposición (PrEP) en tiempo real ha constituido un desafío. Hemos desarrollado DOT Diary, una aplicación para teléfonos inteligentes que combina la terapia automatizada observada de forma directa con un kit de herramientas para visualizar la adherencia a la PrEP, y testeamos su capacidad para medir la adherencia a la PrEP, así como para aumentar la adherencia entre una cohorte variada de hombres jóvenes que tienen sexo con hombres (HSH). Reclutamos a 100 HSH en San Francisco y Atlanta y los asignamos aleatoriamente 2:1 a DOT Diary con respecto a la asistencia estándar. La concordancia entre la medición del DOT Diary y los niveles de fármacos en gotas de sangre seca fue sustancial, con un 91,0% y un 85,3% de concordancia entre el uso del DOT Diary y el de emtricitabina-trifosfato y tenofovir-difosfato, respectivamente. No hubo diferencias significativas en la proporción de participantes con niveles detectables del fármaco de la PrEP a las 24 semanas entre los brazos del estudio. Estos resultados sugieren que DOT Diary es sustancialmente superior a las medidas de adherencia que se notifican de forma personal, aunque hacen falta intervenciones adicionales para mejorar la adherencia a la PrEP a largo plazo.

Sexual behavior and medication adherence in men who have sex with men participating in a pre-exposure prophylaxis study of combinations of Maraviroc, Tenofovir Disoproxil Fumarate and/or Emtricitabine (HPTN 069/ACTG 5305).

HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current analyses assessed antiretroviral (ARV) plasma concentrations in relation to sexual behavior in 224 cisgender men who have sex with men and 2 transgender women at risk for HIV. Poisson generalized estimating equations (GEE) regression were used to test for associations between self-reported sexual behavior, sociodemographic, behavioral variables, and study drug levels The median (IQR) age was 30 [25, 37] years old; 48.2% had completed college; 27.4% were Black and 21.7% Latino. At weeks 24 and 48, one third of participants reported condomless anal sex (CAS) in the prior month with more than one partner. CAS was associated with daily ARV drug use (χ2 = 12.64, p = 0.002). Older individuals and those with greater education were more likely to ingest ARV drugs daily (χ2 = 9.36, p = 0.009 and χ2 = 8.63, p = 0.013, respectively), while neither race nor ethnicity was associated with daily ARV drug use. Participants who reported recent condomless anal sex and/or advanced education had higher rates of daily ARV drug use. These data support the need for ongoing adherence counseling in clinical trials of new PrEP modalities.

DOT Diary: Developing a Novel Mobile App Using Artificial Intelligence and an Electronic Sexual Diary to Measure and Support PrEP Adherence Among Young Men Who Have Sex with Men.

Young men who have sex with men (YMSM) are highly vulnerable to HIV. While pre-exposure prophylaxis (PrEP) has demonstrated effectiveness, adherence has been low among YMSM and difficult to measure accurately. In collaboration with a healthcare company, we configured an automated directly-observed therapy (aDOT) platform for monitoring and supporting PrEP use. Based on interest expressed in focus groups among 54 YMSM, we combined aDOT with an electronic sexual diary to provide feedback on level of protection during sex and to motivate app use. In an 8-week optimization pilot with 20 YMSM in San Francisco and Atlanta, the app was found to be highly acceptable, with median System Usability Scale scores in the "excellent" range (80/100). App use was high, with median PrEP adherence of 91% based on aDOT-confirmed dosing. Most (84%) participants reported the app helped with taking PrEP. These promising findings support further evaluation of DOT Diary in future effectiveness studies.

Cabotegravir Is Not Associated With Weight Gain in Human Immunodeficiency Virus-uninfected Individuals in HPTN 077.

Studies in human immunodeficiency virus (HIV)-infected individuals suggest excess weight gain with integrase inhibitor-based antiretroviral therapy. The HIV Prevention Trials Network Study 077 evaluated changes in weight and fasting metabolic parameters in HIV-uninfected individuals randomized to cabotegravir or a placebo. No differences between arms were found for change in weight or fasting metabolic parameters overall or for subgroups.

Developing and Assessing the Feasibility of a Home-based Preexposure Prophylaxis Monitoring and Support Program.

We piloted PrEP@Home, a preexposure prophylaxis system of remote laboratory and behavioral monitoring designed to replace routine quarterly follow-up visits with home care to reduce the patient and provider burden. The system was highly acceptable and in-demand for future use, and more than one-third of participants reported greater likelihood of persisting in care if available.

Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different Dose Strengths of Vicriviroc (MK-4176) and MK-2048.

BACKGROUND: Vaginal rings (VRs) are a promising approach for sustained delivery of antiretroviral (ARV) medication to prevent human immunodeficiency virus (HIV) infection in women. Combination ARV VRs could increase efficacy. METHODS: MTN-028, a phase 1 trial in 19 HIV-uninfected women, evaluated 2 VRs containing vicriviroc (VCV) and MK-2048. Participants were randomized 2:1 to a low-dose (VCV, 91 mg; MK-2048, 10 mg) or original-dose (VCV, 182 mg; MK-2048, 30 mg) ring used for 28 days. Safety was assessed by documenting adverse events (AEs). Drug concentrations were evaluated in plasma, cervicovaginal fluid (CVF), and cervical tissue samples. RESULTS: All AEs reported were grade 1 or 2, with no statistically significant differences in related genitourinary AEs or grade ≥2 AEs observed between arms (P = >.99). VCV/MK-2048 concentrations rose rapidly, with higher plasma area under the concentration-time curve (AUC) in the original-dose arm (geometric mean ratio, 3.29 for VCV and 1.49 for MK-2048) and similar AUCs across arms for CVF samples. Cervical tissue concentrations were higher in the original-dose arm (geometric mean ratio, 7.94 for VCV and 6.45 for MK-2048), with greater drug released based on residual drug levels. Plasma and CVF concentrations for both drugs fell rapidly after ring removal. CONCLUSIONS: In this first study evaluating 2 doses of a combination VCV/MK-2048 VR, both rings were found to be safe and well tolerated. VCV and MK-2048 were detectable in plasma, CVF, and cervical tissue samples, and drug release and plasma drug exposure were higher for the original-dose than for the low-dose ring.

Randomized Controlled Trial of a Mobile Health Intervention to Promote Retention and Adherence to Preexposure Prophylaxis Among Young People at Risk for Human Immunodeficiency Virus: The EPIC Study.

BACKGROUND: Young men who have sex with men are among the most vulnerable to human immunodeficiency virus (HIV) infection. Although preexposure prophylaxis (PrEP) has demonstrated effectiveness, adherence and retention have been low among youth. METHODS: We conducted a randomized controlled trial to evaluate the impact of a youth-tailored, bidirectional text-messaging intervention (PrEPmate) on study retention and PrEP adherence. Young individuals at risk for HIV initiating PrEP within Chicago's safety-net system were randomized 2:1 to receive PrEPmate or standard of care (SoC) for 36 weeks. The primary retention outcome was study-visit completion, and the primary adherence outcome was tenofovir diphosphate (TFV-DP) concentrations ≥700 fmol/punch (consistent with ≥4 doses/week) assessed at 4, 12, 24, and 36 weeks. The impact of PrEPmate on retention and adherence was evaluated using generalized estimating equation logistic models with robust standard errors. RESULTS: From April 2015 to March 2016, 121 participants enrolled (mean age 24; 27% black, 36% Latino). Participants who received PrEPmate were more likely to attend study visits (86% PrEPmate vs. 71% SoC, odds ratio [OR] = 2.62, 95% confidence interval [CI] 1.24-5.54) and have TFV-DP levels consistent with ≥4 doses/week (72% PrEPmate vs. 57% SoC, OR = 2.05, 95% CI 1.06-3.94). PrEPmate efficacy did not differ significantly by age, race/ethnicity, education, or insurance. Overall, 88% reported PrEPmate to be very/somewhat helpful, and 92% would recommend PrEPmate to others. CONCLUSIONS: An interactive text-messaging intervention had high acceptability and significantly increased study-visit retention and PrEP adherence among young individuals at risk for HIV acquisition. CLINICAL TRIALS REGISTRATION: NCT02371525.

Addressing Gaps in HIV Preexposure Prophylaxis Care to Reduce Racial Disparities in HIV Incidence in the United States.

The potential for human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) to reduce the racial disparities in HIV incidence in the United States might be limited by racial gaps in PrEP care. We used a network-based mathematical model of HIV transmission for younger black and white men who have sex with men (BMSM and WMSM) in the Atlanta, Georgia, area to evaluate how race-stratified transitions through the PrEP care continuum from initiation to adherence and retention could affect HIV incidence overall and disparities in incidence between races, using current empirical estimates of BMSM continuum parameters. Relative to a no-PrEP scenario, implementing PrEP according to observed BMSM parameters was projected to yield a 23% decline in HIV incidence (hazard ratio = 0.77) among BMSM at year 10. The racial disparity in incidence in this observed scenario was 4.95 per 100 person-years at risk (PYAR), a 19% decline from the 6.08 per 100 PYAR disparity in the no-PrEP scenario. If BMSM parameters were increased to WMSM values, incidence would decline by 47% (hazard ratio = 0.53), with an associated disparity of 3.30 per 100 PYAR (a 46% decline in the disparity). PrEP could simultaneously lower HIV incidence overall and reduce racial disparities despite current gaps in PrEP care. Interventions addressing these gaps will be needed to substantially decrease disparities.

High Interest in Doxycycline for Sexually Transmitted Infection Postexposure Prophylaxis in a Multicity Survey of Men Who Have Sex With Men Using a Social Networking Application.

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.

Comparison of Measures of Adherence to Human Immunodeficiency Virus Preexposure Prophylaxis Among Adolescent and Young Men Who Have Sex With Men in the United States.

Background: Young men-who-have-sex-with-men (MSM) are disproportionately impacted by human immunodeficiency virus (HIV). Preexposure prophylaxis (PrEP) could reduce HIV acquisition among youth, but suboptimal adherence threatens effectiveness. Optimal metrics of PrEP adherence among adolescents have remain undefined. Methods: The Adolescent Trials Network 110/113 studies provided daily oral PrEP with tenofovir (TFV) disoproxil fumarate/emtricitabine over 48 weeks to a diverse population of MSM (aged 15-22 years). Self-reported adherence was assessed and PrEP drug concentrations measured from hair and dried blood spot (DBS) samples; 23% of participants received Wisepill electronic monitoring devices. The average number of PrEP doses per week taken was estimated, and concordance between measures assessed. Results: Among 243 participants, hair samples were collected at 1186/1238 (96%) person-visits. The concordance of TFV levels in hair and TFV-diphosphate in DBS around thresholds consistent with taking ≥4 and 7 PrEP doses/week was high (76% and 80%). Hair and DBS concentrations correlated poorly with self-report and Wisepill metrics. Through week 12, 40%-60% of participants (by hair and DBS), ≤31% (Wisepill), and >85% (self-report) were estimated to have taken ≥4 PrEP doses/week (a threshold associated with protection among MSM). For all measures except self-report, adherence declined over time, with half of participants taking <2 doses/week by week 48. Conclusions: Among youth on PrEP, adherence waned over time. Self-report overestimated adherence, and use of Wisepill was limited. Hair collection was highly acceptable and provided similar interpretations to DBS. Incorporation of either metric in future PrEP studies among youth could identify suboptimal adherence and trigger interventions.

Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial.

BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. TRIAL REGISTRATION: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy.

Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals [CIs], 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.).

Incidence of Gonorrhea and Chlamydia Following Human Immunodeficiency Virus Preexposure Prophylaxis Among Men Who Have Sex With Men: A Modeling Study.

Background: Preexposure prophylaxis (PrEP) is highly effective for preventing human immunodeficiency virus (HIV) infection, but risk compensation (RC) in men who have sex with men (MSM) raises concerns about increased sexually transmitted infections (STIs). The Center for Disease Control and Prevention's (CDC's) PrEP guidelines recommend biannual STI screening, which may reduce incidence by treating STIs that would otherwise remain undiagnosed. We investigated these two counteracting phenomena. Methods: With a network-based mathematical model of HIV, Neisseria gonorrhoeae (NG), and Chlamydia trachomatis (CT) transmission dynamics among MSM in the United States, we simulated PrEP uptake following the prescription indications and HIV/STI screening recommendations in the CDC guidelines. Scenarios varied PrEP coverage (the proportion of MSM indicated for PrEP who received it), RC (a reduction in the per-act probability of condom use), and the STI screening interval. Results: In our reference scenario (40% coverage, 40% RC), 42% of NG and 40% of CT infections would be averted over the next decade. A doubling of RC would still result in net STI prevention relative to no PrEP. STIs declined because PrEP-related STI screening resulted in a 17% and 16% absolute increase in the treatment of asymptomatic and rectal STIs, respectively. Screening and timely treatment at quarterly vs biannual intervals would reduce STI incidence an additional 50%. Conclusions: Implementation of the CDC PrEP guidelines while scaling up PrEP coverage could result in a significant decline in STI incidence among MSM. Our study highlights the design of PrEP not only as antiretroviral medication but as combination HIV/STI prevention incorporating STI screening.

MTN-017: A Rectal Phase 2 Extended Safety and Acceptability Study of Tenofovir Reduced-Glycerin 1% Gel.

Background: Human immunodeficiency virus (HIV) disproportionately affects men who have sex with men (MSM) and transgender women (TGW). Safe and acceptable topical HIV prevention methods that target the rectum are needed. Methods: MTN-017 was a phase 2, 3-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced-glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/TDF). In each 8-week study period participants were randomized to RG-TFV rectal gel daily, or RG-TFV rectal gel before and after receptive anal intercourse (RAI; or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. Results: MSM and TGW (n = 195) were enrolled from 8 sites in the United States, Thailand, Peru, and South Africa with mean age of 31.1 years (range 18-64). There were no differences in ≥grade 2 adverse event rates between daily gel (incidence rate ratio [IRR], 1.09; P = .59) or RAI gel (IRR, 0.90; P = .51) compared to FTC/TDF. High adherence (≥80% of prescribed doses assessed by unused product return and Short Message System reports) was less likely in the daily gel regimen (odds ratio [OR], 0.35; P < .001), and participants reported less likelihood of future daily gel use for HIV protection compared to FTC/TDF (OR, 0.38; P < .001). Conclusions: Rectal application of RG TFV gel was safe in MSM and TGW. Adherence and product use likelihood were similar for the intermittent gel and daily oral FTC/TDF regimens, but lower for the daily gel regimen. Clinical Trials Registration: NCT01687218.

HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study.

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.

Awareness and Willingness to Use Pre-exposure Prophylaxis (PrEP) Among Men Who Have Sex with Men and Transgender Women in Brazil.

Antiretroviral pre-exposure prophylaxis (PrEP) is recommended to prevent HIV infection among high-risk men who have sex with men (MSM) though not available in Brazil where the HIV epidemic persists unabated in this group. This cross-sectional study describes PrEP awareness and willingness and associated factors among MSM and transvestite/transgender women (trans women) pre-screened for the PrEP Brasil study. Awareness was reported by 61.3 % of the participants and was associated with age, education, site, study period and prior HIV testing. Most participants (82.1 %) were willing to use PrEP, which was associated with site, study period, number of male condomless anal sexual partners and anal sex with HIV positive/unknown partners. PrEP information is need among young and less educated individuals. Willingness to use PrEP was high and future studies should be conducted to confirm PrEP acceptability and the characteristics of the population who chose to adopt this intervention.

Symptoms, Side Effects and Adherence in the iPrEx Open-Label Extension.

BACKGROUND: Blinded clinical trials have reported a modest and transient "start-up syndrome" with initiation of tenofovir-based pre-exposure prophylaxis (PrEP). We evaluate this phenomenon and its effect on adherence in an open-label PrEP study. METHODS: In the iPrEx open-label extension (OLE) study, an 18-month open-label, multi-site PrEP cohort taking daily oral co-formulated tenofovir/emtricitabine, we examined the prevalence and duration of PrEP-associated symptoms and their effect on adherence, assessed by drug levels in dried blood spots tested monthly for the first 3 months. RESULTS: Symptom reports peaked within the first month, with 39% reporting potentially PrEP-related symptoms compared to 22% at baseline. Symptoms largely resolved to pre-PrEP levels by 3 months.Symptoms varied substantially in frequency by study site (range in 1-month symptoms: 11% to 70%). Nongastrointestinal (GI) symptoms were not associated with adherence (odds ratio [OR] = 1.2, 95% confidence interval [CI], .4-3.7); however, GI-associated symptoms in the first 4 weeks were inversely associated with adherence at 4 weeks (OR = 0.47, 95% CI, .23-.96). Reports of GI symptoms were associated with 7% (95% CI, 4%-11%) of suboptimal adherence in this cohort. CONCLUSIONS: PrEP-associated symptoms in the open-label setting occur in a minority of users and largely resolve within 3 months. GI symptoms are associated with a modest reduction in PrEP adherence, but good adherence is possible even in the presence of frequent symptom reports. CLINICAL TRIALS REGISTRATION: Clinicaltrials.govNCT00458393.

Successful Implementation of HIV Preexposure Prophylaxis: Lessons Learned From Three Clinical Settings.

The past 3 years have marked a transition from research establishing the safety and efficacy of HIV preexposure prophylaxis (PrEP) to questions about how to optimize its implementation. Until recently, PrEP was primarily offered as part of randomized controlled trials or open-label studies. These studies highlighted the key components of PrEP delivery, including regular testing for HIV and other sexually transmitted infections (STIs), adherence and risk-reduction support, and monitoring for renal toxicity. PrEP is now increasingly provided in routine clinical settings. This review summarizes models for PrEP implementation from screening through initiation and follow-up, focusing on the strengths and weaknesses of three delivery systems: a health maintenance organization, an STI clinic, and a primary care practice. These early implementation experiences demonstrate that PrEP can be successfully delivered across a variety of settings and highlight strategies to streamline PrEP delivery in clinical practice.