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.

Uptake, Retention, and Adherence to Pre-exposure Prophylaxis (PrEP) in TRIUMPH: A Peer-Led PrEP Demonstration Project for Transgender Communities in Oakland and Sacramento, California.

BACKGROUND: TRIUMPH (Trans Research-Informed communities United in Mobilization for the Prevention of HIV) was a community-led, transgender-specific pre-exposure prophylaxis (PrEP) demonstration project at 2 community-based clinical sites in California. TRIUMPH used peer health education, community mobilization, and clinical integration of PrEP with hormone therapy to promote PrEP knowledge and acceptability. The goal of this study was to evaluate PrEP uptake, retention, and adherence among TRIUMPH participants and examine site-based differences. METHODS: Eligible participants were adult transgender and gender diverse people interested in PrEP. Participants were seen at baseline and at 1, 3, 6, 9, and 12 months for PrEP provision, clinical visits, and HIV testing. PrEP uptake was defined as dispensation of PrEP, PrEP retention was defined as proportion of expected visits completed among those who initiated PrEP, and PrEP adherence was assessed by measuring tenofovir diphosphate concentrations in dried blood spots. Logistic regression models quantified the association of variables with PrEP outcomes. RESULTS: TRIUMPH enrolled 185 participants; the median age was 28 years (interquartile range: 23-35), 7% was Black, and 58% was Latinx. PrEP uptake was as follows: 78% in Oakland and 98% in Sacramento; 91% among trans women, 96% among trans men, and 70% among nonbinary participants. Almost half (47%) rarely/never believed about HIV, and 42% reported condomless sex act in the past 3 months. Participants who reported higher numbers of sex partners were more likely to be retained and adherent; other predictors of adherence included not having a primary partner and not experiencing violence in the past 3 months. CONCLUSIONS: This community-led, trans-specific PrEP demonstration project documents high levels of PrEP initiation in a young transgender and gender diverse cohort at risk of HIV acquisition.

Non-B variants of HIV-1 in San Francisco, California.

The HIV-1 epidemic in the US has historically been dominated by subtype B. HIV subtype diversity has not been extensively examined in most US cities to determine whether non-B variants have become established, as has been observed in many other global regions. We describe the diversity of non-B variants and present evidence of local transmission of non-B HIV in San Francisco. Viral sequences collected from patients between 2000 and 2016 were matched to the San Francisco HIV/AIDS case registry. HIV subtype was determined using COMET. Phylogenies were reconstructed using the pol region of subtypes A, C, D, G, CRF01_AE, CRF02_AG, and CRF07_BC, with reference sequences from the LANL HIV database. Associations of non-B subtypes and circulating recombinant forms (CRFs) with patient characteristics were assessed using multivariable logistic regression. Out of 11,381 sequences, 10,669 were from 7235 registry cases, of which 141 (2%) had non-B subtypes and CRFs and 72 (1%) had unique recombinant forms. CRF01_AE (0.8%) and subtype C (0.5%) were the most prevalent non-B forms. The frequency of non-B subtypes and CRFs increased in San Francisco during years 2000-2016. Out of 146 transmission events involving non-B study sequences, 18% indicated local transmission within the study population and 74% appeared to be inward migration of the virus. Compared to 7016 cases with only subtype B, 141 cases with non-B sequences were more likely to be of non-US country of birth (aOR = 11.02; p < 0.001), of Asian/Pacific-Islander race/ethnicity (aOR = 3.17; p < 0.001), and diagnosed after 2009 (aOR = 4.81; p < 0.001). Results suggest that most non-B infections were likely acquired outside the US and that local transmission of non-B forms has occurred but so far has not produced extensive transmission networks. Thus, non-B variants were not widely established in San Francisco, an observation that differs from cities worldwide with more diverse epidemics.

Human Enough: A Qualitative Study of Client Experience With Internet-Based Access to Pre-exposure Prophylaxis.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is a way to prevent HIV infection using antiretroviral medications. However, common barriers to PrEP engagement include lack of access to prescribers; discomfort seeking sexual health services; and racism, homophobia, and transphobia in medical contexts. Key populations (eg, communities of color, young men who have sex with men, and transgender women) are underrepresented in terms of PrEP uptake in the United States. Nurx is an innovative company that has offered internet-based access to PrEP since 2016. OBJECTIVE: In this study, in partnership with Nurx, we aim to explore clients' experiences of digital PrEP access-including the difference made by the telehealth format-and to understand whether Nurx helped reduce barriers to PrEP. METHODS: Electronic chart review and semistructured interviews were conducted with 31 PrEP requesters from California, Florida, Illinois, and New York. Interviews were recorded, transcribed, and subjected to inductive and deductive thematic analysis. RESULTS: Some interviewees reported initial skepticism about whether a web-based PrEP service could be legitimate or feasible. Despite this, most clients were effusive about their eventual Nurx experience, and many reported that Nurx eased barriers to PrEP access through the availability of knowledgeable, willing prescribers and minimizing embarrassment and discrimination. Our analysis suggests Nurx produced satisfaction by achieving an acceptable balance between 2 client desires: efficiency and humanity. Efficiency encompasses the simplicity, speed, and convenience of obtaining PrEP, both regarding the Nurx process itself and in comparison with in-person encounters. Humanity covers clients' wish for personalized, responsive interaction and a feeling of connection or care. Nurx's messaging platform was crucial to manifesting these qualities and was largely interpreted through the familiar frame of texting. Clients conceived efficiency and humanity as inversely related in a commercial enterprise and varied in the particular balance they felt was optimal. Those who wished for slightly more humanity than the service afforded used the concept of a trade-off to explain why Nurx remained appealing. CONCLUSIONS: Our findings augment evidence that internet-based PrEP provision can broaden access to this HIV prevention strategy. This important finding, notwithstanding a few provisos, merits mention. Telehealth, as practiced by Nurx, was still dependent on culturally competent medical providers as system inputs, and the very technology used to overcome access barriers (ie, the internet) generated new hurdles for some clients. Furthermore, clients did not interpret Nurx in a vacuum: their past experiences and the social and structural context mattered. Finally, only granular inquiry revealed precisely how Nurx satisfied clients whose experiences and preferences fell within a particular range. Extrapolating from this, we urge scholars not to fetishize technological solutions but rather to interrogate the ways in which any intervention's design works for certain kinds of patients.

Use of Drug-level Testing and Single-genome Sequencing to Unravel a Case of Human Immunodeficiency Virus Seroconversion on Pre-exposure Prophylaxis.

Cases of seroconversion on pre-exposure prophylaxis (PrEP) should be carefully investigated, given their public health implications and rarity. We report a case of transmitted drug resistance causing seroconversion on PrEP in spite of high adherence, confirmed with dried blood spot and segmental hair drug-level testing and single-genome sequencing.

Brief Report: Seroadaptive Behaviors Varied Among Geographically Diverse iPrEx Participants.

BACKGROUND: Seroadaptive behaviors refer to a wide range of harm reduction practices to decrease HIV transmission risk. Effective implementation of seroadaptive behaviors is dependent on knowledge of one's own serostatus and that of one's sexual partners. Partner-level and environmental-level attributes may affect seroadaptation practices. We assessed factors associated with seroadaptive behaviors. METHODS: Men who have sex with men and transgender women were recruited from an HIV pre-exposure prophylaxis clinical trial (iPrEx) with study sites in the US, Peru, Ecuador, Brazil, Thailand, and South Africa. Partnership-level data were collected at the baseline visit for the 3 most recent partners. Participants were considered to have practiced seroadaptive behaviors if: (1) they believed their partner to be HIV-negative, that is, serosorting; or (2) no condomless receptive sex occurred with an HIV-positive or unknown status partner, that is, seropositioning. RESULTS: Of 2331 participants, 41% always practiced seroadaptive behaviors, 36% sometimes did, and 23% never did. Participants enrolled at study sites in the US (P < 0.001) and Peru/Ecuador (P < 0.001) were more likely to practice seroadaptive behaviors, whereas transgender women were less likely to do so (P < 0.001). Seroadaptive behaviors were more likely to occur in relationships with steady partners (P = 0.005) and emotionally close relationships (P = 0.013). CONCLUSIONS: Seroadaptive behaviors were more frequently observed among iPrEx participants from the US, Peru, and Ecuador study sites and among participants in relationships with partners who they were more committed to and felt emotionally close to. Our findings suggest that seroadaptive behaviors may be influenced by social norms that vary geographically and culturally.

Sex Hormone Therapy and Tenofovir Diphosphate Concentration in Dried Blood Spots: Primary Results of the Interactions Between Antiretrovirals And Transgender Hormones Study.

BACKGROUND: Sex hormone and preexposure prophylaxis (PrEP) drug interactions among transgender women (TGW), transgender men (TGM), and cisgender men (CGM) are not fully understood. METHODS: TGM and TGW on at least 6 months of stable sex hormone therapy containing testosterone or estradiol (respectively) were enrolled in a 4-week study of directly observed dosing of daily oral coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). TFV-DP in dried blood spots and sex hormones in serum were measured at weekly intervals. TFV-DP was compared with 2- and 4-week samples from Directly Observed Therapy Dried Blood Spots (DOT-DBS) Study (NCT02022657). RESULTS: From May 2017 to June 2018, 24 TGM and 24 TGW were enrolled. Testosterone (total and free) and estradiol concentrations were comparable before and after 4 weeks of PrEP use in TGM and TGW, respectively. Historical controls included 17 cisgender women (CGW) and 15 CGM. TFV-DP concentrations at week 4 were comparable between TGW and TGM (mean difference, -6%; 95% confidence interval [CI], -21% to 12%; P = .47), comparable between TGW and CGM (mean difference, -12%; 95% CI, -27% to 7%; P = .21) and were lower among TGM compared with CGW (mean difference, -23%; 95% CI, -36% to -7%; P = .007). All persons in all groups were projected to reach the TFV-DP threshold that has been associated with high protection from human immunodeficiency virus. CONCLUSIONS: CGM, TGM, and TGW had comparable TFV-DP concentrations in dried blood spots after 4 weeks of directly observed daily FTC/TDF PrEP use. Serum hormone concentrations were not affected by FTC/TDF PrEP use. CLINICAL TRIALS REGISTRATION: NCT04050371.

Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.

BACKGROUND: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. METHODS: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. INTERPRETATION: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. FUNDING: Gilead Sciences.

"A Good Habit": Telehealth PrEP Users Find Benefit in Quarterly Monitoring Requirements.

In the United States, uptake of daily oral pre-exposure prophylaxis (PrEP) to prevent HIV continues to grow albeit at a slower than desired pace. Innovations in PrEP delivery systems may partially address structural challenges related to PrEP uptake and PrEP persistence, such as difficulty in attending clinic visits or completing laboratory testing. To study PrEP services offered by a telehealth company called Nurx, we conducted 31 in-depth interviews with prospective or current patients. We hypothesized that patients would find the quarterly laboratory monitoring requirements to be onerous especially in light of receiving all other aspects of PrEP care through a telehealth delivery system. However, interviewees characterized navigating laboratory systems as relatively easy and complying with the quarterly monitoring as a supplementary benefit of PrEP use. Our research illustrates that quarterly monitoring requirements are meaningful to some telehealth PrEP users and may facilitate persistent engagement in receipt of PrEP care.

Brief Report: High Accuracy of a Real-Time Urine Antibody-Based Tenofovir Point-of-Care Test Compared With Laboratory-Based ELISA in Diverse Populations.

BACKGROUND: Therapeutic drug monitoring measures antiretroviral adherence more accurately than self-report but has not been available at the point-of-care (POC) until now. We compare a novel POC test for urine tenofovir to laboratory-based enzyme-linked immunosorbent assay (ELISA) testing in diverse patient populations urine pre-exposure prophylaxis (PrEP). SETTING: Urine samples were analyzed using ELISA and the POC lateral flow immunoassay (LFA) test from 2 cohorts of PrEP users taking tenofovir disoproxil fumarate/emtricitabine: the Partners PrEP Study, which recruited Kenyan and Ugandan heterosexual men and women, and the IBrEATHe Study, which recruited US transgender women and men using gender-affirming hormone therapy. METHODS: We calculated the sensitivity, specificity, and accuracy of the POC test compared with ELISA at a cutoff of 1500 ng/mL. RESULTS: Overall, 684 urine samples were tested from 324 participants in the 2 cohorts. In Partners PrEP, 454 samples from 278 participants (41% women) were tested with a median age of 33 years. In IBrEATHe, 231 samples from 46 individuals (50% transwomen) were tested with a median age of 31 years. Comparison of the LFA read-out to ELISA yielded 100% sensitivity [97.5% one-sided confidence interval (CI) = 99.3%], 98.3% specificity (95% CI = 95.2% to 99.7%), and 99.6% accuracy (95% CI = 98.7% to 99.9%). CONCLUSION: The sensitivity, specificity, and accuracy of a novel POC test for urine tenofovir all exceeded 98% when compared with a laboratory-based ELISA method when tested in diverse patient populations. Given the LFA's high accuracy and expected low cost, this POC test is a promising tool to support antiretroviral adherence that could be widely scalable to real-world clinical settings.

Community pharmacy delivered PrEP to STOP HIV transmission: An opportunity NOT to miss!

In the United States, 1.1 million persons are living with human immunodeficiency virus (HIV), and approximately 37,800 new infections occur annually. Ending the HIV epidemic requires reducing HIV transmissions by 90% within the next 10 years and requires expanded HIV testing, antivirals for persons infected with HIV, and scale-up of pre-exposure prophylaxis (PrEP) and postexposure prophylaxis (PEP) to prevent new infections. Community pharmacies are widely accessible and employ highly trained health care professionals on-site who can initiate PrEP and PEP. Recommendations are offered to implement a community pharmacy PrEP program. Pharmacy, government, and HIV prevention leaders must be prepared to support and promote transformative changes, including (1) modification or expansion of existing state-specific scope of practice to initiate PrEP and PEP, (2) encouraging pharmacist education about PrEP and PEP, (3) identification and screening of candidates for PrEP eligibility, (4) incorporating pharmacy laboratory ordering and monitoring logistics, (5) adjusting workflow and ensuring confidential spaces for sensitive discussions, and (6) addressing reimbursement to maintain pharmacist-delivered PrEP and PEP programs. HIV disproportionately affects minority communities and younger individuals who may not be engaged in the health care system. Community pharmacies are accessible and can help increase PrEP use. Expansion of community pharmacy PrEP programs are needed to help end the HIV epidemic. Implementation of PrEP requires adaptation of the pharmacy profession to support incorporation of PrEP in a community pharmacy. Endorsement and support of community pharmacists are needed to implement PrEP to increase HIV prevention efforts and expand pharmacists' scope of practice.

The Effect of Depression on Adherence to HIV Pre-exposure Prophylaxis Among High-Risk South African Women in HPTN 067/ADAPT.

Oral pre-exposure prophylaxis (PrEP) is highly efficacious but low adherence undermines effectiveness. Depression, common in African women, may be a barrier to consistent PrEP use. We aimed to assess the relationship between depression, psychosocial mediators, and PrEP adherence among South African women. We analyzed data from 174 South African women in HPTN 067, an open-label oral PrEP trial conducted from 2011 to 2013. Participants were followed for 24 weeks. PrEP adherence was measured via Wisepill™ and weekly self-report interview data. We considered participants "adherent" at week 24 if Wisepill™ and interviews indicated that ≥ 80% of expected doses were taken in the prior month. Elevated depressive symptoms were assessed using the 20-item Center for Epidemiological Studies-Depression (CES-D) scale. We used marginal structural models to estimate the effect of elevated symptoms at baseline on PrEP adherence at week 24 and to assess whether the direct effect changed meaningfully after accounting for mediating effects of stigma, social support, and PrEP optimism. High PrEP adherence occurred less often among women with elevated depressive symptoms (N = 35; 44.3%) compared with those without (N = 52; 54.7%; adjusted relative risk [aRR]: 0.79; 95% confidence interval [CI] 0.63-0.99). The effect of elevated depressive symptoms on PrEP adherence persisted in models accounting for the mediating influence of stigma (aRR: 0.74; 95% CI 0.51-0.97) and PrEP optimism (aRR: 0.75; 95% CI 0.55-0.99). We also found a direct effect of similar magnitude and direction when accounting for social support as the mediating variable, although this adjusted relative risk estimate was not statistically significant (aRR: 0.77; 95% CI 0.57-1.03). Depressive symptoms were common and associated with lower PrEP adherence among South African women. Future work is needed to determine whether depression services integrated with PrEP delivery could improve PrEP effectiveness among African women.

Facilitators and barriers affecting PrEP adherence among Thai men who have sex with men (MSM) in the HPTN 067/ADAPT Study.

The HPTN 067/ADAPT Study evaluated the feasibility, acceptability, patterns of adherence and coverage for three randomly assigned oral FTC/TDF pre-exposure prophylaxis (PrEP) dosing regimens to prevent HIV infection. Using qualitative methods, we explored facilitators and barriers among a subset of men who have sex with men (MSM) participants in Bangkok, Thailand. Between August 2013 and March 2014, 32 HPTN 067/ADAPT participants joined in 6 focus group discussions, and 6 attended key informant interviews. Facilitators of PrEP adherence included use of strategies to have PrEP available when needed, simplicity in regimen requirements with recognition that more complex regimens may take some time to master, ability to plan for sex, receipt of social and technology support, ability to use a PrEP regimen that best matches to one's own patterns of sex, and experiences with PrEP as a part of health and well-being. Challenges to PrEP adherence included perceptions of no or low HIV risk, difficulties following regimens when intoxicated, concerns about side effects, experience of HIV stigma, and affordability of PrEP outside of study context influencing uptake and use in the community. Preferences for regimens varied, suggesting that multiple PrEP effective regimen options should be available to fit those with different needs.

Predicted Effectiveness of Daily and Nondaily Preexposure Prophylaxis for Men Who Have Sex With Men Based on Sex and Pill-taking Patterns From the Human Immuno Virus Prevention Trials Network 067/ADAPT Study.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 067/Alternative Dosing to Augment PrEP Pill Taking (ADAPT) Study evaluated the feasibility of daily and nondaily human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens. METHODS: An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the preexposure prophylaxis initiative (iPrEx) trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use. RESULTS: We estimated that PrEP was highly protective (85%-96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%-88% efficacy) than in Harlem (62%-81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85%, and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8-9 percentage points in Harlem and by 5-9 percentage points in Bangkok across regimens. CONCLUSIONS: Our analysis suggests that PrEP was more effective among MSM in Thailand than in the United States as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, nondaily PrEP was less effective than daily PrEP, especially in the United States where the sex act coverage associated with daily use was substantially higher.

HIV preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health.

OBJECTIVE: To evaluate the effects of HIV preexposure prophylaxis (PrEP) with tenofovir disoproxial fumurate (TDF)/emtricitabine (FTC) on kidney function and kidney tubular health. DESIGN: The Iniciativa Profilaxis Pre-Exposicion open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. This study included 123 iPrEx-OLE participants who demonstrated PrEP adherence. METHODS: We compared estimated glomerular filtration rate calculated using serum creatinine (eGFRcr), serum cystatin C (eGFRcys), and in combination (eGFRcr-cys), and a panel of 14 urine biomarkers reflecting kidney tubular health before and 6 months after PrEP initiation. RESULTS: At baseline, mean eGFRcr, eGFRcys, and eGFRcr-cys were 108.3, 107.0, and 111.1 ml/min per 1.73 m, respectively. Six months after PrEP initiation, eGFRcr declined by -4% (95% CI: -5.7 to -2.4%), eGFRcys declined by -3.3% (95% CI: -8.3 to 1.9%), and eGFRcr-cys declined by -4.1% (95% CI: -7.5 to -0.7%). From the urine biomarker panel, α1-microglobulin and ß2-microglobulin increased by 22.7% (95% CI: 11.8--34.7%) and 14.1% (95% CI: -6.1 to 38.6%), whereas chitinase-3-like 1 protein and monocyte chemoattractant protein-1 decreased by -37.7% (95% CI: -53.0 to -17.3%) and -15.6% (95% CI: -31.6 to 4.2%), respectively. Ten of the 14 urine biomarkers, including albumin, had estimated changes of less than 12% with wide confidence intervals. CONCLUSION: Six months of PrEP with TDF/FTC was associated with decreases in eGFRcr and eGFRcys. We also observed for the first time changes in flour of 14 urine biomarkers reflecting kidney tubular health. These findings demonstrate that PrEP has direct effects on eGFR and the proximal tubule.

HPTN 067/ADAPT: Correlates of Sex-Related Pre-exposure Prophylaxis Adherence, Thai Men Who Have Sex With Men, and Transgender Women, 2012-2013.

BACKGROUND: We identified correlates of sex-related pre-exposure prophylaxis (PrEP) adherence in HPTN067/ADAPT, a phase 2, open-label feasibility study of daily and nondaily regimens of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)-based PrEP, among Thai men who have sex with men (MSM), and transgender women (TGW), Bangkok. METHODS: Participants were randomly assigned to one of three self-administered dosing regimens for 24 weeks: daily, time-driven, or event-driven. Demographic and behavioral information was obtained at screening. Pill-container opening was recorded with electronic dose monitoring, and self-reported information on PrEP use, sex events, and substance use was obtained during weekly interviews to confirm dose data. Sex-related PrEP adherence was calculated as the proportion of sex events covered by PrEP use (at least one tablet taken within 4 days before sex and at least one tablet taken within 24 hours after sex) to total sex events. We used multivariate modeling with sex event as the unit of analysis to evaluate correlates associated with sex-related PrEP adherence. RESULTS: Among 178 MSM and TGW, sex-related PrEP adherence was similar in the daily and time-driven arms (P = 0.79), both significantly greater than the event-driven arm (P = 0.02 compared to daily). Sex-related PrEP adherence by those reporting stimulant use (74.2%) was similar to those reporting other nonalcohol drug use (76.3%, P = 0.80), but lower than those reporting no substance use (84.6%, P = 0.04). In a multivariable model, randomization to the event-driven arm, a higher prestudy number of reported sex events, and use of stimulant drugs were associated with significantly lower sex-related PrEP adherence. CONCLUSION: Adherence was influenced by treatment schedule and adversely affected by nonalcoholic substance use. Regardless of these factors, Thai MSM and TGW maintained high adherence levels to oral PrEP dosing regimens and coverage of sexual exposures.

Short- and Long-Term Pharmacologic Measures of HIV Pre-exposure Prophylaxis Use Among High-Risk Men Who Have Sex With Men in HPTN 067/ADAPT.

BACKGROUND: The effectiveness of oral emtricitabine (FTC)/tenofovir (TFV) disoproxil fumarate-based HIV pre-exposure prophylaxis (PrEP) depends on adherence. Pharmacologic measures help interpret patterns and predictors of PrEP adherence. SETTING: We analyzed data from the subsample of men who have sex with men enrolled in HPTN 067/ADAPT in Bangkok, Thailand, and Harlem, NY, U.S. METHODS: After a 5-week directly observed therapy period, participants were randomized to daily, time-driven, or event-driven PrEP. Follow-up occurred at weeks 4, 12, and 24 after randomization. Plasma and hair FTC/TFV levels indicated short- and long-term PrEP use, respectively. Electronic pill bottle data (Wisepill) were collected weekly. Pearson correlation coefficients between PrEP use measures were calculated; linear mixed models assessed predictors of plasma and hair drug concentrations. RESULTS: Among 350 participants (median age: 31 years, interquartile range: 25-38), 49.7% were from Harlem, half had less than college education, and 21% reported heavy alcohol use. In multivariable models, being enrolled in Harlem, being in non-daily arms, and having less than college education were associated with lower hair FTC/TFV concentrations; heavy alcohol use was associated with higher concentrations. Similar results were found for plasma concentrations by site and arm, but older age and greater number of sex partners were associated with higher concentrations. Hair and plasma FTC/TFV concentrations were moderately correlated with Wisepill data (r ≥ 0.29) across visits. CONCLUSIONS: In HPTN067, plasma, hair, and Wisepill data correlated with one another and served as complementary adherence measures. Site, arm, education, age, alcohol, and sexual behavior influenced patterns of adherence.

Low Disclosure of PrEP Nonadherence and HIV-Risk Behaviors Associated With Poor HIV PrEP Adherence in the HPTN 067/ADAPT Study.

OBJECTIVE: We evaluated the relationship between 2 types of social relationships, ie, (1) external support for use of HIV pre-exposure prophylaxis (PrEP) and related study supplies and (2) participants' disclosure of PrEP use and condom use and HIV PrEP adherence among daily-dosing regimen participants in HIV Prevention Trials Network (HPTN) 067, an open-label trial of oral tenofovir (TFV) disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg. METHODS: Using HPTN 067 survey data, we developed scales examining (1) Low Perceived External Support for PrEP: low perceived support by others for PrEP use or perceived negative reactions to the pill case (scoring ranges from 0 to 2) and (2) Participant-Staff Disclosure Challenges Scale, which identifies challenges to sharing nonuse of PrEP or condoms to study staff (scoring ranges from 0 to 4); these scales are the primary independent variables. Adherence, the dependent variable, was determined using log-transformed plasma TFV concentrations. generalized estimating equation (GEE) linear regression was used to assess the association between both scales and adherence. RESULTS: Participants (n = 161) included HIV-uninfected women in South Africa, and men who have sex with men and transgender women, in Thailand and the United States. In multivariable analyses, higher scores in the Participant-Staff Disclosure Challenges Scale were significantly associated with lower PrEP adherence [exp(ß) = 0.62, 95% CI: (0.46 to 0.84); P = 0.002] as were increased days since the last PrEP dose [exp(ß) = 0.73, 95% CI: (0.65 to 0.83); P ≤ 0.001]. CONCLUSIONS: Given the association with adherence, study staff-participant interactions and participants' disclosure of PrEP challenges may be worthwhile intervention targets for improving PrEP adherence in confirmatory studies.