Pharmacology of boosted and unboosted integrase strand transfer inhibitors for two-dose event-driven HIV prevention regimens among men.

BACKGROUND: Event-driven HIV prevention strategies are a priority for users who do not require daily pre-exposure prophylaxis (PrEP). Regimens containing integrase strand transfer inhibitors (INSTIs) are under evaluation as alternatives to daily PrEP. To better understand INSTI distribution and inform dosing selection we compared the pharmacology of two-dose boosted elvitegravir and unboosted bictegravir regimens in MSM. MATERIALS AND METHODS: Blood, rectal and penile secretions and rectal biopsies were collected from 63 HIV-negative MSM aged 18-49 years. Specimens were collected up to 96 h after two oral doses of tenofovir alafenamide and emtricitabine with elvitegravir boosted by cobicistat or unboosted bictegravir given 24 h apart. Antiretroviral drugs were measured by LC-MS. RESULTS: Mean bictegravir plasma concentrations remained above the 95% protein-adjusted effective concentration 96 h after dosing [273 (95% CI: 164-456) ng/mL] whereas elvitegravir plasma concentrations became undetectable 48 h after the second dose. Bictegravir and elvitegravir reached rectal tissues within 2 h after the first dose, and elvitegravir tissue concentrations [1.07 (0.38-13.51) ng/mg] were greater than bictegravir concentrations [0.27 (0.15-0.70) ng/mg]. Both INSTIs became undetectable in tissues within 96 h. Elvitegravir and bictegravir were not consistently detected in penile secretions. CONCLUSIONS: Whereas bictegravir plasma concentrations persist at least 4 days after a two-oral-dose HIV prophylaxis regimen, elvitegravir accumulates in mucosal tissues. Differing elvitegravir and bictegravir distribution may result in variable mucosal and systemic antiviral activity and can inform dosing strategies for event-driven HIV prevention.

Antiretroviral drug exposure in urethral and glans surface sampling of the penis.

BACKGROUND: HIV exposure to penile tissues provides a risk of acquisition among men, yet studies evaluating penile antiretroviral (ARV) drug distribution have been lacking. We measured ARVs on urethral and glans surface swabs collected following a dose of tenofovir alafenamide, emtricitabine, elvitegravir, darunavir and cobicistat. METHODS: Thirty-five HIV-negative male participants provided urethral swabs, glans swabs, rectal swabs, blood and urine up to 96 h following a single dose of tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat and darunavir. ARVs were measured by liquid chromatography-mass spectrometry with a lower limit of detection (LOD) of 1 ng/swab for swabs and 10 ng/mL for plasma and urine. Concentrations are reported as median and range. RESULTS: Urethral swab emtricitabine and darunavir concentrations peaked at 4 h for emtricitabine (36 ng/swab; 3-307 ng/swab) and 8 h for darunavir (25 ng/swab; 2-52 ng/swab). Glans swab emtricitabine and darunavir concentrations peaked 24 h after dosing (emtricitabine 14 ng/swab,

Randomised controlled trial of a sexual risk reduction intervention for STI prevention among men who have sex with men in the USA.

OBJECTIVES: Novel interventions to address sexual risk taking and slow rates of STIs are urgently needed, in particular among black men who have sex with men (MSM) in the USA. Serosorting, or limiting condomless sex acts to partners of the same HIV status, is commonly practised among MSM, yet can lead to STI and remains largely unaddressed by public health agencies. METHODS: A two-arm, randomised controlled trial was conducted from 2012 to 2015. This trial assessed the effects of a single-session, sexual partner selection and risk decision intervention (experimental arm) versus a single-session, Centers for Disease Control and Prevention-based, sexual risk reduction intervention (control arm) on psychosocial measures, sexual risk taking and STI. RESULTS: At study follow-ups, multiple beneficial changes were observed on sexual risk beliefs measures (ie, changes in serosorting and condom use beliefs, and HIV risk perceptions) and sexual risk taking among the experimental arm relative to the control arm. Overall main effects, however, of the intervention on STI outcomes on year-long follow-ups were non-significant. There was evidence for short-term effects on STI outcomes, and self-report of multiple STIs and STI symptoms demonstrated positive effects over the follow-up period. CONCLUSIONS: Brief interventions to address sexual risk taking can result in short-term beneficial outcomes and can be incorporated into currently existing infrastructure at healthcare agencies. Additional intervention will be necessary for demonstrating long-term results. TRIAL REGISTRATION NUMBER: NCT02128594.

The Daily Relationship Between Aspects of Food Insecurity and Medication Adherence Among People Living with HIV with Recent Experiences of Hunger.

BACKGROUND: Limited access to resources can significantly impact health behaviors. Previous research on food insecurity and HIV has focused on establishing the relationship between lacking access to nutritious food and antiretroviral (ARV) medication non-adherence in a variety of social contexts. PURPOSE: This study aims to determine if several aspects of food insecurity co-occur with missed doses of medication on a daily basis among a sample of people living with HIV who have recently experienced hunger. METHODS: The current study utilized a prospective, observational design to test the daily relationship between food insecurity and medication non-adherence. Participants were followed for 45 days and completed daily assessments of food insecurity and alcohol use via interactive text message surveys and electronic medication adherence monitoring using the Wisepill. RESULTS: Fifty-nine men and women living with HIV contributed a total of 2,655 days of data. Results showed that severe food insecurity (i.e., hunger), but not less severe food insecurity (i.e., worrying about having food), significantly predicted missed doses of medication on a daily level. Daily alcohol use moderated this relationship in an unexpected way; when individuals were hungry and drank alcohol on a given day, they were less likely to miss a dose of medication. CONCLUSIONS: Among people living with HIV with recent experiences of hunger, this study demonstrates that there is a daily relationship between hunger and non-adherence to antiretroviral therapy. Future research is needed to test interventions designed to directly address the daily relationship between food insecurity and medication non-adherence.

The role of stigma and medical mistrust in the routine health care engagement of black men who have sex with men.

UNLABELLED: Objectives: We assessed how health care-related stigma, global medical mistrust, and personal trust in one's health care provider relate to engaging in medical care among Black men who have sex with men (MSM). METHODS: In 2012, we surveyed 544 Black MSM attending a community event. We completed generalized linear modeling and mediation analyses in 2013. RESULTS: Twenty-nine percent of participants reported experiencing racial and sexual orientation stigma from heath care providers and 48% reported mistrust of medical establishments. We found that, among HIV-negative Black MSM, those who experienced greater stigma and global medical mistrust had longer gaps in time since their last medical exam. Furthermore, global medical mistrust mediated the relationship between stigma and engagement in care. Among HIV-positive Black MSM, experiencing stigma from health care providers was associated with longer gaps in time since last HIV care appointment. CONCLUSIONS: Interventions focusing on health care settings that support the development of greater awareness of stigma and mistrust are urgently needed. Failure to address psychosocial deterrents will stymie progress in biomedical prevention and cripple the ability to implement effective prevention and treatment strategies.

Black men who have sex with men, sexual risk-taking, and willingness to use rapid home HIV tests.

The availability of rapid home-based HIV testing (RHT) in the USA has provided us with a valuable, new option in our efforts to identify more people living with HIV and to do so sooner. Furthermore, it is possible that RHT will be or is currently being used as a means of learning one's own and one's partner's HIV status prior to engaging in condomless intercourse. Data regarding knowledge and willingness to use RHT, however, is very limited. In particular, no studies have investigated RHT use among Black men who have sex with men (BMSM). Understanding RHT use among BMSM is critical as we have observed alarming rates of HIV prevalence among this group, and RHT may provide an opportunity to slow HIV transmission among BMSM. In order to better understand RHT, we assessed knowledge, willingness to use and actual use of RHT, HIV testing history, substance use, and sexual risk-taking among 387 HIV-negative BMSM and 157 HIV-positive BMSM attending a community event in the southeastern USA. We used generalized linear modeling to assess factors associated with their willingness to use RHT. Although familiarity with the availability of RHT was somewhat limited among these men, a substantial portion of BMSM did report an interest in using RHT, including with their sex partners. Among HIV-negative BMSM, however, we found a negative relationship between willingness to use RHT and sexual risk-taking, i.e., higher numbers of condomless anal sex acts were associated with a reduction in willingness to use RHT. It appears that men who report the greatest risk-taking for HIV are least interested in RHT. Future research should focus on better understanding concerns regarding RHT among at-risk HIV-negative men and should investigate the usefulness of using RHT as a HIV prevention method.

Pharmacokinetics of single dose doxycycline in the rectum, vagina, and urethra: implications for prevention of bacterial sexually transmitted infections.

BACKGROUND: Clinical trials showed a single oral dose of doxycycline taken after sex protects against STIs among men who have sex with men (MSM) but not women. Pharmacokinetic data at vaginal, rectal and penile sites of STI exposure are lacking. We examined vaginal, rectal and urethral doxycycline concentrations in men and women to better inform STI prevention. METHODS: Doxycycline pharmacokinetics in male and female participants 18-59 years of age were evaluated in blood and urine and on rectal and vaginal swabs collected at 1, 2, 4, 8, 24, 48, 72, 96 and 168 h after receiving a 200 mg oral doxycycline dose in a non-randomised single dose open label single centre study in Atlanta, Georgia. Rectal, vaginal, and cervical biopsies and male urethral swabs were collected 24 h after dosing (Trial registration: NCT04860505). Doxycycline was measured by liquid chromatography-mass spectrometry. FINDINGS: Eleven male and nine female participants participated in the study. Doxycycline concentrations on rectal and vaginal swabs collected up to 96 h after dosing were approximately twice those of plasma and remained above minimum inhibitory concentrations (MICs) for at least four, three, and two days for Chlamydia trachomatis, Treponema pallidum, and tetracycline-sensitive Neisseria gonorrhoeae, respectively. Geometric mean doxycycline concentrations in male urethral secretions (1.166 µg/mL; 95% CI 0.568-2.394 µg/mL), male rectal (0.596 µg/g; 0.442-0.803 µg/g), vaginal (0.261 µg/g; 0.098-0.696 µg/g) and cervical tissue (0.410 µg/g; 0.193-0.870 µg/g) in biopsies collected 24 h after dosing exceeded MICs. Plasma and urine doxycycline levels defined adherence markers up to four and seven days postdosing, respectively. No adverse events were reported in this study. INTERPRETATION: Doxycycline efficiently distributes to the rectum, vagina and urethra. Findings can help explain efficacy of STI prevention by doxycycline. FUNDING: Funded by CDC intramural funds, CDC contract HCVJCG-2020-45044 (to CFK).

Short Communication: Evaluation of Antiretroviral Drug Concentrations in Minimally Invasive Specimens for Potential Development of Point-of-Care Drug Assays.

Point-of-care (POC) tests for antiretroviral drugs (ARVs) could help improve individual adherence. This study sought to define the utility of urine, blood, and buccal swabs as minimally invasive specimens amenable to development of POC tests for ARVs. Urine, dried blood spots (DBS) and buccal swabs were collected from 35 HIV-negative men between 2 and 96 h after a single dose of tenofovir (TFV) alafenamide/emtricitabine (FTC)/elvitegravir (EVG)/cobicistat and darunavir (DRV). ARV concentrations were measured by high-performance liquid chromatography-mass spectrometry. High concentrations of FTC, DRV, and TFV were detectable in urine at least 24 h after dosing. FTC, DRV, and EVG remained detectable in DBS at least 24 h postdose. FTC and DRV were detectable on buccal swabs up to 2 and 24 h postdose, respectively. TFV was not detectable in DBS or buccal swabs collected between 2 and 96 h after dosing. Variable distribution of ARVs in minimally invasive specimens highlights the challenge of developing POC assays for recent ARV exposure.

Brief Report: Urine Emtricitabine and Tenofovir Concentrations Provide Markers of Recent Antiretroviral Drug Exposure Among HIV-Negative Men Who Have Sex With Men.

BACKGROUND: Urine provides a minimally invasive specimen that may allow for development of rapid tests to detect antiretroviral drugs and provide opportunities to improve individual adherence. This study sought to determine whether urine could provide a biomarker of adherence for currently approved pre-exposure prophylaxis and HIV treatment regimens. METHODS: Urine and blood were collected from 34 HIV-negative men who have sex with men aged 18-49 years, enrolled in a clinical trial comparing 2 antiretroviral regimens. Specimens were collected 4 and 24 hours after a single oral dose of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (n = 10) or tenofovir alafenamide (TAF)/FTC/cobicistat (COBI)/elvitegravir (EVG) (n = 8), or after 4 and 10 days of daily oral TDF/FTC (n = 9) or TAF/FTC/COBI/EVG (n = 7). Tenofovir (TFV), FTC, and EVG were measured by high-performance liquid chromatography-mass spectrometry. RESULTS: Median urine FTC concentrations at 4 and 24 hours were similar between men receiving TDF/FTC (4 hours 147 µg/mL; 24 hours 10 µg/mL) and men receiving TAF/FTC/COBI/EVG (4 hours 333 µg/mL, P = 0.173; 24 hours 13 µg/mL, P = 0.681). Median urine TFV concentrations were lower among men receiving TAF/FTC/COBI/EVG (4 hours 1.2 µg/mL; 24 hours 0.8 µg/mL) compared with men receiving TDF/FTC (4 hours 17 µg/mL, P < 0.001; 24 hours 7 µg/mL, P = 0.001). Urine TFV concentrations remained reduced among men receiving TAF/FTC/COBI/EVG compared with men receiving TDF/FTC after daily dosing. EVG was not consistently measurable in urine. CONCLUSIONS: High urine FTC and TFV concentrations could provide an indication of adherence to daily oral dosing with TDF or TAF-based regimens used for treatment and prevention.

Minimal Awareness and Stalled Uptake of Pre-Exposure Prophylaxis (PrEP) Among at Risk, HIV-Negative, Black Men Who Have Sex with Men.

In the United States, rates of HIV infection are highest among black men who have sex with men (BMSM). Pre-exposure prophylaxis (PrEP) is a highly effective form of HIV prevention, but the uptake of this strategy has been slow since FDA approval in 2012, and it is unknown whether information about PrEP is reaching BMSM. Four hundred and thirty-six BMSM in Atlanta, GA were surveyed from January 2012 (6 months prior to PrEP approval) to March 2014 (20 months after approval). Analyses revealed no association between date of survey assessment and awareness of PrEP (20.5% were aware of PrEP before approval and 23.4% were aware after approval; OR=0.99 [0.98-1.02], p=0.952). In a multivariate model, BMSM unaware of PrEP reported lower rates of HIV testing knowledge, fewer experiences with HIV testing, and higher rates of transactional sex than BMSM who were aware of PrEP. Our findings suggest that there is limited understanding of PrEP and that there is considerable groundwork that needs to be achieved in order to reap the full benefits of PrEP. The current findings call attention to the need to both prioritize and better understand how to strengthen the bridge between medical advances and community uptake.

Psychosocial factors related to willingness to use pre-exposure prophylaxis for HIV prevention among Black men who have sex with men attending a community event.

UNLABELLED: Objectives In the US, Black men who have sex with men (BMSM) are disproportionately affected by HIV/AIDS. Pre-exposure prophylaxis (PrEP) holds tremendous promise for curbing the HIV/AIDS epidemic among these men. However, many psychosocial components must be addressed in order to implement this prevention tool effectively among BMSM. METHODS: We assessed PrEP knowledge and use, health care access experiences, race-based medical mistrust, sexual partners and behaviours, and drug and alcohol use among 699 men attending a community event in the south-eastern United States. We used generalised linear modelling to assess factors associated with their willingness to use PrEP. RESULTS: Three hundred and ninety-eight men reported being BMSM and having HIV-negative status. Among these men, 60% reported being willing to use PrEP. Lack of being comfortable with talking to a health care provider about having sex with men, not having discussed having sex with a man with a health care provider, race-based medical mistrust, and alcohol consumption and substance use were all identified as barriers to willingness to use PrEP. Sexual risk-taking, number of sex partners and STI diagnosis were not associated with willingness to use PrEP. CONCLUSIONS: Findings from the current paper demonstrate the importance of acknowledging the role of various psychosocial factors in the uptake of PrEP. It is imperative that we prioritise research into understanding these barriers better, as the failure to do so will impede the tremendous potential of this prevention technology.