High HIV diversity, recombination, and superinfection revealed in a large outbreak among persons who inject drugs in Kentucky and Ohio, USA.

We investigated transmission dynamics of a large human immunodeficiency virus (HIV) outbreak among persons who inject drugs (PWID) in KY and OH during 2017-20 by using detailed phylogenetic, network, recombination, and cluster dating analyses. Using polymerase (pol) sequences from 193 people associated with the investigation, we document high HIV-1 diversity, including Subtype B (44.6 per cent); numerous circulating recombinant forms (CRFs) including CRF02_AG (2.5 per cent) and CRF02_AG-like (21.8 per cent); and many unique recombinant forms composed of CRFs with major subtypes and sub-subtypes [CRF02_AG/B (24.3 per cent), B/CRF02_AG/B (0.5 per cent), and A6/D/B (6.4 per cent)]. Cluster analysis of sequences using a 1.5 per cent genetic distance identified thirteen clusters, including a seventy-five-member cluster composed of CRF02_AG-like and CRF02_AG/B, an eighteen-member CRF02_AG/B cluster, Subtype B clusters of sizes ranging from two to twenty-three, and a nine-member A6/D and A6/D/B cluster. Recombination and phylogenetic analyses identified CRF02_AG/B variants with ten unique breakpoints likely originating from Subtype B and CRF02_AG-like viruses in the largest clusters. The addition of contact tracing results from OH to the genetic networks identified linkage between persons with Subtype B, CRF02_AG, and CRF02_AG/B sequences in the clusters supporting de novo recombinant generation. Superinfection prevalence was 13.3 per cent (8/60) in persons with multiple specimens and included infection with B and CRF02_AG; B and CRF02_AG/B; or B and A6/D/B. In addition to the presence of multiple, distinct molecular clusters associated with this outbreak, cluster dating inferred transmission associated with the largest molecular cluster occurred as early as 2006, with high transmission rates during 2017-8 in certain other molecular clusters. This outbreak among PWID in KY and OH was likely driven by rapid transmission of multiple HIV-1 variants including de novo viral recombinants from circulating viruses within the community. Our findings documenting the high HIV-1 transmission rate and clustering through partner services and molecular clusters emphasize the importance of leveraging multiple different data sources and analyses, including those from disease intervention specialist investigations, to better understand outbreak dynamics and interrupt HIV spread.

Weekly Oral Tenofovir Alafenamide Protects Macaques from Vaginal and Rectal Simian HIV Infection.

Pre-exposure prophylaxis (PrEP) with a weekly oral regimen of antiretroviral drugs could be a suitable preventative option for individuals who struggle with daily PrEP or prefer not to use long-acting injectables. We assessed in macaques the efficacy of weekly oral tenofovir alafenamide (TAF) at doses of 13.7 or 27.4 mg/kg. Macaques received weekly oral TAF for six weeks and were exposed twice-weekly to SHIV vaginally or rectally on day 3 and 6 after each dose. Median TFV-DP levels in PBMCs following the 13.7 mg/kg dose were 3110 and 1137 fmols/106 cells on day 3 and 6, respectively. With the 27.4 mg/kg dose, TFV-DP levels were increased (~2-fold) on day 3 and 6 (6095 and 3290 fmols/106 cells, respectively). Both TAF doses (13.7 and 27.4 mg/kg) conferred high efficacy (94.1% and 93.9%, respectively) against vaginal SHIV infection. Efficacy of the 27.4 mg/kg dose against rectal SHIV infection was 80.7%. We estimate that macaque doses of 13.7 and 27.4 mg/kg are equivalent to approximately 230 and 450 mg of TAF in humans, respectively. Our findings demonstrate the effectiveness of a weekly oral PrEP regimen and suggest that a clinically achievable oral TAF dose could be a promising option for non-daily PrEP.

Low CD4 Count or Being Out of Care Increases the Risk for Mpox Hospitalization Among People With Human Immunodeficiency Virus and Mpox.

Human immunodeficiency virus (HIV)-associated immunosuppression may increase the risk of hospitalization with mpox. Among persons diagnosed with mpox in the state of Georgia, we characterized the association between hospitalization with mpox and HIV status. People with HIV and a CD4 count <350 cells/mm3 or who were not engaged in HIV care had an increased risk of hospitalization.

Mixed methods evaluation of vaping and tobacco product use prevention interventions among youth in the Florida 4-H program.

INTRODUCTION: Novel prevention programs are developed to address the increase in e-cigarette use (vaping) among children. However, it remains paramount to test their feasibility in rural settings. This pilot study implemented and evaluated the feasibility and outcomes of two innovative programs, CATCH My Breath and smokeSCREEN, among youth in rural settings in Florida. METHODS: We conducted four focus groups with youth aged 11-17 recruited from 4-H rural clubs in Florida. In a subsequent randomized trial, we recruited 82 youth participants and assigned them to one of three arms: CATCH My Breath, smokeSCREEN, or control. CATCH My Breath and smokeSCREEN participants attended online group intervention sessions while the control group received educational material. Pre- and post-surveys were administered to all participants to assess knowledge, susceptibility, perceived positive outcomes and risk perceptions related to tobacco and e-cigarette use. Other feasibility parameters were also assessed. RESULTS: Focus group discussions provided insights about feasibility and informed the implementation of both interventions in terms of delivery format, scheduling of sessions and incentives. After the intervention, CATCH My Breath participants significantly improved their general tobacco-related knowledge (post-pre = 16.21-12.92 = 3.3, p <.01) and risk perceptions towards other flavored tobacco products (post-pre = 19.29-17.71 = 1.6, p <.05). smokeSCREEN participants significantly improved their general tobacco knowledge (post-pre = 18.77-13.77 = 5.0, p <.01), knowledge about e-cigarettes (post-pre = 9.08-6.31 = 2.8, p <.01) and risk perception towards e-cigarettes (post-pre = 24.69-21.92 = 2.8, p <.05). CONCLUSIONS: This study demonstrated feasibility of delivering the interventions via participant engagement, participants' willingness to be randomized, assessment of outcome measures, and exploration of different recruitment methods. Despite the potential positive influence of CATCH My Breath and smokeSCREEN on youth participants, further evaluation with larger samples is needed.

The Cooperative Re-Engagement Controlled Trial (CoRECT): Durable Viral Suppression Assessment.

BACKGROUND: A collaborative, data-to-care strategy to identify persons with HIV (PWH) newly out-of-care, combined with an active public health intervention, significantly increases the proportion of PWH re-engaged in HIV care. We assessed this strategy's impact on durable viral suppression (DVS). METHODS: A multisite, prospective randomized controlled trial for out-of-care individuals using a data-to-care strategy and comparing public health field services to locate, contact, and facilitate access to care versus the standard of care. DVS was defined as the last viral load, the viral load at least 3 months before, and any viral load between the 2 were all <200 copies/mL during the 18-month postrandomization. Alternative definitions of DVS were also analyzed. RESULTS: Between August 1, 2016-July 31, 2018, 1893 participants were randomized from Connecticut (n = 654), Massachusetts (n = 630), and Philadelphia (n = 609). Rates of achieving DVS were similar in the intervention and standard-of-care arms in all jurisdictions (all sites: 43.4% vs 42.4%, P = 0.67; Connecticut: 46.7% vs 45.0%, P = 0.67; Massachusetts: 40.7 vs 44.4%, P = 0.35; Philadelphia: 42.4% vs 37.3%, P = 0.20). There was no association between DVS and the intervention (RR: 1.01, CI: 0.91-1.12; P = 0.85) adjusting for site, age categories, race/ethnicity, birth sex, CD4 categories, and exposure categories. CONCLUSION: A collaborative, data-to-care strategy, and active public health intervention did not increase the proportion of PWH achieving DVS, suggesting additional support to promote retention in care and antiretroviral adherence may be needed. Initial linkage and engagement services, through data-to-care or other means, are likely necessary but insufficient for achieving DVS for all PWH.

Hospitalizations for COVID-19 Among American Indian and Alaska Native Adults (≥ 18 Years Old) - New Mexico, March-September 2020.

To assess the presence of racial disparity during the COVID-19 pandemic, the New Mexico Department of Health (NMDOH) sought to compare the case rate and risk of hospitalization between persons of American Indian and Alaska Native (AI/AN) race and persons of other races in New Mexico from March 1 through September 30, 2020. Using NMDOH COVID-19 surveillance data, age-standardized COVID-19 case and hospitalization risks were compared between adults (≥ 18 years old) of AI/AN and other races. We compared age, sex, and comorbidities between hospitalized adults of AI/AN and other races. Among AI/AN persons, age-standardized COVID-19 case and hospitalization risks were 3.7 (95% CI 3.6-3.8) and 10.5 (95% CI 9.8-11.2) times as high as persons of other races. Hospitalized AI/AN patients had higher proportions of diabetes mellitus (48% vs. 33%, P < 0.0001) and chronic liver disease (8% vs. 5%, P = 0.0004) compared to hospitalized patients of other races. AI/AN populations have disproportionately higher risk of COVID-19 hospitalization compared to other races in New Mexico. By identifying etiologic factors that contribute to inequity, public health partners can implement culturally appropriate health interventions to mitigate disease severity within AI/AN communities.

Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques.

BACKGROUND: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. METHODS: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). FINDINGS: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%-98.8%) and 100% (95% CI = undefined), respectively. INTERPRETATION: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. FUNDING: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.

Risk-Factors for Exposure Associated With SARS-CoV-2 Detection After Recent Known or Potential COVID-19 Exposures Among Patients Seeking Medical Care at a Large Urban, Public Hospital in Fulton County, Georgia - A Cross-Sectional Investigation.

We aimed to describe frequency of COVID-19 exposure risk factors among patients presenting for medical care at an urban, public hospital serving mostly uninsured/Medicare/Medicaid clients and risk factors associated with SARS-CoV-2 infection. Consenting, adult patients seeking care at a public hospital from August to November 2020 were enrolled in this cross-sectional investigation. Saliva, anterior nasal and nasopharyngeal swabs were collected and tested for SARS-CoV-2 using RT-PCR. Participant demographics, close contact, and activities ≤14 days prior to enrollment were collected through interview. Logistic regression was used to identify risk factors associated with testing positive for SARS-CoV-2. Among 1,078 participants, 51.8% were male, 57.0% were aged ≥50 years, 81.3% were non-Hispanic Black, and 7.6% had positive SARS-CoV-2 tests. Only 2.7% reported COVID-19 close contact ≤14 days before enrollment; this group had 6.79 adjusted odds of testing positive (95%CI = 2.78-16.62) than those without a reported exposure. Among participants who did not report COVID-19 close contact, working in proximity to ≥10 people (adjusted OR = 2.17; 95%CI = 1.03-4.55), choir practice (adjusted OR = 11.85; 95%CI = 1.44-97.91), traveling on a plane (adjusted OR = 5.78; 95%CI = 1.70-19.68), and not participating in an essential indoor activity (i.e., grocery shopping, public transit use, or visiting a healthcare facility; adjusted OR = 2.15; 95%CI = 1.07-4.30) were associated with increased odds of testing positive. Among this population of mostly Black, non-Hispanic participants seeking care at a public hospital, we found several activities associated with testing positive for SARS-CoV-2 infection in addition to close contact with a case. Understanding high-risk activities for SARS-CoV-2 infection among different communities is important for issuing awareness and prevention strategies.

Specimen self-collection for SARS-CoV-2 testing: Patient performance and preferences-Atlanta, Georgia, August-October 2020.

Self-collected specimens can expand access to SARS-CoV-2 testing. At a large inner-city hospital 1,082 participants self-collected saliva and anterior nasal swab (ANS) samples before healthcare workers collected nasopharyngeal swab (NPS) samples on the same day. To characterize patient preferences for self-collection, this investigation explored ability, comfort, and ease of ANS and saliva self-collection for SARS-CoV-2 testing along with associated patient characteristics, including medical history and symptoms of COVID-19. With nearly all participants successfully submitting a specimen, favorable ratings from most participants (at least >79% in ease and comfort), and equivocal preference between saliva and ANS, self-collection is a viable SARS-CoV-2 testing option.

Sexually transmitted infections and depot medroxyprogesterone acetate do not impact protection from simian HIV acquisition by long-acting cabotegravir in macaques.

OBJECTIVE: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STIs) that are known to increase HIV susceptibility in women. DESIGN: Two macaque models of increasing vaginal STI severity were used for efficacy assessment. METHODS: The first study (n = 11) used a double STI model that had repeated exposures to two vaginal STI, Chlamydia trachomatis and Trichomonas vaginalis. Six animals were CAB-LA treated and five were controls. The second study (n = 9) included a triple STI model with repeated exposures to C. trachomatis, T. vaginalis and syphilis, and the contraceptive, depot medroxyprogesterone acetate (DMPA). Six animals were CAB-LA treated and three were controls. All animals received up to 14 vaginal SHIV challenges. A survival analysis was performed to compare the number of SHIV challenges to infection in the drug-treated group compared with untreated controls over time. RESULTS: All six CAB-LA treated animals in both models, the double STI or the triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges, while the untreated animals became SHIV-infected after a median of two challenges (log-rank P < 0.001) or one challenge (log-rank P = 0.002), respectively. Both models recapitulated human STI disease, with vaginal discharge, ulcers, and seroconversion. CONCLUSION: In these high and sustained susceptibility models spanning more than 3 months, CAB-LA maintained complete efficacy, demonstrating robustness of the CAB-LA dose used in clinical trials, and suggesting its insensitivity to multiple STIs and DMPA.

HIV Stigma Among a National Probability Sample of Adults with Diagnosed HIV-United States, 2018-2019.

HIV stigma is a barrier to achieving the goals of the US Ending the HIV Epidemic initiative. We analyzed data from the Medical Monitoring Project (MMP) collected during 6/2018-5/2019 from 4050 US adults with diagnosed HIV. We reported national estimates of HIV stigma and assessed their associations with sociodemographic and clinical characteristics. Disclosure concerns and stigma related to negative public attitudes were common. Stigma was higher among younger age groups, women and transgender people, Black and Hispanic/Latino men and women, and Black and Hispanic/Latino men who have sex with men. Stigma was associated with lower antiretroviral therapy use and adherence, missed HIV care visits, and symptoms of depression or anxiety. The estimates presented provide a benchmark from which the nation can monitor its progress. The findings suggest the need for enhanced stigma-reduction efforts among specific groups and the importance of addressing stigma around disclosure and community attitudes.

Effects of Patient Characteristics on Diagnostic Performance of Self-Collected Samples for SARS-CoV-2 Testing.

We evaluated the performance of self-collected anterior nasal swab (ANS) and saliva samples compared with healthcare worker-collected nasopharyngeal swab specimens used to test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used the same PCR diagnostic panel to test all self-collected and healthcare worker-collected samples from participants at a public hospital in Atlanta, Georgia, USA. Among 1,076 participants, 51.9% were men, 57.1% were >50 years of age, 81.2% were Black (non-Hispanic), and 74.9% reported >1 chronic medical condition. In total, 8.0% tested positive for SARS-CoV-2. Compared with nasopharyngeal swab samples, ANS samples had a sensitivity of 59% and saliva samples a sensitivity of 68%. Among participants tested 3-7 days after symptom onset, ANS samples had a sensitivity of 80% and saliva samples a sensitivity of 85%. Sensitivity varied by specimen type and patient characteristics. These findings can help physicians interpret PCR results for SARS-CoV-2.

The effect of depot medroxyprogesterone acetate on tenofovir alafenamide in rhesus macaques.

Prevention of HIV infection and unintended pregnancies are public health priorities. In sub-Saharan Africa, where HIV prevalence is highest, depot medroxyprogesterone acetate (DMPA) is widely used as contraception. Therefore, understanding potential interactions between DMPA and antiretrovirals is critical. Here, we use a macaque model to investigate the effect of DMPA on the pharmacology of the antiretroviral tenofovir alafenamide (TAF). Female rhesus macaques received 30 mg of DMPA (n = 9) or were untreated (n = 9). Macaques received a human equivalent dose of TAF (1.5 mg/kg) orally by gavage. Tenofovir (TFV) and TFV-diphosphate (TFV-DP) were measured in blood, secretions, and tissues over 72 h. The median area under the curve (AUC0-72h) values for TFV-DP in peripheral blood mononuclear cells were similar in DMPA-treated (6991 fmol*h/106 cells) and untreated controls (5256 fmol*h/106 cells) (P = 0.174). Rectal tissue TFV-DP concentrations from DMPA+ animals [median: 20.23 fmol/mg of tissue (range: 4.94-107.95)] were higher than the DMPA- group [median: below the limit of quantification (BLOQ-11.92)], (P = 0.019). TFV-DP was not detectable in vaginal tissue from either group. A high-dose DMPA treatment in macaques was associated with increased rectal TFV-DP levels, indicating a potential tissue-specific drug-drug interaction. The lack of detectable TFV-DP in the vaginal tissue warrants further investigation of PrEP efficacy with single-agent TAF products. DMPA did not affect systemic TAF metabolism, with similar PBMC TFV-DP in both groups, suggesting that DMPA use should not alter the antiviral activity of TAF.

The Cooperative Re-Engagement Controlled trial (CoRECT): A randomised trial to assess a collaborative data to care model to improve HIV care continuum outcomes.

Background: Persons with HIV (PWH), aware of their HIV infection but not in care account for an estimated 42.6% of HIV transmissions in the United States. Health departments and clinics implemented a collaborative data-to-care strategy to identify persons newly out-of-care with the objective of increasing re-engagement, retention in medical care, and viral load suppression. Methods: A multi-site, prospective randomised trial was conducted to identify newly out-of-care PWH using surveillance and clinic data in Connecticut (CT), Massachusetts (MA) and Philadelphia (PHL). All out-of-care participants were randomised to receive standard of care or an active public health intervention. Re-engagement in care was defined as having a documented CD4 count and/or HIV viral load within 90 days of randomization. Retention was defined as having at least two CD4 count and/or HIV viral load results ≥ 3 months apart within 12 months of randomization, and viral load suppression as having a viral load < 200 copies/ml within 12 months of randomization. Findings: Between August 2016 and July 2018, 1893 out-of-care participants were randomised from CT (N = 654), MA (N = 630), and PHL (N = 609). Participants were male (69.5%), non-Hispanic Black (48.3%) and men who have sex with men (38.8%). Re-engagement within 90 days was significantly higher for the intervention group overall and in all three jurisdictions (All sites: 54.9% vs 42.1%, p < 0.0001; CT: 51.2% vs 41.9%, p = 0.02; MA: 52.7% vs 44.1%, p = 0.03; PHL 61.2% vs 40.3%, p < 0.0001). Retention in care over 12 months improved overall (p = 0.04). Median time to viral suppression was reduced overall (p = 0.0006); CT (p = 0.32), MA (p = 0.02) and PHL (p < 0.0001). Interpretation: This trial showed that a collaborative, data-to-care strategy, and active public health intervention led by health departments significantly increases the proportion of PWH re-engaged in HIV care and may improve retention in care and decrease time to viral suppression.

Altered Antibody Responses in Persons Infected with HIV-1 While Using Preexposure Prophylaxis.

Preexposure prophylaxis (PrEP) is an effective HIV prevention tool, although effectiveness is dependent upon adherence. It is important to characterize the impact of PrEP on HIV antibody responses in people who experience breakthrough infections to understand the potential impact on timely diagnosis and treatment. Longitudinal HIV-1-specific antibody responses were evaluated in 42 people who inject drugs (PWID) from the Bangkok Tenofovir Study (BTS) (placebo = 28; PrEP = 14) who acquired HIV while receiving PrEP. HIV-1 antibody levels and avidity to three envelope proteins (gp41, gp160, and gp120) were measured in the plasma using a customized Bio-Plex (Bio-Rad Laboratories, Hercules, CA) assay. A time-to-event analysis was performed for each biomarker to compare the distribution of times at which study subjects exceeded the recent/long-term assay threshold, comparing PrEP and placebo treatment groups. We fit mixed-effects models to identify longitudinal differences in antibody levels and avidity between groups. Overall, longitudinal antibody levels and avidity were notably lower in the PrEP breakthrough group compared to the placebo group. Time-to-event analyses demonstrated a difference in time to antibody reactivity between treatment groups for all Bio-Plex biomarkers. Longitudinal gp120 antibody levels within the PrEP breakthrough group were decreased compared to the placebo group. When accounting for PrEP adherence, both gp120 and gp160 antibody levels were lower in the PrEP breakthrough group compared to the placebo group. We demonstrate hindered envelope antibody maturation in PWID who became infected while receiving PrEP in the BTS, which has significant implications for HIV diagnosis. Delayed maturation of the antibody response to HIV may increase the time to detection for antibody-based tests. Clinical Trial Registration Number, NCT00119106.

Benchmarks for HIV Testing: What Is Needed to Achieve Universal Testing Coverage at U.S. Ambulatory Healthcare Facilities.

BACKGROUND: Black and Hispanic men have the highest rates of HIV diagnoses. To decrease the number of U.S. men who are unaware of their HIV status, they should be tested at least once. Our objective was to estimate the increases needed in HIV testing rates at ambulatory health care visits to achieve universal coverage. METHODS: We analyzed nationally representative medical record abstraction data to estimate the number of visits per person to physician offices, emergency departments, and outpatient clinics among men aged 18-39 years during 2009-2016, and the percentage of visits with an HIV test. We calculated the increase in the percentage of visits with an HIV test needed to achieve universal testing coverage of men by age 39 years. RESULTS: Men had a mean of 75.3 million ambulatory visits per year and 1.67 visits per person. An HIV test was performed at 0.9% of the ambulatory visits made by white men, 2.5% by black men, and 2.4% by Hispanic men. A 3-fold increase in the percentage of visits with an HIV test would result in coverage of 46.2% of white, 100% of black, and 100% of Hispanic men; an 11-fold increase would be needed to result in coverage of 100% of white men. CONCLUSIONS: HIV testing rates of men at ambulatory health care visits were too low to provide HIV testing coverage of all men by aged 39 years. A 3-fold increase in the percentage of visits with an HIV test would result in universal testing coverage of black and Hispanic men by age 39 years.

Single oral dose for HIV pre or post-exposure prophylaxis: user desirability and biological efficacy in macaques.

BACKGROUND: Daily oral pre- or post-exposure prophylaxis (PrEP or PEP) is highly effective in preventing HIV infection. However, many people find it challenging to adhere to a daily oral regimen. Chemoprophylaxis with single oral doses of antiretroviral drugs taken before or after sex may better adapt to changing or unanticipated sexual practices and be a desirable alternative to daily PrEP or PEP. We investigated willingness to use a single oral pill before or after sex among men who have sex with men (MSM) and assessed the biological efficacy of a potent antiretroviral combination containing elvitegravir (EVG), emtricitabine (FTC), and tenofovir alafenamide (TAF). METHODS: Data on willingness to use single-dose PrEP or PEP were obtained from the 2017 cycle of the American Men's Internet Survey (AMIS), an annual online behavioral surveillance survey of MSM in the United States. Antiretroviral drug levels were measured in humans and macaques to define drug distribution in rectal tissue and identify clinically relevant doses for macaque modeling studies. The biological efficacy of a single dose of FTC/TAF/EVG as PrEP or PEP was investigated using a repeat-challenge macaque model of rectal HIV infection. FINDINGS: Through pharmacokinetic assessment in humans and macaques we found that EVG penetrates and concentrates in rectal tissues supporting its addition to FTC/TAF to boost and extend chemoprophylactic activity. Efficacy estimates for a single oral dose given to macaques 4h before or 2h after SHIV exposure was 91•7%[35•7%-98•9%] and 100%, respectively, compared to 80•1%[13•9%-95•4%] and 64•6%[-19•4%-89•5%] when single doses were given 6 and 24h post challenge, respectively. A two-dose regimen at 24h and 48h after exposure was also protective [77•1%[1•7%-94•7%]. INTERPRETATION: Informed by user willingness, human and macaque pharmacokinetic data, and preclinical efficacy we show that single-dose prophylaxis before or after sex is a promising HIV prevention strategy. Carefully designed clinical trials are needed to determine if any of these strategies will be effective in humans. FUNDING: Funded by CDC intramural funds, CDC contract HCVJCG2-2016-03948 (to CFK), and a grant from the MAC AIDS Fund and by the National Institutes of Health [P30AI050409] - the Emory Center for AIDS Research (to MZ and TS).

Long-Acting Cabotegravir Protects Macaques Against Repeated Penile Simian-Human Immunodeficiency Virus Exposures.

We used a novel penile simian-human immunodeficiency virus (SHIV) transmission model to investigate whether long-acting cabotegravir (CAB LA) prevents penile SHIV acquisition in macaques. Twenty-two macaques were exposed to SHIV via the foreskin and urethra once weekly for 12 weeks. Of these, 6 received human-equivalent doses of CAB LA, 6 received oral emtricitabine/tenofovir disoproxil fumarate, and 10 were untreated. The efficacy of CAB LA was high (94.4%; 95% confidence interval, 58.2%-99.3%) and similar to that seen with oral emtricitabine/tenofovir disoproxil fumarate (94.0%; 55.1%-99.2%). The high efficacy of CAB LA in the penile transmission model supports extending the clinical advancement of CAB LA preexposure prophylaxis to heterosexual men.

HIV-1 genetic diversity to estimate time of infection and infer adherence to preexposure prophylaxis.

OBJECTIVE: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for preexposure prophylaxis (PrEP) and relate infection with adherence patterns. DESIGN: We used the diversity structure of the virus population at the first HIV RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). METHODS: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10-25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. RESULTS: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median = 47 [IQR = 35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and nonadherence in three. CONCLUSION: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%.