Mini All-Suture Anchors for Repairing the Central Slip of the Extensor Tendon at the Proximal Interphalangeal Joint: A Biomechanical Investigation.

PURPOSE: This study evaluated 1.0-mm mini suture anchors for repairing the central slip of the extensor mechanism at the proximal interphalangeal joint. Studies have reported a requirement for central slip fixation to withstand 15 N during postoperative rehabilitation exercises and 59 N during forceful contraction. METHODS: Index and middle fingers from 10 matched pairs of cadaveric hands were prepared with 1.0-mm mini suture anchors with 2-0 sutures or threaded with 2-0 sutures through a bone tunnel (BTP). In total, 10 index fingers from unmatched hands were prepared with suture anchors and fixed to the extensor tendons to evaluate the tendon/suture interface response. Each distal phalanx was secured to a servohydraulic testing machine, and ramped tensile loads were applied to suture or tendon until failure. RESULTS: All anchors for the all-suture bone tests failed because of pullout from the bone (Mean failure force = 52.5+/-17.3 N). Three anchors from the tendon-suture pull out test failed by pullout from the bone and seven failed at the tendon/suture interface (Mean failure force = 49.0+/-10.1 N). CONCLUSIONS: The 1.0-mm mini suture anchor provides enough strength for early short-arc motion, but it may not be adequate for forceful contraction in the early postoperative rehabilitation stage. CLINICAL RELEVANCE: The site of fixation, the type of anchor, and the type of suture used are key factors to consider for early range of motion, after surgery.

Concerns in the Blurred Divisions between Medical and Consumer Neurotechnology.

Neurotechnology has traditionally been central to the diagnosis and treatment of neurological disorders. While these devices have initially been utilized in clinical and research settings, recent advancements in neurotechnology have yielded devices that are more portable, user-friendly, and less expensive. These improvements allow laypeople to monitor their brain waves and interface their brains with external devices. Such improvements have led to the rise of wearable neurotechnology that is marketed to the consumer. While many of the consumer devices are marketed for innocuous applications, such as use in video games, there is potential for them to be repurposed for medical use. How do we manage neurotechnologies that skirt the line between medical and consumer applications and what can be done to ensure consumer safety? Here, we characterize neurotechnology based on medical and consumer applications and summarize currently marketed uses of consumer-grade wearable headsets. We lay out concerns that may arise due to the similar claims associated with both medical and consumer devices, the possibility of consumer devices being repurposed for medical uses, and the potential for medical uses of neurotechnology to influence commercial markets related to employment and self-enhancement.

A Roadmap Towards Standards for Neurally Controlled End Effectors.

The control and manipulation of various types of end effectors such as powered exoskeletons, prostheses, and 'neural' cursors by brain-machine interface (BMI) systems has been the target of many research projects. A seamless "plug and play" interface between any BMI and end effector is desired, wherein similar user's intent cause similar end effectors to behave identically. This report is based on the outcomes of an IEEE Standards Association Industry Connections working group on End Effectors for Brain-Machine Interfacing that convened to identify and address gaps in the existing standards for BMI-based solutions with a focus on the end-effector component. A roadmap towards standardization of end effectors for BMI systems is discussed by identifying current device standards that are applicable for end effectors. While current standards address basic electrical and mechanical safety, and to some extent, performance requirements, several gaps exist pertaining to unified terminologies, data communication protocols, patient safety and risk mitigation.

Full body mobile brain-body imaging data during unconstrained locomotion on stairs, ramps, and level ground.

Human locomotion is a complex process that requires the integration of central and peripheral nervous signalling. Understanding the brain's involvement in locomotion is challenging and is traditionally investigated during locomotor imagination or observation. However, stationary imaging methods lack the ability to infer information about the peripheral and central signalling during actual task execution. In this report, we present a dataset containing simultaneously recorded electroencephalography (EEG), lower-limb electromyography (EMG), and full body motion capture recorded from ten able-bodied individuals. The subjects completed an average of twenty trials on an experimental gait course containing level-ground, ramps, and stairs. We recorded 60-channel EEG from the scalp and 4-channel EOG from the face and temples. Surface EMG was recorded from six muscle sites bilaterally on the thigh and shank. The motion capture system consisted of seventeen wireless IMUs, allowing for unconstrained ambulation in the experimental space. In this report, we present the rationale for collecting these data, a detailed explanation of the experimental setup, and a brief validation of the data quality.

Damage in a Distal Radius Fracture Model Treated With Locked Volar Plating After Simulated Postoperative Loading.

PURPOSE: "Damage" is an engineering term defining a period between a state of material perfection and the onset of crack initiation. Clinically, it is a loss of fixation due to microstructural breakdown, indirectly measured as a reduction of stiffness of the bone-implant construct, normalized by the cross-sectional area and length of the bone. The purpose of this study was to characterize damage in a cadaver model of extra-articular distal radius fracture with dorsal comminution treated using 2-column volar distal radius plates. METHODS: Ten matched distal radii were randomly divided into 2 groups: group I specimens were treated with a volar distal radius plate with an independent, 2-tiered scaffold design; group II specimens (contralateral limbs) were treated with a volar plate with a single-head design for enhanced ulnar buttressing. Specimens were cyclically loaded to simulate a 6-month postoperative load-bearing period. We report damage after a defined protocol of cyclical loading and load to failure simulating a fall on an outstretched hand. RESULTS: Group II specimens experienced more damage under cyclic loading conditions than group I specimens. Group I specimens were stiffer than group II specimens under load-to-failure conditions. Ultimate force at failure in group I and group II specimens was not different. Specimens failed by plate bending (group I, n = 6/10; group II, n = 2/10) and fracture of the lunate facet (group I, n = 4/10; group II, n = 8/10). CONCLUSIONS: Group I specimens had less screw cutout at the lunate facet than group II specimens under cyclic loading as indicated by lower damage measures and fewer facet fractures during load-to-failure testing. The overall strength of the construct is not affected by plate design. CLINICAL RELEVANCE: Microstructural damage or a loss of fixation due to an overly rigid volar plate design may cause malunion or nonunion of fracture fragments and lead to bone-implant instability.

Electrocortical correlates of human level-ground, slope, and stair walking.

This study investigated electrocortical dynamics of human walking across different unconstrained walking conditions (i.e., level ground (LW), ramp ascent (RA), and stair ascent (SA)). Non-invasive active-electrode scalp electroencephalography (EEG) signals were recorded and a systematic EEG processing method was implemented to reduce artifacts. Source localization combined with independent component analysis and k-means clustering revealed the involvement of four clusters in the brain during the walking tasks: Left and Right Occipital Lobe (LOL, ROL), Posterior Parietal Cortex (PPC), and Central Sensorimotor Cortex (SMC). Results showed that the changes of spectral power in the PPC and SMC clusters were associated with the level of motor task demands. Specifically, we observed α and ß suppression at the beginning of the gait cycle in both SA and RA walking (relative to LW) in the SMC. Additionally, we observed significant ß rebound (synchronization) at the initial swing phase of the gait cycle, which may be indicative of active cortical signaling involved in maintaining the current locomotor state. An increase of low γ band power in this cluster was also found in SA walking. In the PPC, the low γ band power increased with the level of task demands (from LW to RA and SA). Additionally, our results provide evidence that electrocortical amplitude modulations (relative to average gait cycle) are correlated with the level of difficulty in locomotion tasks. Specifically, the modulations in the PPC shifted to higher frequency bands when the subjects walked in RA and SA conditions. Moreover, low γ modulations in the central sensorimotor area were observed in the LW walking and shifted to lower frequency bands in RA and SA walking. These findings extend our understanding of cortical dynamics of human walking at different level of locomotion task demands and reinforces the growing body of literature supporting a shared-control paradigm between spinal and cortical networks during locomotion.

Deployment of Mobile EEG Technology in an Art Museum Setting: Evaluation of Signal Quality and Usability.

Electroencephalography (EEG) has emerged as a powerful tool for quantitatively studying the brain that enables natural and mobile experiments. Recent advances in EEG have allowed for the use of dry electrodes that do not require a conductive medium between the recording electrode and the scalp. The overall goal of this research was to gain an understanding of the overall usability and signal quality of dry EEG headsets compared to traditional gel-based systems in an unconstrained environment. EEG was used to collect Mobile Brain-body Imaging (MoBI) data from 432 people as they experienced an art exhibit in a public museum. The subjects were instrumented with either one of four dry electrode EEG systems or a conventional gel electrode EEG system. Each of the systems was evaluated based on the signal quality and usability in a real-world setting. First, we describe the various artifacts that were characteristic of each of the systems. Second, we report on each system's usability and their limitations in a mobile setting. Third, to evaluate signal quality for task discrimination and characterization, we employed a data driven clustering approach on the data from 134 of the 432 subjects (those with reliable location tracking information and usable EEG data) to evaluate the power spectral density (PSD) content of the EEG recordings. The experiment consisted of a baseline condition in which the subjects sat quietly facing a white wall for 1 min. Subsequently, the participants were encouraged to explore the exhibit for as long as they wished (piece-viewing). No constraints were placed upon the individual in relation to action, time, or navigation of the exhibit. In this freely-behaving approach, the EEG systems varied in their capacity to record characteristic modulations in the EEG data, with the gel-based system more clearly capturing stereotypical alpha and beta-band modulations.

Electrocortical amplitude modulations of human level-ground, slope, and stair walking.

This study investigates if the electrocortical amplitude modulations relative to the mean gait cycle are different across walking conditions (i.e., level-ground (LW), ramp ascent (RA), and stair ascent (SA)). Non-invasive electroencephalography (EEG) signals were recorded and a systematic EEG processing method was implemented to reduce artifacts. Source localization using independent component analysis and k-means clustering revealed the involvement of four clusters in the brain (Left and Right Occipital Lobe, Posterior Parietal Cortex (PPC), and Sensorimotor Area) during the walking tasks. We found that electrocortical amplitude modulations varied across different walking conditions. Specifically, our results showed that the modulations in the PPC shifted to higher frequency bands when the subjects walked in RA and SA conditions. Moreover, we found low γ modulations in the sensorimotor area in LW walking and the modulations in this cluster shifted to lower frequency bands in RA and SA walking. These results are a promising step toward the development of a non-invasive Neural-machine Interface (NMI) for locomotion mode recognition.

A Biomechanical Comparison Of Pin Configurations Used For Percutaneous Pinning Of Distal Tibia Fractures In Children.

BACKGROUND: Percutaneous pin fixation is often used in conjunction with closed-reduction and cast immobilization to treat pediatric distal tibia fractures. The goal of this procedure is to maintain reduction and provide improved stabilization, in effort to facilitate a more anatomic union. We conducted a biomechanical study of the torsional and bending stability of three commonly used pin configurations in distal tibia fracture fixation. METHODS: A transverse fracture was simulated at the metaphyseal/diaphyseal junction in 15 synthetic tibias. Each fracture was reduced and fixed with two Kirschner wires, arranged in one of three pin configurations: parallel, retrograde, medial to lateral pins entering at the medial malleolus distal to the fracture (group A); parallel, antegrade, medial to lateral pins entering at the medial diaphysis proximal to the fracture (group B); or a cross-pin configuration with one retrograde, medial to lateral pin entering the medial malleolus distal to the fracture and the second an antegrade, medial to lateral pin entering at the medial diaphysis proximal to the fracture (group C). Stability of each construct was assessed by resistance to torsion and bending. RESULTS: Resistance to external rotation stress was significantly higher in group A than group B (P = 0.044). Resistance to internal rotation stress was significantly higher in group C than group B (P = 0.003). There was no significant difference in torsional stiffness when comparing group A with group C. Under a medial-directed load, group B and C specimens were significantly stiffer than those in group A (28 N/mm and 24 N/mm vs. 14 N/mm for A; P = 0.001 and P = 0.009, respectively). CONCLUSIONS: None of the three pin configurations produced superior results with respect to all variables studied. Group A configuration provided the highest resistance to external rotation forces, which is the most clinically relevant variable under short-cast immobilization. Parallel, retrograde, medial to lateral pins entering at the medial malleolus provide the greatest resistance to external rotation of the foot while minimizing the potential for iatrogenic injury to soft tissue structures.

Powered exoskeletons for bipedal locomotion after spinal cord injury.

OBJECTIVE: Powered exoskeletons promise to increase the quality of life of people with lower-body paralysis or weakened legs by assisting or restoring legged mobility while providing health benefits across multiple physiological systems. Here, a systematic review of the literature on powered exoskeletons addressed critical questions: What is the current evidence of clinical efficacy for lower-limb powered exoskeletons? What are the benefits and risks for individuals with spinal cord injury (SCI)? What are the levels of injury considered in such studies? What are their outcome measures? What are the opportunities for the next generation exoskeletons? APPROACH: A systematic search of online databases was performed to identify clinical trials and safety or efficacy studies with lower-limb powered exoskeletons for individuals with SCI. Twenty-two studies with eight powered exoskeletons thus selected, were analyzed based on the protocol design, subject demographics, study duration, and primary/secondary outcome measures for assessing exoskeleton's performance in SCI subjects. MAIN RESULTS: Findings show that the level of injury varies across studies, with T10 injuries being represented in 45.4% of the studies. A categorical breakdown of outcome measures revealed 63% of these measures were gait and ambulation related, followed by energy expenditure (16%), physiological improvements (13%), and usability and comfort (8%). Moreover, outcome measures varied across studies, and none had measures spanning every category, making comparisons difficult. SIGNIFICANCE: This review of the literature shows that a majority of current studies focus on thoracic level injury as well as there is an emphasis on ambulatory-related primary outcome measures. Future research should: 1) develop criteria for optimal selection and training of patients most likely to benefit from this technology, 2) design multimodal gait intention detection systems that engage and empower the user, 3) develop real-time monitoring and diagnostic capabilities, and 4) adopt comprehensive metrics for assessing safety, benefits, and usability.

Uptake of antiretroviral therapy and male circumcision after community-based HIV testing and strategies for linkage to care versus standard clinic referral: a multisite, open-label, randomised controlled trial in South Africa and Uganda.

BACKGROUND: Male circumcision decreases HIV acquisition by 60%, and antiretroviral therapy (ART) almost eliminates HIV transmission from HIV-positive people who are virally suppressed; however, coverage of these interventions has lagged behind targets. We aimed to assess whether community-based HIV testing with counsellor support and point-of-care CD4 cell count testing would increase uptake of ART and male circumcision. METHODS: We did this multisite, open-label, randomised controlled trial in six research-naive communities in rural South Africa and Uganda. Eligible HIV-positive participants (aged ≥16 years) were randomly assigned (1:1:1) in a factorial design to receive lay counsellor clinic linkage facilitation, lay counsellor follow-up home visits, or standard-of-care clinic referral, and then (1:1) either point-of-care CD4 cell count testing or referral for CD4 testing. HIV-negative uncircumcised men (aged 16-49 years) who could receive secure mobile phone text messages were randomly assigned (1:1:1) to receive text message reminders, lay counsellor visits, or standard clinic referral. The study biostatistician generated the randomisation schedule via a computer-generated random number program with varying block sizes (multiples of six or three) stratified by country. Primary outcomes for HIV-positive people were obtaining a CD4 cell count, linkage to an HIV clinic, ART initiation, and viral suppression at 9 months, and for HIV-negative uncircumcised men were visiting a circumcision facility and uptake of male circumcision at 3 months. We assessed social harms as a safety outcome throughout the study. We did the primary analyses by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02038582. FINDINGS: Between June 6, 2013, and March 11, 2015, 15 332 participants were tested. 2339 (15%) participants tested HIV positive, of whom 1325 (57%) were randomly assigned to receive lay counsellor clinic linkage facilitation (n=437), lay counsellor follow-up home visits (n=449), or standard clinic referral (n=439), and then point-of-care CD4 cell testing (n=206, n=220, and n=213, respectively) or referral for CD4 testing (n=231, n=229, and n=226, respectively). 12 993 (85%) participants tested HIV negative, of whom 750 (6%) uncircumcised men were randomly assigned to receive clinic referral (n=230), text message reminders (n=288), or lay counsellor follow-up visits (n=232). 1218 (93%) of 1303 HIV-positive participants were linked to care, but only 488 (37%) participants initiated ART. Overall, 635 (50%) of 1272 HIV-positive individuals achieved viral suppression at 9 months: 219 (52%) of 419 participants in the clinic facilitation group, 202 (47%) of 431 participants in the lay counsellor follow-up group, and 214 (51%) of 422 participants in the clinic referral group, with no significant differences between groups (p=0·668 for clinic facilitation and p=0·273 for lay counsellor follow-up vs clinic referral). 523 (72%) of 734 HIV-negative men visited a circumcision facility, with no difference between groups. 62 (28%) of 224 men were circumcised in the male circumcision clinic referral group compared with 137 (48%) of 284 men in the text message reminder group (relative risk 1·72, 95% CI 1·36-2·17; p<0·0001) and 106 (47%) of 226 men in the lay counsellor follow-up group (1·67, 1·29-2·14; p=0·0001). No cases of study-related social harm were reported, including probing about partnership separation, unintended disclosure, gender-based violence, and stigma. INTERPRETATION: All the community-based strategies achieved high rates of linkage of HIV-positive people to HIV clinics, roughly a third of whom initiated ART, and of those more than 80% were virally suppressed at 9 months. Uptake of male circumcision was almost two-times higher in men who received text message reminders or lay counsellor visits than in those who received standard-of-care clinic referral. Clinic barriers to ART initiation should be addressed in future strategies to increase the proportion of HIV-positive people accessing treatment and achieving viral suppression. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Corticomuscular coherence variation throughout the gait cycle during overground walking and ramp ascent: A preliminary investigation.

Recent designs of neural-machine interfaces (NMIs) incorporating electroencephalography (EEG) or electromyography (EMG) have been used in lower limb assistive devices. While the results of previous studies have shown promise, a NMI which takes advantage of early movement-related EEG activity preceding movement onset, as well as the improved signal-to-noise ratio of EMG, could prove to be more accurate and responsive than current NMI designs based solely on EEG or EMG. Previous studies have demonstrated that the activity of the sensorimotor cortex is coupled to the firing rate of motor units in lower limb muscles during voluntary contraction. However, the exploration of corticomuscular coherence during locomotive tasks has been limited. In this study, coupling between the motor cortex and right tibialis anterior muscle activity was preliminarily investigated during self-paced over-ground walking and ramp ascent. EEG at the motor cortex and surface EMG from the tibialis anterior were collected from one able-bodied subject. Coherence between the two signals was computed and studied across gait cycles. The EEG activity led the EMG activity in the low gamma band in swing phase of level ground walking and in stance phase of ramp ascent. These results may inform the future design of EEG-EMG multimodal NMIs for lower limb devices that assist locomotion of people with physical disabilities.

Noninvasive EEG correlates of overground and stair walking.

Automated walking intention detection remains a challenge in lower-limb neuroprosthetic systems. Here, we assess the feasibility of extracting motor intent from scalp electroencephalography (EEG). First, we evaluated the corticomuscular coherence between central EEG electrodes (C1, Cz, C2) and muscles of the shank and thigh during walking on level ground and stairs. Second, we trained decoders to predict the linear envelope of the surface electromyogram (EMG). We observed significant EEG-led corticomuscular coupling between electrodes and sEMG (tibialis anterior) in the high delta (3-4 Hz) and low theta (4-5 Hz) frequency bands during level walking, indicating efferent signaling from the cortex to peripheral motor neurons. The coherence was increased between EEG and vastus lateralis and tibialis anterior in the delta band (<; 2 Hz) during stair ascent, indicating a task specific modulation in corticomuscular coupling. However, EMG was the leading signal for biceps femoris and gastrocnemius coherence during stair ascent, possibly representing afferent feedback loops from periphery to the motor cortex. Decoder validation showed that EEG signals contained information about the sEMG patterns during over ground walking, however, the accuracy of the predicted sEMG patterns decreased during the stair condition. Overall, these initial findings support the feasibility of integrating sEMG and EEG into a hybrid decoder for volitional control of lower limb neuroprostheses.

Your Brain on Art: Emergent Cortical Dynamics During Aesthetic Experiences.

The brain response to conceptual art was studied with mobile electroencephalography (EEG) to examine the neural basis of aesthetic experiences. In contrast to most studies of perceptual phenomena, participants were moving and thinking freely as they viewed the exhibit The Boundary of Life is Quietly Crossed by Dario Robleto at the Menil Collection-Houston. The brain activity of over 400 subjects was recorded using dry-electrode and one reference gel-based EEG systems over a period of 3 months. Here, we report initial findings based on the reference system. EEG segments corresponding to each art piece were grouped into one of three classes (complex, moderate, and baseline) based on analysis of a digital image of each piece. Time, frequency, and wavelet features extracted from EEG were used to classify patterns associated with viewing art, and ranked based on their relevance for classification. The maximum classification accuracy was 55% (chance = 33%) with delta and gamma features the most relevant for classification. Functional analysis revealed a significant increase in connection strength in localized brain networks while subjects viewed the most aesthetically pleasing art compared to viewing a blank wall. The direction of signal flow showed early recruitment of broad posterior areas followed by focal anterior activation. Significant differences in the strength of connections were also observed across age and gender. This work provides evidence that EEG, deployed on freely behaving subjects, can detect selective signal flow in neural networks, identify significant differences between subject groups, and report with greater-than-chance accuracy the complexity of a subject's visual percept of aesthetically pleasing art. Our approach, which allows acquisition of neural activity "in action and context," could lead to understanding of how the brain integrates sensory input and its ongoing internal state to produce the phenomenon which we term aesthetic experience.

Structures at Risk During Volar Percutaneous Fixation of Scaphoid Fractures: A Cadaver Study.

BACKGROUND: Fracture of the scaphoid bone can be treated with cast immobilization or surgery. Historically, surgery was reserved for displaced fractures. However, because weeks of cast immobilization may result in stiffness, loss of strength, loss of bone density and an inability to work or participate in recreational activities for a prolonged period, operative treatment of non-displaced fractures has become increasingly common. Several surgical techniques for fixation have been described, but their risks and benefits have not yet been clearly elucidated. In a study in cadavers, we investigated whether one approach--volar percutaneous fixation--might pose a risk of injury to surrounding structures. METHODS: In 15 cadaver upper limbs with the wrist structures intact, a K-wire was inserted in a volar percutaneous manner under fluoroscopic guidance, distal to proximal and through the scaphoid waist into the center-center position. The volar aspect of the wrist and hand were then dissected around the K-wire, with isolation of surrounding structures. The distance between the K-wire and several individual structures was then measured with use of a digital caliper. RESULTS: The K-wire was at least 4 mm from the superficial radial nerve, the first dorsal extensor compartment, the recurrent motor branch of the median nerve, and the radial artery (RA) in all specimens. However, the K-wire had penetrated die flexor carpi radialis (FCR) tendon in four specimens and was directly adjacent to it in another four. In one specimen, the K-wire was directly adjacent to the superficial volar branch of die RA. CONCLUSIONS: The K-wire may penetrate the FCR tendon and the superficial volar branch of the radial artery during volar percutaneous scaphoid fixation. The possible long-term clinical implications of this finding require investigation. CLINICAL RELEVANCE: Our findings indicate that modification of the volar percutaneous approach to scaphoid fixation may be advisable to avoid damage to adjacent structures. We suggest use of a "mini-open" percutaneous procedure.

Successful discontinuation of the placebo arm and provision of an effective HIV prevention product after a positive interim efficacy result: the partners PrEP study experience.

BACKGROUND: Dissemination of research results to study participants and stakeholders and provision of proven effective products in the immediate post-trial period are core elements of the conduct of biomedical HIV prevention clinical trials. Few biomedical HIV prevention trials have demonstrated HIV protection with novel interventions, and thus, communication of positive trial results and provision of an effective product have not been tested in many situations. METHODS: In July 2011, the independent Data and Safety Monitoring Board of the Partners PrEP Study, a randomized, placebo-controlled efficacy trial of daily oral antiretroviral preexposure prophylaxis (PrEP) for HIV prevention among 4747 African heterosexual HIV serodiscordant couples, recommended discontinuation of the trial's placebo arm due to demonstration of PrEP efficacy. We describe dissemination of results, discontinuation of the placebo arm, and provision of active PrEP to participants' formerly assigned placebo. RESULTS: Within 72 hours, of the Data and Safety Monitoring Board meeting the study results were publicly released and disseminated to stakeholders and study participants. Within 3 months, the study protocol was modified to permit participants initially assigned to the study's placebo arm to be offered active PrEP. Of the 1418 participants initially randomized to placebo who were clinically eligible to receive PrEP, 89.1% (1264/1418) consented. CONCLUSIONS: Prompt dissemination of a positive HIV prevention trial result and subsequent provision of effective product to research participants was feasible and efficient for >4700 HIV serodiscordant couples in East Africa. The extent to which study sponsors can assure continued product access to research participants remains a subject of discussion for future HIV prevention clinical trials.

HIV protective efficacy and correlates of tenofovir blood concentrations in a clinical trial of PrEP for HIV prevention.

BACKGROUND: Antiretroviral pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy for which adherence is a known determinant of efficacy. Blood concentrations of PrEP medications are one objective marker of adherence. METHODS: In a placebo-controlled PrEP efficacy trial of tenofovir disoproxil fumarate (TDF) and TDF with emtricitabine (FTC/TDF) among 4747 African women and men with an HIV-infected partner, we measured plasma tenofovir concentrations from participants in the active PrEP arms: 29 HIV seroconverters (cases) and 196 randomly selected controls who remained uninfected. RESULTS: Among controls, 71% of visits had tenofovir concentrations >40 ng/mL, consistent with steady-state daily dosing, compared with 21% of cases at the visit HIV was first detected. Pill count data indicated that 96% of controls and 66% of cases had >80% adherence for these same visits. The estimated protective effect of PrEP against HIV, based on concentrations >40 ng/mL, was 88% (95% confidence interval: 60 to 96, P < 0.001) for individuals receiving TDF and 91% (95% confidence interval: 47 to 98, P = 0.008) for individuals receiving FTC/TDF. Controls had consistent patterns of PrEP concentrations during follow-up; among the 81% with concentrations >40 ng/mL at month 1, 75% maintained this concentration at month 12. Only 5 of 29 seroconverters seemed to be consistently adherent to PrEP. Tenofovir concentrations >40 ng/mL were associated with older age and shorter time on study; concentrations ≤40 ng/mL occurred more commonly when participants reported no sex with their HIV-infected partner. CONCLUSIONS: Plasma concentrations of tenofovir consistent with daily dosing were highly predictive of protection from HIV acquisition. Most of those who took PrEP seemed to have high and consistent adherence.