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1.  Potential Interventions to Support Adherence to HIV Preexposure Prophylaxis (PrEP): A Systematic Review 
HIV medicine  2014;15(7):385-395.
Objectives
Adherence is critical for maximizing the effectiveness of preexposure prophylaxis (PrEP) in preventing HIV infection. Strategies for promoting adherence to HIV treatment, and their potential application to PrEP adherence, have received considerable attention. However, adherence promotion strategies for prevention medications have not been well characterized and may be more applicable to PrEP. We aimed to identify adherence support interventions that have been effective in other prevention fields and could be applied in the HIV prevention context to support pill taking among PrEP users.
Methods
To identify adherence support interventions that could be evaluated and applied in the PrEP context, we conducted a systematic review across the following prevention fields: hypertension, latent tuberculosis infection, hyperlipidemia, oral contraceptives, osteoporosis, malaria prophylaxis, and post-exposure prophylaxis for HIV infection. We included randomized controlled trials that evaluated the efficacy of interventions to improve adherence to daily oral medications prescribed for primary prevention in healthy individuals or for secondary prevention in asymptomatic individuals.
Results
Our searches identified 585 studies, of which 48 studies met the eligibility criteria and were included in the review; nine evaluated multiple strategies, yielding 64 separately tested interventions. Interventions with the strongest evidence for improving adherence included complex, resource-intensive interventions, which combined multiple adherence support approaches, and low-cost, low-intensity interventions that provided education or telephone calls for adherence support.
Conclusions
Our review identified adherence interventions with strong evidence of efficacy across prevention fields and provides recommendations for evaluating these interventions in upcoming PrEP studies.
doi:10.1111/hiv.12132
PMCID: PMC4107052  PMID: 24580813
medication adherence; preventive therapy; preexposure prophylaxis (PrEP); antiretroviral medications; human immunodeficiency virus (HIV); review
2.  Antiretroviral pre-exposure prophylaxis implementation in the United States: a work in progress 
Journal of the International AIDS Society  2015;18(4Suppl 3):19980.
Introduction
After the initial approval of the use of tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) by the US Food and Drug Administration in 2012 for anti-HIV pre-exposure prophylaxis (PrEP), uptake was initially limited, but more recent community surveys and expert opinion suggest wider acceptance in some key populations.
Discussion
Demonstration projects are underway to determine the best practices in the United States to identify at-risk individuals in primary care and sexually transmitted disease clinics who could benefit from PrEP. Studies of PrEP in combination with behavioural interventions are being evaluated. Studies to evaluate the use of PrEP by HIV-uninfected women in HIV-discordant couples interested in safe conception are also getting underway. The optimal deployment of PrEP as part of a comprehensive national HIV/AIDS strategy in the United States has been limited by lack of knowledge among some at-risk people and by some medical providers indicating that they do not feel sufficiently knowledgeable and comfortable in prescribing PrEP. Studies are underway to determine how to assist busy clinicians to determine which of their patients could benefit from PrEP. Although most federal health insurance programmes will cover most of the costs associated with PrEP, underinsured patients in states that have not enacted health reform face additional challenges in paying for PrEP medication and appropriate clinical monitoring.
Conclusions
PrEP implementation in the United States is a work in progress, with increasing awareness and uptake among some individuals in key populations.
doi:10.7448/IAS.18.4.19980
PMCID: PMC4509893  PMID: 26198345
PrEP; pre-exposure prophylaxis; tenofovir-emtricitabine
4.  Knowledge, Indications and Willingness to Take Pre-Exposure Prophylaxis among Transwomen in San Francisco, 2013 
PLoS ONE  2015;10(6):e0128971.
Safe and effective HIV prevention strategies are needed for transwomen. Transwomen in the US have a 34 times greater odds of being infected with HIV than all adults age 15-49, and in San Francisco, California 42.4% of transwomen are estimated to be infected with HIV. Pre-exposure prophylaxis (PrEP) is the first biomedical intervention with promise for reducing HIV acquisition in transwomen. However, little is known about whether transwomen know about PrEP, are taking PrEP and would be good candidates for PrEP based on their risk profile and behaviors. A population-based dataset was analyzed to determine how many transwomen in San Francisco knew about PrEP by the end of 2013 – more than a year after iPrex results demonstrated efficacy of PrEP in preventing HIV. We found that of 233 transwomen, only 13.7% had heard of PrEP. Transwomen who were living with HIV compared to those who were HIV-negative, and those who recently injected drugs compared to non-injection drug users were more likely to have heard of PrEP. Based on CDC guidelines for PrEP among MSM and IDU, 45 (30.2%) transwomen of the 149 HIV-negative transwomen in the sample were candidates for PrEP. This estimate based on CDC criteria is arguably low. Given that almost half of transwomen in San Francisco are living with HIV, this findings points to a need for further consideration of PrEP criteria that are specific and tailored to the risks for HIV faced by transwomen that are different from MSM and injection drug users. Research to scale up access and test the effectiveness of PrEP for transwomen is also urgently needed.
doi:10.1371/journal.pone.0128971
PMCID: PMC4454556  PMID: 26039511
5.  Who should be offered HIV pre-exposure prophylaxis (PrEP)?: A secondary analysis of a Phase 3 PrEP efficacy trial in men who have sex with men and transgender women 
The Lancet infectious diseases  2014;14(6):468-475.
Background
Pre-exposure prophylaxis (PrEP) has been proven to reduce HIV acquisition in men who have sex with men and transgender women (MSM/TGW). For maximal impact, PrEP should be targeted to subpopulations accounting for the largest proportion of infections (population attributable fraction, PAF) and for whom the number needed to treat (NNT) to prevent infection is lowest.
Methods
The iPrEx study was a randomized controlled efficacy trial of tenofovir-disoproxil-fumarate/emtricitabine PrEP in 2499 MSM/TGW on 4 continents. We calculated the association between demographic and risk behavior during screening with subsequent seroconversion among placebo recipients using a Poisson model, and the PAF and NNT for risk behavior subgroups.
Findings
Of 1248 placebo participants enrolled, 83 became HIV infected in follow-up. Participants reporting non-condom receptive anal intercourse (ncRAI) seroconverted significantly more often than MSM/TGW reporting no condomless anal sex (adjusted hazard ratio (AHR) 5·11, 95% CI 1·55-16·79). The overall PAF for MSM/TGW reporting ncRAI was 64% (prevalence=60%). Most of this risk came from ncRAI with unknown serostatus partners (PAF 53%, prevalence=54%, AHR 4·76); in contrast, the PAF for ncRAI with an HIV positive partner, an uncommon practice, was only 1% (prevalence 1%, AHR=7·11). The overall NNT per year for the cohort was 62 (95% CI 44-147). NNTs were lower for MSM/TGW self-reporting ncRAI, cocaine use, or a sexually transmitted infection (NNT= 36, 12, and 41 respectively). Having a single partner or non-condom insertive anal sex had the highest NNTs.
Interpretation
PrEP may be most effective at a population level if targeted toward MSM/TGW reporting ncRAI, even with partners perceived to be HIV negative. Substance use history and testing for STIs may also inform individual decisions to start PrEP. Considering PAF and NNT can aid in discussing the benefits and risks of PrEP with MSM/TGW.
Funding
Funded by the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number NCT00458393.
doi:10.1016/S1473-3099(14)70025-8
PMCID: PMC4133171  PMID: 24613084
6.  Ventromedial prefrontal cortex stimulation enhances memory and hippocampal neurogenesis in the middle-aged rats 
eLife  null;4:e04803.
Memory dysfunction is a key symptom of age-related dementia. Although recent studies have suggested positive effects of electrical stimulation for memory enhancement, its potential targets remain largely unknown. In this study, we hypothesized that spatially targeted deep brain stimulation of ventromedial prefrontal cortex enhanced memory functions in a middle-aged rat model. Our results show that acute stimulation enhanced the short-, but not the long-term memory in the novel-object recognition task. Interestingly, after chronic high-frequency stimulation, both the short- and long-term memories were robustly improved in the novel-object recognition test and Morris water-maze spatial task compared to sham. Our results also demonstrated that chronic ventromedial prefrontal cortex high-frequency stimulation upregulated neurogenesis-associated genes along with enhanced hippocampal cell proliferation. Importantly, these memory behaviors were strongly correlated with the hippocampal neurogenesis. Overall, these findings suggest that chronic ventromedial prefrontal cortex high-frequency stimulation may serve as a novel effective therapeutic target for dementia-related disorders.
DOI: http://dx.doi.org/10.7554/eLife.04803.001
eLife digest
Memory loss in older people is a serious and widespread problem that affects up to 50% of those over the age of 85. It is a key symptom of dementia, but despite the growing impact of this disease on society, there are no treatments currently available that can effectively stop or delay the progression of the symptoms.
One therapy that may reduce memory loss is called deep brain stimulation. Electrodes are implanted into the brain and used to stimulate brain cells in particular areas of the brain to alter mental and emotional processes. Deep brain stimulation is already used to treat Parkinson's disease, depression and other conditions that affect how the brain works.
Liu et al. studied the effect of deep brain stimulation on memory in rats. The experiments show that middle-aged rats performed less well in short- and long-term memory tests than young rats. Next, Liu et al. investigated whether deep brain stimulation could improve memory in the middle-aged rats. The electrodes were positioned to stimulate a region near the front of the brain called the ‘ventromedial prefrontal cortex’; this region is important for the formation and recall of memories. Liu et al. then gave the rats a series of memory tasks that tested their recall after 90 minutes (to test their short-term memory), and after 24 hours (to test long-term memory).
The experiments reveal that a brief stimulation of brain cells in this region of the brain improved the rats' short-term memory, but not their long-term memory. However, more sustained stimulation of this region of the brain improved both the short-term and long-term memory of the rats. Furthermore, deep brain stimulation led to the formation of new brain cells in another region of the brain called the hippocampus, which is also involved in memory. The hippocampus had not been in direct contact with the electrodes so the increase in brain cells was due to its connections with the stimulated ventromedial prefrontal cortex.
Liu et al.'s findings suggest that deep brain stimulation of the ventromedial prefrontal cortex has the potential to be developed into a therapy to treat dementia and other conditions that lead to memory loss in humans.
DOI: http://dx.doi.org/10.7554/eLife.04803.002
doi:10.7554/eLife.04803
PMCID: PMC4381300  PMID: 25768425
deep brain stimulation; learning and memory; ventromedial prefrontal cortex; hippocampus; neurogenesis; rat
7.  Conformational Preferences of N,N-Dimethylsuccinamate as a Function of Alkali and Alkaline Earth Metal Salts: Experimental Studies in DMSO and Water As Determined by 1H NMR Spectroscopy 
The Journal of Physical Chemistry. a  2014;118(11):1965-1970.
The fraction of gauche conformers of N,N-dimethylsuccinamic acid (1) and its Li+, Na+, K+, Mg2+, Ca2+, and N(Bu)4+ salts were estimated in DMSO and D2O solution by comparing the experimental vicinal proton–proton couplings determined by 1H NMR spectroscopy with those calculated using the Haasnoot, de Leeuw, and Altona (HLA) equation. In DMSO, the gauche preferences were found to increase with decreasing Ahrens ionic radius of the metal counterion. The same trend was not seen in D2O, where the gauche fraction for all of the metallic salts were estimated to be approximately statistical or less. This highlights the importance of metal chelation on the conformation of organic molecules in polar aprotic media, which has implications for protein folding.
doi:10.1021/jp4106508
PMCID: PMC3983401  PMID: 24506581
8.  Age, Race/Ethnicity, and Behavioral Risk Factors Associated with Per-Contact Risk of HIV Infection Among Men Who Have Sex with Men in the United States 
Objective
Young men who have sex with men (MSM) and MSM of color have the highest HIV incidence in the US. To explore possible explanations for these disparities and known individual risk factors we analyzed the per-contact risk (PCR) of HIV seroconversion in the early highly active antiretroviral therapy era.
Methods
Data from three longitudinal studies of MSM, HIVNET Vaccine Preparedness Study, EXPLORE behavioral efficacy trial, and VAX004 vaccine efficacy trial were pooled. The analysis included visits where participants reported unprotected receptive anal intercourse (URA), protected receptive anal intercourse (PRA), or unprotective insertive anal intercourse (UIA) with an HIV seropositive, unknown HIV serostatus, or an HIV seronegative partner. We used regression standardization to estimate average PCRs for each type of contact, with bootstrap confidence intervals.
Results
The estimated PCR was highest for URA with an HIV seropositive partner (0.73%; 95%BCI 0.45%-0.98%) followed by URA with a partner of unknown HIV serostatus (0.49%; 95%BCI 0.32%-0.62%). The estimated PCR for PRA and UIA with an HIV seropositive partner was 0.08% (95%BCI 0.0%-0.19%) and 0.22% (95%BCI 0.05%-0.39%) respectively. Average PCRs for URA and UIA with HIV seropositive partners were higher by 0.14-0.34% among younger participants and higher by 0.08% for UIA among Latino participants compared to White participants. Estimated PCRs increased with increasing number of sexual partners, use of methamphetamines or poppers, and history of sexually transmitted infection.
Conclusions
Susceptibility or partner factors may explain the higher HIV conversion risk for younger MSM, some MSM of color, and those reporting individual risk factors.
doi:10.1097/QAI.0b013e3182a98bae
PMCID: PMC3894586  PMID: 24419067
HIV; MSM; USA; per contact risk
9.  Participant Experiences and Facilitators and Barriers to Pill Use Among Men Who Have Sex with Men in the iPrEx Pre-Exposure Prophylaxis Trial in San Francisco 
AIDS Patient Care and STDs  2013;27(10):560-566.
Abstract
In 2010, the iPrEx study demonstrated efficacy of daily emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) pre-exposure prophylaxis (PrEP) in reducing HIV acquisition among men who have sex with men. Adherence to study product was critical for PrEP efficacy, and varied considerably, with FTC/TDF detection rates highest in the United States. We conducted a qualitative study to gain insights into the experiences of iPrEx participants in San Francisco (SF) where there was high confirmed adherence, to understand individual and contextual factors influencing study product use in this community. In 2009 and 2011, we conducted focus groups and in-depth interviews in 36 and 16 SF iPrEx participants, respectively. Qualitative analyses indicate that participants joined the study out of altruism. They had a clear understanding of study product use, and pill taking was facilitated by establishing or building on an existing routine. Participants valued healthcare provided by the study and relationships with staff, whom they perceived as nonjudgmental, and found client-centered counseling to be an important part of the PrEP package. This facilitated pill taking and accurate reporting of missed doses. Adherence barriers included changes in routine, side effects/intercurrent illnesses, and stress. Future PrEP adherence interventions should leverage existing routines and establish client-centered relationships/ environments to support pill taking and promote accurate reporting.
doi:10.1089/apc.2013.0116
PMCID: PMC3791030  PMID: 24093809
10.  Sexual risk behavior among HIV-uninfected men who have sex with men (MSM) participating in a tenofovir pre-exposure prophylaxis (PrEP) randomized trial in the United States 
Objective
To evaluate for changes in sexual behaviors associated with daily pill-use among MSM participating in a PrEP trial.
Design
Randomized, double-blind, placebo-controlled trial. Participants were randomized 1:1:1:1 to receive tenofovir disoproxil fumarate or placebo at enrollment or after a 9-month delay and followed for 24 months.
Methods
400 HIV-negative MSM reporting anal sex with a man in the past 12 months and meeting other eligibility criteria enrolled in San Francisco, Atlanta, and Boston. Sexual risk was assessed at baseline and quarterly visits using Audio Computer-Assisted Self-Interview. The association of pill-taking with sexual behavior was evaluated using logistic and negative-binomial regression for repeated measures.
Results
Overall indices of behavioral risk declined or remained stable during follow-up. Mean numbers of partners and proportion reporting unprotected anal sex (UAS) declined during follow-up (p<0.05), and mean UAS episodes remained stable. During the initial 9 months, changes in risk practices were similar in the group that began pills immediately vs. those in the delayed arm. These indices of risk did not differ significantly after initiation of pill-use in the delayed arm or continuation of study medication in the immediate arm. Use of poppers, amphetamines, and sexual performance-enhancing drugs were independently associated with one or more indices of sexual risk.
Conclusions
There was no evidence of risk compensation among HIV-uninfected MSM in this clinical trial. Monitoring for risk compensation should continue now that PrEP has been shown to be efficacious in MSM and other populations and will be provided in open-label trials and other contexts.
doi:10.1097/QAI.0b013e31828f097a
PMCID: PMC3904758  PMID: 23481668
risk compensation; behavioral disinhibition; sexual risk behavior; PrEP; MSM
11.  Integrated Strategies for Combination HIV Prevention: Principles and examples for men who have sex with men in the Americas and heterosexual African populations 
Combination HIV prevention is a high priority for increasing the impact of partially efficacious HIV prevention interventions for specific populations and settings. Developing the package requires critical review of local epidemiology of HIV infection regarding populations most impacted and most at risk, drivers of HIV infection, and available interventions to address these risk factors. Interventions should be considered in terms of the evidence basis for efficacy, potential synergies, feasibility of delivery at scale, which is important in order to achieve high coverage and impact, coupled with high acceptability to populations, which will impact uptake, adherence, and retention. Evaluation requires process measures of uptake, adherence, retention, and outcome measures of reduction in HIV infectiousness and acquisition. Three examples of combination prevention concepts are summarized for men who have sex with men (MSM) in the Americas, young women in sub-Saharan Africa, and HIV-1 serodiscordant couples.
doi:10.1097/QAI.0b013e3182986f3a
PMCID: PMC3708491  PMID: 23764638
Combination HIV prevention; integrated prevention; men who have sex with men; young women in Africa; HIV-1 serodiscordant couples
12.  Pre-exposure prophylaxis for HIV prevention: where have we been and where are we going? 
Pre-exposure prophylaxis (PrEP), in which HIV-uninfected persons with ongoing HIV risk use antiretroviral medications to reduce their risk of acquiring HIV infection, is an efficacious and promising new HIV prevention strategy. The past two years have seen significant new advances in knowledge regarding PrEP, including definitive demonstration that PrEP reduces the risk of HIV acquisition, regulatory approval of combination oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as the first PrEP agent with a label indication for sexual HIV prevention, and the development of normative guidance for clinical prescribing of PrEP. In PrEP clinical trials, HIV protection was strongly correlated with PrEP adherence; therefore understanding and supporting adherence to PrEP are key to maximizing its public health impact. As would be expected for any new HIV prevention approach, questions remain, including how to motivate uptake of and sustain adherence to PrEP for HIV prevention in high-risk populations, how much use is sufficient to achieve HIV protection, and the potential of “next-generation” PrEP agents to improve this effective prevention strategy. At this important transition point – from demonstration of efficacy in clinical trials to thinking about implementation and effectiveness – this review addresses where we have been and where we are going with PrEP for HIV prevention.
doi:10.1097/QAI.0b013e3182986f69
PMCID: PMC3710117  PMID: 23764623
HIV prevention; pre-exposure prophylaxis; sexual HIV transmission
13.  Syphilis Predicts HIV Incidence Among Men and Transgender Women Who Have Sex With Men in a Preexposure Prophylaxis Trial 
Syphilis infection was associated with HIV incidence in an HIV-prevention trial that randomized participants to once-daily emtricitabine/tenofovir (FTC/TDF) vs placebo. FTC/TDF had no effect on the association between incident syphilis and HIV acquisition; syphilis infection did not decrease FTC/TDF efficacy.
Background. Syphilis infection may potentiate transmission of human immunodeficiency virus (HIV). We sought to determine the extent to which HIV acquisition was associated with syphilis infection within an HIV preexposure prophylaxis (PrEP) trial and whether emtricitabine/tenofovir (FTC/TDF) modified that association.
Methods. The Preexposure Prophylaxis Initiative (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily FTC/TDF or placebo. Syphilis prevalence at screening and incidence during follow-up were measured. Hazard ratios for the effect of incident syphilis on HIV acquisition were calculated. The effect of FTC/TDF on incident syphilis and HIV acquisition was assessed.
Results. Of 2499 individuals, 360 (14.4%) had a positive rapid plasma reagin test at screening; 333 (92.5%) had a positive confirmatory test, which did not differ between the arms (FTC/TDF vs placebo, P = .81). The overall syphilis incidence during the trial was 7.3 cases per 100 person-years. There was no difference in syphilis incidence between the study arms (7.8 cases per 100 person-years for FTC/TDF vs 6.8 cases per 100 person-years for placebo, P = .304). HIV incidence varied by incident syphilis (2.8 cases per 100 person-years for no syphilis vs 8.0 cases per 100 person-years for incident syphilis), reflecting a hazard ratio of 2.6 (95% confidence interval, 1.6–4.4; P < .001). There was no evidence for interaction between randomization to the FTC/TDF arm and incident syphilis on HIV incidence.
Conclusions. In HIV-seronegative MSM, syphilis infection was associated with HIV acquisition in this PrEP trial; a syphilis diagnosis should prompt providers to offer PrEP unless otherwise contraindicated.
doi:10.1093/cid/ciu450
PMCID: PMC4166980  PMID: 24928295
chemoprophylaxis; HIV prevention; MSM; preexposure prophylaxis; syphilis
14.  Daily Oral Emtricitabine/Tenofovir Preexposure Prophylaxis and Herpes Simplex Virus Type 2 among Men Who Have Sex with Men 
PLoS ONE  2014;9(3):e91513.
Background
In addition to protecting against HIV acquisition, antiretroviral preexposure prophylaxis (PrEP) using topical 1% tenofovir gel reduced Herpes simplex virus type 2 (HSV-2) acquisition by 51% among women in the CAPRISA 004 study. We examined the effect of daily oral emtricitabine/tenofovir (FTC/TDF) PrEP on HSV-2 seroincidence and ulcer occurrence among men who have sex with men (MSM) in the iPrEx trial.
Methods
HSV-2 serum testing was performed at screening and every six months. Among HSV-2-seronegative individuals, we used Cox regression models to estimate hazard ratios (HRs) of HSV-2 seroincidence associated with randomization to FTC/TDF. We used multiple imputation and Cox regression to estimate HRs for HSV-2 seroincidence accounting for drug exposure. We assessed ulcer occurrence among participants with prevalent or incident HSV-2 infection.
Results
Of the 2,499 participants, 1383 (55.3%) tested HSV-2-seronegative at baseline, 892 (35.7%) tested positive, 223 (8.9%) had indeterminate tests, and one test was not done. Of the 1,347 HSV-2-seronegative participants with follow-up, 125 (9.3%) had incident HSV-2 infection (5.9 per 100 person-years). Compared with participants receiving placebo, there was no difference in HSV-2 seroincidence among participants receiving FTC/TDF (HR 1.1, 95% CI: 0.8–1.5; P = 0.64) or among participants receiving FTC/TDF with a concentration of tenofovir diphosphate >16 per million viable cells (HR 1.0, 95% CI: 0.3–3.5; P = 0.95). Among participants with HSV-2 infection, the proportion with ≥1 moderate or severe ulcer adverse event was twice as high in the placebo vs. active arm (5.9% vs. 2.9%, P = 0.02), but there were no differences in the proportions with ≥1 clinical examination during which perianal or groin ulcers were identified.
Conclusions
Tenofovir in daily oral FTC/TDF PrEP may reduce the occurrence of ulcers in individuals with HSV-2 infection but does not protect against HSV-2 incidence among MSM.
doi:10.1371/journal.pone.0091513
PMCID: PMC3956614  PMID: 24637511
15.  Early Experiences Implementing Pre-exposure Prophylaxis (PrEP) for HIV Prevention in San Francisco 
PLoS Medicine  2014;11(3):e1001613.
Albert Liu and colleagues report early experiences with uptake and delivery of pre-exposure prophylaxis(PrEP)for HIV prevention in three different settings in San Francisco. PrEP can be an important component of a comprehensive HIV prevention program and can complement efforts to increase HIV testing, linkage to care, and early initiation of antiretroviral therapy.
Please see later in the article for the Editors' Summary
doi:10.1371/journal.pmed.1001613
PMCID: PMC3942317  PMID: 24595035
16.  Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP) 
PLoS ONE  2014;9(1):e83736.
Background
Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults.
Methods
A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs).
Results
Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair.
Conclusions
This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs.
Trial Registration
ClinicalTrials.gov +NCT00903084.
doi:10.1371/journal.pone.0083736
PMCID: PMC3885443  PMID: 24421901
17.  No Evidence of Sexual Risk Compensation in the iPrEx Trial of Daily Oral HIV Preexposure Prophylaxis 
PLoS ONE  2013;8(12):e81997.
Objective
Preexposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) reduced HIV acquisition in the iPrEx trial among men who have sex with men and transgender women. Self-reported sexual risk behavior decreased overall, but may be affected by reporting bias. We evaluated potential risk compensation using biomarkers of sexual risk behavior.
Design and methods
Sexual practices were assessed at baseline and quarterly thereafter; perceived treatment assignment and PrEP efficacy beliefs were assessed at 12 weeks. Among participants with ≥1 follow-up behavioral assessment, sexual behavior, syphilis, and HIV infection were compared by perceived treatment assignment, actual treatment assignment, and perceived PrEP efficacy.
Results
Overall, acute HIV infection and syphilis decreased during follow-up. Compared with participants believing they were receiving placebo, participants believing they were receiving FTC/TDF reported more receptive anal intercourse partners prior to initiating drug (12.8 vs. 7.7, P = 0.04). Belief in receiving FTC/TDF was not associated with an increase in receptive anal intercourse with no condom (ncRAI) from baseline through follow-up (risk ratio [RR] 0.9, 95% confidence interval [CI]: 0.6–1.4; P = 0.75), nor with a decrease after stopping study drug (RR 0.8, 95% CI: 0.5–1.3; P = 0.46). In the placebo arm, there were trends toward lower HIV incidence among participants believing they were receiving FTC/TDF (incidence rate ratio [IRR] 0.8, 95% CI: 0.4–1.8; P = 0.26) and also believing it was highly effective (IRR 0.5, 95% CI: 0.1–1.7; P = 0.12).
Conclusions
There was no evidence of sexual risk compensation in iPrEx. Participants believing they were receiving FTC/TDF had more partners prior to initiating drug, suggesting that risk behavior was not a consequence of PrEP use.
doi:10.1371/journal.pone.0081997
PMCID: PMC3867330  PMID: 24367497
18.  Sexual frequency and planning among at-risk men who have sex with men (MSM) in the US: implications for event-based intermittent pre-exposure prophylaxis (iPrEP) 
Intermittent dosing of pre-exposure prophylaxis (iPrEP) has potential to decrease costs, improve adherence, and minimize toxicity. Practical event-based dosing of iPrEP requires men who have sex with men (MSM) to be sexually active on fewer than 3 days each week and plan for sexual activity. MSM who may be most suitable for event-based dosing were older, more educated, more frequently used sexual networking websites, and more often reported that their last sexual encounter was not with a committed partner. A substantial proportion of these MSM endorse high-risk sexual activity, and event-based iPrEP may best target this population.
doi:10.1097/QAI.0b013e31825bd87d
PMCID: PMC3427423  PMID: 22592590
intermittent pre-exposure prophylaxis (iPrEP); pre-exposure prophylaxis (PrEP); event-based dosing; men-who-have-sex-with-men (MSM); HIV; sexual frequency; sexual planning
20.  Emtricitabine-tenofovir exposure and pre-exposure prophylaxis efficacy in men who have sex with men 
Science translational medicine  2012;4(151):151ra125.
Drug concentrations associated with protection from HIV-1 acquisition have not been determined. This study evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial,(1) a randomized placebo controlled trial of daily oral emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (PrEP). Any detectable drug in blood plasma and viably cryopreserved peripheral blood mononuclear cells (vPBMCs) was less frequent in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% vs 44%, P<0.001) and in the 90 days prior to that visit (11% vs 51%, P<0.001). An intracellular tenofovir-diphosphate (TFV-DP) concentration of 16 fmol per million vPBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, STRAND, yielded TFV-DP concentrations that, when analyzed with this iPrEx model, corresponded with HIV-1 risk reduction of 76% for 2 doses per week, 96% for 4 doses per week, 99% for 7 doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.
doi:10.1126/scitranslmed.3004006
PMCID: PMC3721979  PMID: 22972843
21.  Absence of reproducibly detectable low-level HIV viremia in highly exposed seronegative men and women. 
AIDS (London, England)  2011;25(5):619-623.
Objective
Transient HIV infections have been invoked to account for the cellular immune responses detected in highly virus-exposed individuals who have remained HIV seronegative. We tested for very low levels of HIV RNA in 524 seronegative plasma samples from 311 highly exposed women and men from 3 longitudinal HIV cohorts.
Design
2073 transcription mediated amplification (TMA) HIV RNA tests were performed for an average of 3.95 TMA assays per plasma sample. Quadruplicate TMA assays, analyzing a total of 2 ml of plasma, provided an estimated sensitivity of 3.5 HIV RNA copies/ml.
Results
Four samples from subjects who did not sero-convert within the following six months were positive for HIV RNA. For one sample, human polymorphism DNA analysis indicated a sample mix up. Borderline HIV RNA detection signals were detected for the other three positive samples and further replicate TMA testing yielded no positive results. Nested PCR assays (n=254) for HIV proviral DNA on PBMC from these 3 subjects were negative.
Conclusions
Transient viremia was not reproducibly detected in highly HIV exposed seronegative men and women. If transient infections do occur, plasma HIV RNA levels may remain below the detection limits of the sensitive assay used here, be of very short duration, or viral replication may be restricted to mucosal surfaces or their draining lymphoid tissues.
doi:10.1097/QAD.0b013e3283440269
PMCID: PMC3458706  PMID: 21297421
22.  Bone Mineral Density in HIV-Negative Men Participating in a Tenofovir Pre-Exposure Prophylaxis Randomized Clinical Trial in San Francisco 
PLoS ONE  2011;6(8):e23688.
Background
Pre-exposure prophylaxis (PrEP) trials are evaluating regimens containing tenofovir-disoproxil fumarate (TDF) for HIV prevention. We determined the baseline prevalence of low bone mineral density (BMD) and the effect of TDF on BMD in men who have sex with men (MSM) in a PrEP trial in San Francisco.
Methods/Findings
We evaluated 1) the prevalence of low BMD using Dual Energy X-ray Absorptiometry (DEXA) in a baseline cohort of 210 HIV-uninfected MSM who screened for a randomized clinical trial of daily TDF vs. placebo, and 2) the effects of TDF on BMD in a longitudinal cohort of 184 enrolled men. Half began study drug after a 9-month delay to evaluate changes in risk behavior associated with pill-use. At baseline, 20 participants (10%) had low BMD (Z score≤−2.0 at the L2–L4 spine, total hip, or femoral neck). Low BMD was associated with amphetamine (OR = 5.86, 95% CI 1.70–20.20) and inhalant (OR = 4.57, 95% CI 1.32–15.81) use; men taking multivitamins, calcium, or vitamin D were less likely to have low BMD at baseline (OR = 0.26, 95% CI 0.10–0.71). In the longitudinal analysis, there was a 1.1% net decrease in mean BMD in the TDF vs. the pre-treatment/placebo group at the femoral neck (95% CI 0.4–1.9%), 0.8% net decline at the total hip (95% CI 0.3–1.3%), and 0.7% at the L2–L4 spine (95% CI −0.1–1.5%). At 24 months, 13% vs. 6% of participants experienced >5% BMD loss at the femoral neck in the TDF vs. placebo groups (p = 0.13).
Conclusions
Ten percent of HIV-negative MSM had low BMD at baseline. TDF use resulted in a small but statistically significant decline in BMD at the total hip and femoral neck. Larger studies with longer follow-up are needed to determine the trajectory of BMD changes and any association with clinical fractures.
Trial Registration
ClinicalTrials.gov: NCT00131677
doi:10.1371/journal.pone.0023688
PMCID: PMC3163584  PMID: 21897852
23.  Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men 
The New England journal of medicine  2010;363(27):2587-2599.
BACKGROUND
Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition.
METHODS
We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC–TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections.
RESULTS
The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC–TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P = 0.005). In the FTC–TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC–TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P = 0.57).
CONCLUSIONS
Oral FTC–TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.)
doi:10.1056/NEJMoa1011205
PMCID: PMC3079639  PMID: 21091279
24.  Pre-Exposure Prophylaxis and the Promise of Combination Prevention Approaches 
AIDS and Behavior  2011;15(Suppl 1):72-79.
Pre-exposure prophylaxis (PrEP) for HIV prevention is a promising experimental approach currently being tested globally. A number of PrEP trials are evaluating the safety and effectiveness of PrEP in men who have sex with men (MSM) and other populations at risk for HIV, and results will be available from this first generation of efficacy trials over the next few years. Here we review the rationale for orally-administered antiretrovirals for prevention, and outline issues the first generation trials will address as well as questions that may be addressed in future studies. We also describe the rationale for combination prevention approaches that may combine PrEP with other prevention modalities as part of a larger prevention package.
doi:10.1007/s10461-011-9894-1
PMCID: PMC3064892  PMID: 21331801
Pre-exposure prophylaxis; Clinical trials; HIV prevention; Combination prevention
25.  Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis 
AIDS (London, England)  2014;28(6):851-859.
Objective:
Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons.
Design and methods:
The Iniciativa Profilaxis Pre-Exposición (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily TDF coformulated with emtricitabine (FTC/TDF) or placebo. Serum creatinine and phosphorus during randomized treatment and after discontinuation were measured, and creatinine clearance (CrCl) was estimated by the Cockcroft–Gault equation. Indicators of proximal renal tubulopathy (fractional excretion of phosphorus and uric acid, urine protein, and glucose) were measured in a substudy.
Results:
There was a small but statistically significant decrease in CrCl from baseline in the active arm, compared to placebo, which was first observed at week 4 (mean change: −2.4 vs. −1.1 ml/min; P = 0.02), persisted through the last on-treatment visit (mean change: +0.3 vs. +1.8 ml/min; P = 0.02), and resolved after stopping pre-exposure prophylaxis (mean change: −0.1 vs. 0.0 ml/min; P = 0.83). The effect was confirmed when stratifying by drug detection. The effect of FTC/TDF on CrCl did not vary by race, age, or history of hypertension. There was no difference in serum phosphate trends between the treatment arms. In the substudy, two participants receiving placebo had indicators of tubulopathy.
Conclusions:
In HIV-seronegative MSM, randomization to FTC/TDF was associated with a very mild nonprogressive decrease in CrCl that was reversible and managed with routine serum creatinine monitoring.
doi:10.1097/QAD.0000000000000156
PMCID: PMC3966916  PMID: 24499951
chemoprophylaxis; HIV prevention; MSM; pre-exposure prophylaxis; renal; side effects; tenofovir

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