Concomitant contraceptive implant and efavirenz use in women living with HIV: perspectives on current evidence and policy implications for family planning and HIV treatment guidelines.

IntroductionPreventing unintended pregnancies is important among all women, including those living with HIV. Increasing numbers of women, including HIV-positive women, choose progestin-containing subdermal implants, which are one of the most effective forms of contraception. However, drug-drug interactions between contraceptive hormones and efavirenz-based antiretroviral therapy (ART) may reduce implant effectiveness. We present four inter-related perspectives on this issue.DiscussionFirst, as a case study, we discuss how limited data prompted country-level guidance against the use of implants among women concomitantly using efavirenz in South Africa and its subsequent negative effects on the use of implants in general. Second, we discuss the existing clinical data on this topic, including the observational study from Kenya showing women using implants plus efavirenz-based ART had three-fold higher rates of pregnancy than women using implants plus nevirapine-based ART. However, the higher rates of pregnancy in the implant plus efavirenz group were still lower than the pregnancy rates among women using common alternative contraceptive methods, such as injectables. Third, we discuss the four pharmacokinetic studies that show 50-70% reductions in plasma progestin concentrations in women concurrently using efavirenz-based ART as compared to women not on any ART. These pharmacokinetic studies provide the biologic basis for the clinical findings. Fourth, we discuss how data on this topic have marked implications for both family planning and HIV programmes and policies globally.ConclusionThis controversy underlines the importance of integrating family planning services into routine HIV care, counselling women appropriately on increased risk of pregnancy with concomitant implant and efavirenz use, and expanding contraceptive method mix for all women. As global access to ART expands, greater research is needed to explore implant effectiveness when used concomitantly with newer ART regimens. Data on how HIV-positive women and their partners choose contraceptives, as well as information from providers on how they present and counsel patients on contraceptive options are needed to help guide policy and service delivery. Lastly, greater collaboration between HIV and reproductive health experts at all levels are needed to develop successful strategies to ensure the best HIV and reproductive health outcomes for women living with HIV

Midwest Pharmacists\u27 Familiarity, Experience, and Willingness to Provide Pre-Exposure Prophylaxis (PrEP) for HIV

INTRODUCTION: Pharmacist provision of pre-exposure prophylaxis (PrEP) through collaborative practice agreements with physicians could expand access to people at risk for HIV. We characterized pharmacists\u27 familiarity with and willingness to provide PrEP services in Nebraska and Iowa. METHODS: An invitation to complete an 18-question survey was emailed to 1,140 pharmacists in Nebraska and Iowa in June and July of 2016. Descriptive analyses and Pearson chi-square tests were used to determine to what extent demographics, familiarity and experience were associated with respondent willingness to provide PrEP. Wilcoxon rank-sum tests compared ages and years of experience between groups of respondents. RESULTS: One hundred forty pharmacists (12.3%) responded. Less than half were familiar with the use of PrEP (42%) or the CDC guidelines for its use (25%). Respondents who were older (p = .015) and in practice longer (p = .005) were less likely to be familiar with PrEP. Overall, 54% indicated they were fairly or very likely to provide PrEP services as part of a collaborative practice agreement and after additional training. While familiarity with PrEP use or guidelines did not affect respondents\u27 willingness to provide PrEP, respondents were more likely to provide PrEP with prior experience counseling HIV-infected patients on antiretroviral therapy (OR 2.43; p = 0.023) or PrEP (OR 4.67; p = 0.013), and with prior HIV-related continuing education (OR 2.77; p = 0.032). CONCLUSIONS: Pharmacist respondents in Nebraska and Iowa had limited familiarity and experience with PrEP, but most indicated willingness to provide PrEP through collaborative practice agreements after additional training. Provision of PrEP-focused continuing education may lead to increased willingness to participate in PrEP programs

A Pharmacist-Led Medication Switch Protocol in an Academic HIV Clinic: Patient Knowledge and Satisfaction

BACKGROUND: Tenofovir alafenamide (TAF) is associated with less renal and bone toxicity compared with tenofovir disoproxil (TDF). TAF\u27s recent FDA approval has spurred HIV providers to consider switching antiretroviral therapy (ART) regimens containing TDF to TAF to minimize long term risks. Patient views on the process of such medication switches have not been explored. METHODS: Patients taking elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) following the Food and Drug Administration\u27s (FDA) approval of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) received medication education from an HIV pharmacist prior to switching to the tenofovir alafenamide (TAF) formulation. Patients were asked to complete a cross-sectional survey assessing satisfaction with the switch process and knowledge about the new medication 4 to 8 weeks post-switch. RESULTS: Sixty five patients completed the switch and 57 (88%) completed a follow-up survey. Most (86%) reported understanding why the switch was made, while 91% correctly identified that TAF is associated with reduced renal toxicity, and 73% correctly identified that TAF is associated with reduced bone toxicity. No statistically significant difference was found in satisfaction with or understanding of why the medication switch was made when assessed by sex, age, race, or education, but there was a trend toward significance in the distribution of answers based on education level with those with a high school diploma, General Educational Development (GED) or less being more likely to be satisfied with the medication switch (p = 0.074). CONCLUSIONS: Education from an ambulatory clinic-based HIV pharmacist resulted in high rates of patient satisfaction and understanding of the switch from TDF to TAF-containing ART

EUSO science

EUSO is a mission to explore the extreme universe by the probe of Ultra High Energy Cosmic Rays (UHECRs) and UHE neutrinos. EUSO monitors a gigantic volume of atmosphere from Space and measures showers induced by UHECRs and UHE neutrinos. Scientifically, it is important to measure the energy spectrum of UHECRs well beyond GZK energy with high statistics. EUSO ensures the observation of UHECRs up to 10$^{21}$eV even in the case of GZK mechanism working, and gives us a clear picture of the existence / non-existence of the GZK effect and the behavior of the spectrum beyond GZK energy, which represents the contributions from nearby sources. The anisotropy study of UHECR arrival directions in a small scale angle above GZK energy may allow us to identify individual source, because of the limited propagation distance and the high rigidity of particles. If event clusters observed by AGASA are real, it is expected from Monte Carlo simulation that EUSO will see ~100 particles from individual brightest sources and will give us a good opportunity to test the relativity in high precision. The UHE neutrino is a unique channel to explore the universe much deeper than UHECRs. EUSO essentially can measure UHE neutrinos free from background proton showers. The number of GZK neutrino events in a EUSO three years' mission is expected to be only a few. Nevertheless, it is a definitely conceivable opportunity to begin UHE neutrino astrophysics at GZK energy

Accumulation of Protease Mutations among Patients Failing Second-Line Antiretroviral Therapy and Response to Salvage Therapy in Nigeria

Background: To date, antiretroviral therapy (ART) guidelines and programs in resource-limited settings (RLS) have focused on 1st- and 2nd-line (2 L) therapy. As programs approach a decade of implementation, policy regarding access to 3rd-line (3 L) ART is needed. We aimed to examine the impact of maintaining patients on failing 2 L ART on the accumulation of protease (PR) mutations. Methods and Findings: From 2004–2011, the Harvard/APIN PEPFAR Program provided ART to >100,000 people in Nigeria. Genotypic resistance testing was performed on a subset of patients experiencing 2 L failure, defined as 2 consecutive viral loads (VL)>1000 copies/mL after ≥6 months on 2 L. Of 6714 patients who received protease inhibitor (PI)-based ART, 673 (10.0%) met virologic failure criteria. Genotypes were performed on 61 samples. Patients on non-suppressive 2 L therapy for 24 months. Patients developed a median of 0.6 (IQR: 0–1.4) IAS PR mutations per 6 months on failing 2 L therapy. In 38% of failing patients no PR mutations were present. For patients failing >24 months, high- or intermediate-level resistance to lopinavir and atazanavir was present in 63%, with 5% to darunavir. Conclusions: This is the first report assessing the impact of duration of non-suppressive 2 L therapy on the accumulation of PR resistance in a RLS. This information provides insight into the resistance cost of failing to switch non-suppressive 2 L regimens and highlights the issue of 3 L access

SUSY Resonances from UHE neutralinos in Neutrino Telescopes and in the Sky

In the Top-down scenarios, the decay of super-heavy particles (m~10^{12-16}GeV), situated in dark-matter halos not very far from our Galaxy, can explain the ultra-high-energy (UHE) cosmic-ray spectrum beyond the Griesen-Zatasepin-Kuzmin cut-off. In the MSSM, a major component of the UHE cosmic-ray flux at PeV-EeV energies could be given by the lightest neutralino \chi, that is the lightest stable supersymmetric particle. Then, the signal of UHE \chi's on earth might emerge over the interactions of a comparable neutrino component. We compute the event rates for the resonant production of "right" selectrons and "right" squarks in mSUGRA, when UHE neutralinos of energy larger than 10^5 GeV scatter off electrons and quarks in an earth-based detector like IceCube. When the resonant channel dominates in the total \chi-e,\chi-q scattering cross section, the only model parameters affecting the corresponding visible signal rates turn out to be the physical masses of the resonant right-scalar and of the lightest neutralino. We compare the expected number of supersymmetric events with the rates corresponding to the expected Glashow W resonance and to the continuum UHE \nu-N scattering for realistic power-law spectra. We find that the event rate in the leptonic selectron channel is particularly promising, and can reach a few tens for a one-year exposure in IceCube. Finally, we note that UHE neutralinos at much higher energies (up to hundreds ZeV) may produce sneutrino resonances by scattering off relic neutrinos in the Local Group hot dark halo. The consequent \tilde{\nu}-burst into hadronic final states could mimic Z-burst events, although with quite smaller conversion efficiency.Comment: 23 pages, 4 figures; one reference adde

Propagation of ultra-high energy protons in the nearby universe

We present a new calculation of the propagation of protons with energies above $10^{19}$ eV over distances of up to several hundred Mpc. The calculation is based on a Monte Carlo approach using the event generator SOPHIA for the simulation of hadronic nucleon-photon interactions and a realistic integration of the particle trajectories in a random extragalactic magnetic field. Accounting for the proton scattering in the magnetic field affects noticeably the nucleon energy as a function of the distance to their source and allows us to give realistic predictions on arrival energy, time delay, and arrival angle distributions and correlations as well as secondary particle production spectra.Comment: 12 pages, 9 figures, ReVTeX. Physical Review D, accepte

Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug–drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART

Background HIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low levonorgestrel exposure and unintended pregnancy. Objectives To investigate clinically applicable dose-adjustment strategies to overcome the known drug–drug interaction (DDI) between levonorgestrel and efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach. Methods A PBPK model was qualified against clinical data to predict levonorgestrel plasma concentrations when standard-dose (150 mg) levonorgestrel implants were administered alone (control group), as well as when standard-dose or increased-dose (300 mg) levonorgestrel implants were coadministered with either 600 or 400 mg of efavirenz. Results No difference was seen between in vivo clinical and PBPK-model-simulated levonorgestrel plasma concentrations (P > 0.05). Simulated levonorgestrel plasma concentrations were ∼50% lower at 48 weeks post-implant-placement in virtual individuals receiving standard-dose levonorgestrel with either 600 or 400 mg of efavirenz compared with the control group (efavirenz:control geometric mean ratio = 0.42 and 0.49, respectively). Conversely, increased-dose levonorgestrel in combination with either 600 or 400 mg of efavirenz was sufficient to restore levonorgestrel concentrations to levels similar to those observed in the 150 mg levonorgestrel control group 48 weeks post-implant-placement (efavirenz:control geometric mean ratio = 0.86 and 1.03, respectively). Conclusions These results suggest that the clinically significant DDI between efavirenz and levonorgestrel is likely to persist despite efavirenz dose reduction, whereas dose escalation of implantable levonorgestrel may represent a successful clinical strategy to circumvent efavirenz–levonorgestrel DDIs and will be of use to inform clinical trial design to assess coadministration of efavirenz and levonorgestrel implants

The Particle Physics Reach of High-Energy Neutrino Astronomy

We discuss the prospects for high-energy neutrino astronomy to study particle physics in the energy regime comparable to and beyond that obtainable at the current and planned colliders. We describe the various signatures of high-energy cosmic neutrinos expected in both neutrino telescopes and air shower experiments and discuss these measurements within the context of theoretical models with a quantum gravity or string scale near a TeV, supersymmetry and scenarios with interactions induced by electroweak instantons. We attempt to access the particle physics reach of these experiments.Comment: Mini-review article for New Journal of Physics, "Focus on Neutrinos" issue. 27 pages, 11 figure

Protein Binding of Lopinavir and Ritonavir During 4 Phases of Pregnancy: Implications for Treatment Guidelines

To investigate the intraindividual pharmacokinetics of total (protein bound + unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100mg/25mg) can overcome any pregnancy-associated changes