Use of doxycycline and other antibiotics as bacterial sexually transmitted infection prophylaxis in a U.S. sample of primarily gay and bisexual men.

BACKGROUND: Doxycycline used as post-exposure prophylaxis (doxyPEP) within 72 hours of sex reduces the risk of bacterial sexually transmitted infections (STIs) in people assigned male sex at birth. Little is known about current use of antibiotics as STI prophylaxis in U.S. populations likely to benefit from doxyPEP. METHODS: We conducted an online survey in September 2023 of U.S. adults recruited via sexual networking apps used mainly by gay and bisexual men (GBM). Respondents were asked about the use of antibiotics around the time of sex to prevent bacterial STIs. RESULTS: Of 903 respondents, most (96.2%) identified as GBM; 19.0% were living with HIV and 42.5% using HIV pre-exposure prophylaxis. Half (49.1%) had heard of using antibiotics to prevent STIs and 95.6% were interested in use. Overall, 21.0% had used antibiotic STI prophylaxis and 15.9% had done so in the past year. Among those reporting any use, most (78.1%) had used doxycycline; some used amoxicillin (16.7%), azithromycin (14.5%), or other antibiotics (14.1%). Among those reporting use in the past year, 46.9% used it for some, 28.1% for most, and 25.0% for all sex acts with casual partners during that period. Most (78.3%) of STI prophylaxis users reported their condom use did not change during periods of STI prophylaxis use, 17.2% indicated their condom use declined, and 4.5% indicated their condom use increased. For doxyPEP specifically, 35.7% had heard of it and 13.0% had used it in the past year, of whom 21.0% had used a dosage other than the 200 mg dose shown to be effective. CONCLUSIONS: In this sample of primarily GBM, interest in bacterial STI prophylaxis was nearly universal. However, some of the use was not informed by current clinical guidance or evidence from research studies. Efforts are needed to increase awareness of effective dosing and monitor real-world use.

Weighing the Options: Which PrEP (Pre-exposure Prophylaxis) Modality Attributes Influence Choice for Young Gay and Bisexual Men in the United States?

Pre-exposure prophylaxis (PrEP) is effective in preventing HIV transmission, but uptake and adherence among young men who have sex with men (YMSM) remains suboptimal. New PrEP formulations may enhance PrEP use, but little is known about their acceptability. We enrolled 39 cis- and transgender YMSM (age 18-34) from Boston, MA; Jackson, MS; Birmingham, AL; and New Orleans, LA, who participated in video-based focus groups (n = 30) or in-depth interviews (n = 9) to examine how new PrEP products (e.g., injections, monthly pills, implants) are perceived and might be improved for YMSM. Focus groups were transcribed, coded, and analyzed using grounded theory and content analysis. Nearly half (46%) of participants were Black; 11% identified as Hispanic. Seventy-nine percent were PrEP experienced. Product preference was driven by the desire for flexible, safe, effective, and affordable PrEP options. A majority of participants preferred subcutaneous injections every 6 months or monthly pills dispersed in 3 or 4 doses. Subcutaneous injections and batched monthly pills were favored by those with demanding schedules and those who desired fewer provider visits; monthly pills were more appealing for those who feared needles. Despite broad preferences for longer-acting products for convenience, participants raised concerns regarding side effects and waning protection after missed doses. Participants felt that more education about safety and efficacy profiles of new products could influence their attitudes. These findings suggest that it is important to prioritize YMSM's dynamic lifestyles during product development, and that product safety and efficacy information should be accessible in youth-friendly language.

Prevalence and Correlates of SARS-CoV-2 Vaccine Uptake and Hesitancy Among People With HIV Across the United States.

BACKGROUND: People with HIV (PWH) have higher risk of COVID-19 mortality. SARS-CoV-2 vaccination is highly effective among PWH, although vaccine hesitancy could limit the population-level impact. SETTING: From February 2021 to April 2022, PWH from 8 sites in the Centers for AIDS Research Network of Integrated Clinical Systems completed a vaccine hesitancy instrument as part of routine care. METHODS: Participants were defined as vaccine hesitant if they had not received the SARS-CoV-2 vaccine and would probably/definitely not receive it. We assessed factors associated with SARS-CoV-2 vaccine hesitancy using logistic regression adjusted for demographics, unsuppressed viral load (VL > 200 copies/mL), month, and time on ART; using inverse probability weighting for survey nonresponse. RESULTS: Overall, 3288 PWH with a median age of 55 were included; 18% were female and 94% were virally suppressed. At the time of survey, 27% reported they had not received the SARS-CoV-2 vaccine, and 9% (n = 279) reported vaccine hesitancy. Factors associated with vaccine hesitancy included female sex (adjusted odds ratio [AOR] = 2.3; 95% confidence interval (CI): 1.6-3.2), Black vs. White race (AOR 1.7; 95% CI: 1.2 to 2.4), younger age (AOR 1.4; 95% CI: 1.2 to 1.5), and unsuppressed VL (AOR 1.9; 95% CI: 1.3 to 3.0). CONCLUSION: Overall, over one-quarter of PWH in this multisite cohort were unvaccinated for SARS-CoV-2 when interviewed February 21-April 22. Vaccine hesitancy was reported by approximately 9% of PWH and was higher among women, Black PWH, younger PWH, PWH with unsuppressed VL, and those in the South/Midwest. Renewed efforts are needed to address concerns of PWH about vaccinations against COVID-19 as the pandemic evolves, and vaccines in general, given the potential for future pandemics.

Missed Opportunities: A Narrative Review on Why Nonoccupational Postexposure Prophylaxis for HIV Is Underutilized.

Postexposure prophylaxis (PEP) is an important tool for preventing HIV infection but remains underutilized. In this narrative review, we aim to summarize the frequency of missed opportunities for prescribing PEP among studies from around the world, discuss the complexities of the challenges facing PEP provision, and describe possible solutions. We identified 20 studies published in the last 10 years among 43 832 individuals, of whom an estimated 41 477 were eligible for PEP. Of those eligible for PEP, PEP was prescribed among 27 705 (66.8%). There was a significant difference in PEP prescriptions in acute compared with non-acute care settings (63.5% vs 94.5%; P < .001). Emergent themes contributing to PEP underutilization included lack of provider and patient awareness, reduced PEP acceptability, HIV stigma and homophobia, lack of access (either to care or to medication), and stigmatizing policies. Each of those issues should be the focus of future PEP implementation efforts.

Preventive Service Usage and New Chronic Disease Diagnoses: Using PCORnet Data to Identify Emerging Trends, United States, 2018-2022.

Background: Data modernization efforts to strengthen surveillance capacity could help assess trends in use of preventive services and diagnoses of new chronic disease during the COVID-19 pandemic, which broadly disrupted health care access. Methods: This cross-sectional study examined electronic health record data from US adults aged 21 to 79 years in a large national research network (PCORnet), to describe use of 8 preventive health services (N = 30,783,825 patients) and new diagnoses of 9 chronic diseases (N = 31,588,222 patients) during 2018 through 2022. Joinpoint regression assessed significant trends, and health debt was calculated comparing 2020 through 2022 volume to prepandemic (2018 and 2019) levels. Results: From 2018 to 2022, use of some preventive services increased (hemoglobin A1c and lung computed tomography, both P < .05), others remained consistent (lipid testing, wellness visits, mammograms, Papanicolaou tests or human papillomavirus tests, stool-based screening), and colonoscopies or sigmoidoscopies declined (P < .01). Annual new chronic disease diagnoses were mostly stable (6% hypertension; 4% to 5% cholesterol; 4% diabetes; 1% colonic adenoma; 0.1% colorectal cancer; among women, 0.5% breast cancer), although some declined (lung cancer, cervical intraepithelial neoplasia or carcinoma in situ, cervical cancer, all P < .05). The pandemic resulted in health debt, because use of most preventive services and new diagnoses of chronic disease were less than expected during 2020; these partially rebounded in subsequent years. Colorectal screening and colonic adenoma detection by age group aligned with screening recommendation age changes during this period. Conclusion: Among over 30 million patients receiving care during 2018 through 2022, use of preventive services and new diagnoses of chronic disease declined in 2020 and then rebounded, with some remaining health debt. These data highlight opportunities to augment traditional surveillance with EHR-based data.

Interventions for Improving HIV Care Continuum Outcomes Among LGBTQ+ Youth in the United States: A Narrative Review.

Lesbian, gay, bisexual, transgender, queer, and all sexually and gender diverse (LGBTQ+) youth with HIV face multiple barriers to progression along the HIV care continuum. We searched PubMed, PsycInfo, clinicaltrials.gov, and the Adolescent Medicine Trials Network for HIV/AIDS Interventions for interventions focused on improving linkage to care, retention in care, adherence to antiretroviral therapy, or viral suppression (VS) among LGBTQ+ youth with HIV in the United States. Included studies were published in English between January 1, 2017 and December 31, 2022, took place in the United States, and had samples with a minimum age of 12 years, a median or mean age of 24 years or less, and with ≥50% reporting an LGBTQ+ identity. Our search identified 11 interventions that met our criteria, of which only three were designed and tailored exclusively for LGBTQ+ populations. Interventions used a variety of modalities, including remote electronic delivery, in-person delivery, or both. Interventions most commonly aimed to enhance self-efficacy, HIV health knowledge, and medication self-management to facilitate improvements in HIV care continuum outcomes. Only two interventions showed statistically significant improvements in VS. More interventions tailored for LGBTQ+ youth are needed to end the HIV epidemic in the United States.

HIV Immunocapture Reveals Particles Expressed in Semen Under Integrase Strand Transfer Inhibitor-Based Therapy Are Largely Myeloid Cell-Derived and Disparate.

As use of human immunodeficiency virus (HIV) integrase strand transfer inhibitors (INSTI) increases and formulations are being developed for maintenance therapies and chemoprophylaxis, assessing virus suppression under INSTI-based regimens in prevention-relevant biologic compartments, such as the male genital tract, is timely. We used cell-source marker virion immunocapture to examine amplification of particle RNA then assessed the phylogenetic relatedness of seminal and blood viral sequences from men with HIV who were prescribed INSTI-based regimens. Seminal plasma immunocaptures yielded amplifiable virion RNA from 13 of 24 (54%) men, and the sequences were primarily associated with markers indicative of macrophage and resident dendritic cell sources. Genetic distances were greatest (>2%) between seminal virions and circulating proviruses, pointing to ongoing low-level expression from tissue-resident cells. While the low levels in semen predict an improbable likelihood of transmission, viruses with large genetic distances are expressed under potent INSTI therapy and have implications for determining epidemiologic linkages if adherence is suboptimal.

Leveraging A Digital Pill System to Understand Prevention-Effective Adherence to Oral Hiv Pre-Exposure Prophylaxis Among Men Who Have Sex with Men with Substance Use.

Daily oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, though efficacy depends on adherence. Digital pill systems (DPS) can enable direct, real-time adherence measurement. HIV-negative men who have sex with men (MSM) with substance use (excluding alcohol) utilized a DPS over 90 days and completed weekly surveys reporting sexual activity, condom use, and substance use. Responses indicating (1) any sexual activity and substance use or (2) condomless anal intercourse (CAI) in the prior week were categorized as high risk for HIV acquisition. PrEP adherence data for the 7-day period preceding each response was dichotomized as ≤ 3 and ≥ 4 doses/week, indicating prevention-effective adherence, and compared by HIV risk level. Thirteen MSM were analyzed (median age: 32). Of 113 surveys, 48.7% indicated high HIV risk, with 12.4% reporting CAI alone, 16.8% any sexual activity and substance use, and 19.5% both CAI and substance use. Weekly mean PrEP adherence was 90.3% (6.3 of 7 doses/week), with ≥ 4 doses/week recorded during 92.0% of weeks. The proportion of participants with ≥ 4 recorded doses/week was 88.9% during weeks with CAI alone, 89.5% during weeks with any sexual activity and substance use, 92.0% during weeks with both CAI and substance use, and 92.8% during lower risk weeks. Participants ingested ≥ 4 doses/week during 89.1% of all high-risk weeks and 94.8% of low-risk weeks. Overall, participants maintained high levels of PrEP adherence while engaging in HIV risk behaviors. DPS can be deployed concurrently with data collection tools to assess ingestion patterns during periods of elevated risk.

Pharmacologic Drug Detection and Self-Reported Adherence in the HPTN069/ACTG5305 Phase II PrEP Trial.

Adherence drives efficacy in PrEP clinical trials. We compared drug concentrations and self-reported adherence in HPTN069/ACTG5305, a double-blinded, randomized trial of the safety and tolerability of candidate PrEP regimens that included maraviroc (MVC), tenofovir (TDF), and emtricitabine (FTC). Plasma drug concentrations and self-reported adherence by computer-assisted self-interview (CASI) were assessed at study weeks 24 and 48. Descriptive statistics and a generalized linear model were used to assess the association between selected demographic factors, self-report of daily medication adherence and plasma drug concentrations consistent with daily adherence. Among 718 paired observations from 370 participants, 43% (306/718) reported daily adherence by CASI, 65% (467/718) had drug concentrations consistent with daily adherence and 11% (81/718) had CASI responses that reported daily adherence despite having drug concentrations consistent with less-than-daily adherence. In adjusted analyses, participants who were assigned male at birth (aOR 1.42 [95% CI 1.02, 1.97]), older (5-year increments aOR 1.10 [95% CI 1.09, 1.11]), White (aOR 2.2 [95% CI 1.88, 2.56]), had advanced education (aOR 3.89 [95% CI 2.97, 5.09]), were employed (aOR 1.89 [95% CI 1.50, 2.40]), or partnered/married (aOR 2 [95% CI 1.72, 2.32]) were more likely to have drug concentrations consistent with daily adherence. Participants who were not employed (aOR 2.7 [95% CI 1.31, 5.55]) or who were single/not partnered (aOR 2.33 [CI 95% 1.25, 4.34]) were more likely to have drug concentrations that did not reflect daily adherence despite self-reported PrEP adherence. These findings support the need for ongoing adherence counseling in clinical trials of new PrEP regimens.

Incentivizing adherence to pre-exposure prophylaxis for HIV prevention: a randomized pilot trial among male sex workers in Mexico.

Low adherence to preventative medications against life-long health conditions is a major contributor to global morbidity and mortality. We implemented a pilot randomized controlled trial in Mexico to measure the extent to which conditional economic incentives help male sex workers increase their adherence to pre-exposure prophylaxis (PrEP) for HIV prevention. We followed n = 110 male sex workers over 6 months. At each quarterly visit (at months 0, 3, and 6), all workers received a $10 transport reimbursement, a free 3-month PrEP supply, and completed socio-behavioral surveys. The primary outcome was an objective biomarker of medication adherence based on tenofovir (TFV) drug concentration levels in hair collected at each visit. Individuals randomized to the intervention received incentives based on a grading system as a function of PrEP adherence: those with high (> 0.043 ng/mg TFV concentration), medium (0.011 to 0.042 ng/mg), or low (< 0.011 ng/mg) adherence received $20, $10, or $0, respectively. Six-month pooled effects of incentives on PrEP adherence were analyzed using population-averaged gamma generalized estimating equation models. We estimated heterogeneous treatment effects by sex worker characteristics. The incentive intervention led to a 28.7% increase in hair antiretroviral concentration levels over 6 months consistent with increased PrEP adherence (p = 0.05). The effect of incentives on PrEP adherence was greater for male sex workers who were street-based (vs. internet) workers (p < 0.10). These pilot findings suggest that modest conditional economic incentives could be effective, at scale, for improving PrEP adherence among male sex workers, and should be tested in larger implementation trials. ClinicalTrials.gov Identifier: NCT03674983.

Social, economic, and physical side effects impact PrEP uptake and persistence among transgender women in Peru.

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) for HIV-1 infection is over 99% effective in protecting against HIV acquisition when used consistently and appropriately. However, PrEP uptake and persistent use remains suboptimal, with a substantial gap in utilization among key populations who could most benefit from PrEP. In Latin America specifically, there is poor understanding of barriers to PrEP uptake and persistence among transgender (trans) women. METHODS: In April-May 2018, we conducted qualitative interviews lasting 25-45 min as part of an end-of-project evaluation of TransPrEP, a pilot RCT that examined the impact of a social network-based peer support intervention on PrEP adherence among trans women in Lima, Peru. Participants in the qualitative evaluation, all adult trans women, included individuals who either (1) screened eligible to participate in the TransPrEP pilot, but opted not to enroll (n = 8), (2) enrolled, but later withdrew (n = 6), (3) were still actively enrolled at the time of interview and/or successfully completed the study (n = 16), or (4) were study staff (n = 4). Interviews were audio recorded and transcribed verbatim. Codebook development followed an immersion/crystallization approach, and coding was completed using Dedoose. RESULTS: Evaluation participants had a mean age of 28.2 years (range 19-47). When describing experiences taking PrEP, participant narratives highlighted side effects that spanned three domains: physical side effects, such as prolonged symptoms of gastrointestinal distress or somnolence; economic challenges, including lost income due to inability to work; and social concerns, including interpersonal conflicts due to HIV-related stigma. Participants described PrEP use within a broader context of social and economic marginalization, with a focus on daily survival, and how PrEP side effects negatively contributed to these stressors. Persistence was, in some cases, supported through the intervention's educational workshops. CONCLUSION: This research highlights the ways that physical, economic, and social side effects of PrEP can impact acceptability and persistence among trans women in Peru, amplifying and layering onto existing stressors including economic precarity. Understanding the unique experiences of trans women taking PrEP is crucial to informing tailored interventions to improve uptake and persistence.

HIV-1 infection kinetics, drug resistance, and long-term safety of pre-exposure prophylaxis with emtricitabine plus tenofovir alafenamide (DISCOVER): week 144 open-label extension of a randomised, controlled, phase 3 trial.

BACKGROUND: Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up. METHODS: The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (ß2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide. INTERPRETATION: Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities. FUNDING: Gilead Sciences.

Pediatrician Preferences for Electronic Clinical Decision Support to Facilitate HIV Pre-Exposure Prophylaxis.

PURPOSE: Pediatric primary care clinicians are often uncertain about patients' HIV infection risk and pre-exposure prophylaxis (PrEP) prescribing guidelines. This study was conducted to help identify ways to design and deliver useful electronic health record (EHR)-based alerts for PrEP to help mitigate this issue. METHODS: Individual interviews and focus groups with pediatricians explored provider preferences for clinical decision support around PrEP in the EHR. Key themes were identified via the immersion-crystallization qualitative analytic technique. RESULTS: Clinicians described ideal decision support tools as succinct, helpful in identifying patients at risk of acquiring HIV, providing automated follow-up, and linking to evidence-based prescribing guidelines. Concerns emerged about alert fatigue. DISCUSSION: This study summarizes clinicians' preferences for EHR tool development to support PrEP provision among pediatricians with limited comfort and experience with prescribing PrEP. These findings can inform the development of PrEP decision support by implementing provider-centered feedback.

Posttraumatic Stress Disorder Symptoms and Incarceration: The Impact on Sexual Risk-Taking, Sexually Transmitted Infections, and Depression Among Black Sexual Minority Men in HIV Prevention Trials Network (HPTN) 061.

Black men and people belonging to sexual minority groups are disproportionately impacted by criminal legal involvement and sexually transmitted infections (STIs). Traumatic experiences are often associated with later criminal legal involvement, depression symptoms, sexual risk behavior, and STIs. Research on the joint influence of trauma and incarceration on STI risk among racial and/or sexual minority people is limited. This study tested the association between post-traumatic stress disorder (PTSD) symptoms and incarceration on sexual risk behavior and STI among Black sexual minority men, a population that may be at higher risk for contracting STIs. Using data from the HIV Prevention Trials Network 061 Study, a longitudinal study of adult Black sexual minority men in six U.S. cities (N = 855), we tested associations between past six-month incarceration and subsequent sexual risk behavior, STI, and depression symptoms, for those with and without pre-incarceration PTSD symptoms. PTSD symptoms were elevated among participants who reported Hispanic ethnicity, having sex with both men and women, and previous incarceration. Although there were not significant differences between recent incarceration and sexual risk for those with and without PTSD, incarceration was linked to some sexual risk behaviors regardless of PTSD symptoms. Among people with PTSD symptoms, there was a higher prevalence of sexual risk and depression symptoms, regardless of incarceration. These findings suggest a potentially compounding influence of PTSD symptoms and incarceration on sexual risk and infection among Black sexual minority men.

Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.

BACKGROUND: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. METHODS AND FINDINGS: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). CONCLUSIONS: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. TRIAL REGISTRATION: ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).

Safety and immunogenicity of a polyvalent DNA-protein HIV vaccine with matched Env immunogens delivered as a prime-boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial.

BACKGROUND: An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens. METHODS: HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection. The DNA vaccine comprised five plasmids: four copies expressing Env gp120 (clades A, B, C, and AE) and one gag p55 (clade C). The protein vaccine included four DNA vaccine-matched GLA-SE-adjuvanted recombinant gp120 proteins. Participants were enrolled across six clinical sites in the USA and were randomly assigned to placebo or one of two vaccine groups (ie, prime-boost or coadministration) in a 5:1 ratio in part A and a 7:1 ratio in part B. Vaccines were delivered via intramuscular needle injection. The primary outcomes were safety and tolerability, assessed via frequency, severity, and attributability of local and systemic reactogenicity and adverse events, laboratory safety measures, and early discontinuations. Part A evaluated safety. Part B evaluated safety and immunogenicity of two regimens: DNA prime (administered at months 0, 1, and 3) with protein boost (months 6 and 8), and DNA-protein coadministration (months 0, 1, 3, 6, and 8). All randomly assigned participants who received at least one dose were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT03409276) and is closed to new participants. FINDINGS: Between April 19, 2018 and Feb 13, 2019, 60 participants (12 in part A [five men and seven women] and 48 in part B [21 men and 27 women]) were enrolled. All 60 participants received at least one dose, and 14 did not complete follow-up (six of 21 in the prime-boost group and eight of 21 in the coadminstration group). 11 clinical adverse events deemed by investigators as study-related occurred in seven of 48 participants in part B (eight of 21 in the prime-boost group and three of 21 in the coadministration group). Local reactogenicity in the vaccine groups was common, but the frequency and severity of reactogenicity signs or symptoms did not differ between the prime-boost and coadministration groups (eg, 20 [95%] of 21 in the prime-boost group vs 21 [100%] of 21 in the coadministration group had either local pain or tenderness of any severity [p=1·00], and seven [33%] vs nine [43%] had either erythema or induration [p=0·97]), nor did laboratory safety measures. There were no delayed-type hypersensitivity reactions or vasculitis or any severe clinical adverse events related to vaccination. The most frequently reported systemic reactogenicity symptoms in the active vaccine groups were malaise or fatigue (five [50%] of ten in part A and 17 [81%] of 21 in the prime-boost group vs 15 [71%] of 21 in the coadministration group in part B), headache (five [50%] and 18 [86%] vs 12 [57%]), and myalgia (four [40%] and 13 [62%] vs ten [48%]), mostly of mild or moderate severity. INTERPRETATION: Both vaccine regimens were safe, warranting evaluation in larger trials. FUNDING: US National Institutes of Health and US National Institute of Allergy and Infectious Diseases.

Performance of the Applied Biosystems HIV-1 Genotyping Kit with Integrase.

HIV genotyping is used to assess HIV susceptibility to antiretroviral drugs. The Applied Biosystems HIV-1 Genotyping Kit with Integrase (AB kit, Thermo Fisher Scientific) detects resistance-associated mutations (RAMs) in HIV protease (PR), reverse transcriptase (RT), and integrase (IN). We compared results from the AB kit with results obtained previously with the ViroSeq HIV-1 Genotyping System. DNA amplicons from the AB kit were also analyzed using next-generation sequencing (NGS). HIV RNA was extracted using the MagNA Pure 24 instrument (Roche Diagnostics; 96 plasma samples, HIV subtype B, viral load range: 530-737,741 copies/mL). FASTA files were generated from AB kit data using Exatype (Hyrax Biosciences). DNA amplicons from the AB kit were also analyzed by NGS using the Nextera XT kit (Illumina). Drug resistance was predicted using the Stanford HIV Drug Resistance Database. The mean genetic distance for sequences from ViroSeq and the AB kit was 0.02% for PR/RT and 0.04% for IN; 103 major RAMs were detected by both methods. Four additional major RAMs were detected by the AB kit only. These four major RAMs were also detected by NGS (detected in 18.1%-38.2% of NGS reads). NGS detected 27 major RAMs that were not detected with either of the Sanger sequencing-based kits. All major RAMs detected with ViroSeq were detected with the AB kit; additional RAMs were detected with the AB kit only. DNA amplicons from the AB kit can be used for NGS for more sensitive detection of RAMs.

High Rates of Missed HIV Testing Among Oral PrEP Users in the United States From 2018-2021: A National Assessment on Compliance With HIV Testing Recommendations of the CDC PrEP Guidelines.

Background: The US Centers for Disease Control and Prevention recommends HIV testing every 3 months in oral PrEP users. We performed a national assessment of HIV testing compliance among oral PrEP users. Methods: We analyzed 408 910 PrEP prescriptions issued to 39 809 PrEP users using a national insurance claims database that contained commercial and Medicaid claims. We identified PrEP use based on pharmacy claims and outpatient diagnostic coding. We evaluated the percentage of PrEP prescription refills without HIV testing (identified by CPT codes) within the prior 3, 6, and 12 months using time to event methods. We performed subgroup and multivariate analyses by age, gender, race, insurance type, and geography. Results: Of 39 809 persons, 36 197 were commercially insured, 3612 were Medicaid-insured, and 96% identified as male; the median age (interquartile range) was 34 (29-44) years, and the Medicaid-insured PrEP users were 24% Black/African American, 44% White, and 9% Hispanic/Latinx. Within the prior 3, 6, and 12 months, respectively, the percentage of PrEP prescription fills in individuals without HIV Ag/Ab testing was 34.3% (95% CI, 34.2%-34.5%), 23.8% (95% CI, 23.7%-23.9%), and 16.6% (95% CI, 16.4%-16.7%), and the percentage without any type of HIV test was 25.8% (95% CI, 25.6%-25.9%), 14.6% (95% CI, 14.5%-14.7%), and 7.8% (95% CI, 7.7%-7.9%). Conclusions: Approximately 1 in 3 oral PrEP prescriptions were filled in persons who had not received an HIV Ag/Ab test within the prior 3 months, with evidence of health disparities. These findings inform clinical PrEP monitoring efforts and compliance with national HIV testing guidance to monitor PrEP users.