Orthopaedic and trauma surgeons' prioritisation of app quality principles based on their demographic background.

BACKGROUND: Although apps are becoming increasingly relevant in healthcare, there is limited knowledge about how healthcare professionals perceive "quality" in this context and how quality principles that can aid them in assessing health-related apps may be prioritised. The objective was to investigate physicians' views of predefined (general) quality principles for health apps and to determine whether a ranking algorithm applied to the acquired data can provide stable results against various demographic influences and may thus be appropriate for prioritisation. METHODS: Participants of an online survey of members of two German professional orthopaedics associations conducted between 02/12/2019 and 02/01/2020 were asked about their perception of a set of quality principles for health apps (i.e., "practicality," "risk adequacy," "ethical soundness," "legal conformity," "content validity," "technical adequacy," "usability," "resource efficiency," and "transparency"). Structured as a Kano survey, for each principle, there were questions about its perceived relevance and opinions regarding the presence or absence of corresponding characteristics. The available data were evaluated descriptively, and a newly developed method for prioritisation of the principles was applied overall and to different demographic strata (for validation). RESULTS: Three hundred eighty-two datasets from 9503 participants were evaluated. Legal conformity, content validity, and risk adequacy filled ranks one to three, followed by practicability, ethical soundness, and usability (ranks 4 to 6). Technical adequacy, transparency, and resource efficiency ranked last (ranks 7 to 9). The ranking based on the proposed method was relatively stable, irrespective of demographic factors. The principles were seen as essential, with one exception ("resource efficiency"). Only those with little to no interest in digitisation (22/382, 5.8%) rated the nine principles indifferently. CONCLUSIONS: The specified quality principles and their prioritisation can lay a foundation for future assessments of apps in the medical field. Professional societies build upon this to highlight opportunities for digital transformations in medicine and encourage their members to participate.

Medical studies in times of a pandemic - concepts of digital teaching for Orthopaedics and Trauma at german universities.

BACKGROUND: Due to the Covid-19 pandemic, on-site classroom teaching became limited at most German medical universities. This caused a sudden demand for digital teaching concepts. How the transfer from classroom to digital teaching or digitally assisted teaching was conducted was decided by each university and/or department individually. As a surgical discipline, Orthopaedics and Trauma have a particular focus on hands-on teaching as well as direct contact to patients. Therefore, specific challenges in designing digital teaching concepts were expected to arise. Aim of this study was to evaluate medical teaching at German universities one year into the pandemic as well as to identify potentials and pitfalls in order to develop possible optimization approaches. METHODS: A questionnaire with 17 items was designed and sent to the professors in charge of organising the teaching in Orthopaedics and Trauma at each medical university. A differentiation between Orthopaedics and Trauma was not made to allow a general overview. We collected the answers and conducted a qualitative analysis. RESULTS: We received 24 replies. Each university reported a substantial reduction of their classroom teaching and efforts to transfer their teaching to digital formats. Three sites were able to switch to digital teaching concepts completely, whereas others tried to enable classroom and bedside teaching at least for students of higher edcuational levels. The online platforms used varied depending on the university as well as the format it was supposed to support. CONCLUSION: One year into the pandemic significant differences concerning the proportions of classroom and digital teaching for Orthopaedics and Trauma can be observed. Simultaneously huge differences in concepts used to create digital teaching are present. Since a complete suspense of classroom teaching was never mandatory, several universities developed hygiene concepts to enable hands-on and bedside teaching. Despite these differences, some similarities were observed: the lack of time and personnel to generate adequate teaching material was reported as the leading challenge by all participants of this study.

Dexamethasone is a dose-dependent perpetrator of drug-drug interactions: implications for use in people living with HIV.

Global use of dexamethasone in COVID-19 patients has revealed a poor understanding of the drug-drug interaction (DDI) potential of dexamethasone, particularly with antiretroviral agents (ARVs). Dexamethasone is both a substrate and a dose-dependent inducer of cytochrome P450 3A4 (CYP3A4). As many ARVs are substrates and/or inhibitors or inducers of CYP3A4, there is concern about DDIs with dexamethasone either as a perpetrator or a victim. Assessment of DDIs that involve dexamethasone is complex as dexamethasone is used at a range of daily doses (generally 0.5 up to 40 mg) and a treatment course can be short, long, or intermittent. Moreover, DDIs with dexamethasone have been evaluated only for a limited number of drugs. Here, we summarize the available in vitro and in vivo data on the interaction potential of dexamethasone and provide recommendations for the management of DDIs with ARVs, considering various dexamethasone dosages and treatment durations.

Potential of digitalization within physiotherapy: a comparative survey.

BACKGROUND: Due to the global digitalization, implementation of digital elements into daily work can support physiotherapists' work but may also pose some challenges. Only little is known about physiotherapists' attitude towards digitalization. This study primarily aimed to analyze physiotherapists' attitude towards digitalization and to what extend digital tools have been implemented into their daily work. In second analysis, participants' characteristics such as age, working place, gender and mode of survey participation were assessed. METHODS: A 12-main-item survey amongst voluntary course participants of one physiotherapeutic training center was conducted via paper-based as well as online questionnaires between July 2018 and June 2019 including questions on participants' general as well as particular attitude towards digitalization, the use of (mobile) applications and possible advantages and disadvantages of the ongoing digital transformation. Sub-analysis was performed for age (≤40 years versus > 40 years), gender, mode of participation (paper vs. online) and working place (practice vs. hospital). RESULTS: Overall, 488 physiotherapists participated in the survey. In comparison of the age groups, younger participants had more concerns about data security (p = 0.042) and insufficient financial remuneration (p < 0.001). Younger participants stated higher satisfaction with data literacy than their counterparts (p = 0.0001). Physiotherapists working in the outpatient sector, rather than in hospitals, expected digitalization to increase more in relevance (p < 0.001). The online respondents (OG) indicated that they had more knowledge about key aspects of the current legal situation regarding digitalization than participants completing the paper-based survey (p = 0.002). 50.4% of the considered digitalization as useful for their job. CONCLUSIONS: The majority of participants saw high potential for digitalization in the physiotherapy sector. Younger physiotherapists seem to be more concerned about data security and insufficient financial remuneration. Physiotherapists in the outpatient sector seem to see more potential in digital transformations. General concerns like missing reimbursement, lack of data security or knowledge on legal frameworks should be addressed in the future. Further studies should focus on identifying specific digital tools which can support physiotherapists.

How far has the digitization of medical teaching progressed in times of COVID-19? A multinational survey among medical students and lecturers in German-speaking central Europe.

BACKGROUND: To ensure successful medical education despite the COVID-19 pandemic, the demand for online instruction has substantially increased. Fast and efficient teaching in a digital format poses a great challenge for medical students and lecturers as well as the universities. OBJECTIVE: The aim of this study is to capture the readiness of medical students and faculty members to participate in rapidly- evolving online education. METHODS: This cross-sectional study is based on two questionnaires distributed among medical students and associate deans for education in Germany, Austria and Switzerland. Questions included decision- making questions, categorical questions, and open-ended questions, all addressing the frequency and format of the digital education offered, the perceived quality of digital education, and medical student satisfaction with digital education. Questions about missing content and areas for improvement from the perspectives of medical students were included. The associate deans were asked for their opinions about the impact of the pandemic on teaching, the organizational setup and implementation of digital education by universities, and plans for future initiatives. RESULTS: Three thousand and thirty medical students (m = 752 and f = 2245) from 53 universities participated in the study. The study showed that 92% of students were affected by the pandemic, and 19% of the students viewed the changes as entirely negative. 97% of the medical students were able to participate in digital courses, but only 4% were able to learn exclusively online. For 77% of the medical students, digital offerings accounted for over 80% of the education offered. In terms of content, medical students complained about a lack of practical teaching, such as contact with patients, lecturers, fellow medical students, and a poor perceived quality of teaching due to dubbing, frequent changeover of seminars, problem-oriented learning groups and in-person teaching, a lack of interaction possibilities and a lack of technical equipment, such as lecturers' knowledge and server capacities, at the universities. Overall, almost half of the medical students (42%) rated the implementation of digital teaching at their universities as good or very good. Forty-one of the 53 associate deans responded to the questionnaire, and 35 felt medical education was influenced by the pandemic. The associate deans (80%; 33/41) felt that the digitalization of medical education was negatively influenced by the pandemic. Only 44% (18/41) felt that their universities were well or very well positioned for digital teaching. All the associate deans believe that digital teaching in medicine will continue after the pandemic. CONCLUSIONS: In the German-speaking world, the rapid conversion of medical teaching to a digital format has been well implemented in many cases. The perceived quality of the implementation of digital education still lacks practical relevance and the use of new digital media, such as learning games, VR, and online question time. The digital format of medical education will likely continue beyond the COVID-19 pandemic.

An Augmented Reality Device for Remote Supervision of Ultrasound Examinations in International Exercise Science Projects: Usability Study.

BACKGROUND: Support for long-distance research and clinical collaborations is in high demand and has increased owing to COVID-19-related restrictions on travel and social contact. New digital approaches are required for remote scientific exchange. OBJECTIVE: This study aims to analyze the options of using an augmented reality device for remote supervision of exercise science examinations. METHODS: A mobile ultrasound examination of the diameter and intima-media thickness of the femoral and carotid arteries was remotely supervised using a head-mounted augmented reality device. All participants were provided with a link to a YouTube video of the technique in advance. In part 1, 8 international experts from the fields of engineering and sports science were remotely connected to the study setting. Internet connection speed was noted, and a structured interview was conducted. In part 2, 2 remote supervisors evaluated 8 physicians performing an examination on a healthy human subject. The results were recorded, and an evaluation was conducted using a 25-item questionnaire. RESULTS: In part 1, the remote experts were connected over a mean distance of 1587 km to the examination site. Overall transmission quality was good (mean upload speed: 28.7 Mbps, mean download speed: 97.3 Mbps, mean ping: 21.6 milliseconds). In the interview, participants indicated that the main potential benefits would be to the fields of education, movement analysis, and supervision. Challenges regarding internet connection stability and previous training with the devices used were reported. In part 2, physicians' examinations showed good interrater correlation (interclass correlation coefficient: 0.84). Participants valued the experienced setting as highly positive. CONCLUSIONS: The study showed the good feasibility of the chosen design and a highly positive attitude of all participants toward this digital approach. Head-mounted augmented reality devices are generally recommended for collaborative research projects with physical examination-based research questions.

Instructing Ultrasound-guided Examination Techniques Using a Social Media Smartphone App.

Social media applications on smartphones allow for new avenues of instruction in sports medicine and exercise sciences. This study tested the feasibility of instructing health care personnel through videos of ultrasound vascular measurements distributed by a social media messenger application. After two training sessions with an ultrasound device, voluntary physicians (n=10) and nurses (n=10) received a video for the performance of an ultrasound-guided determination of intima-media-thickness and diameter of the femoral arteries via a social media messenger application. All participants examined the same healthy human subject. There was no significant difference between the groups regarding overall time of performance, measurements of the femoral arteries, or a specifically designed "assessment of mobile imparted arterial ultrasound determination" score. The physicians group achieved significantly higher scores in the established "objective structured assessment of ultrasound skills" score (p=0.019). Approval of the setting was high in both groups. Transmission of videos via social media applications can be used for instructions on the performance of ultrasound-guided vascular examinations in sports medicine, even if investigators' performances differ depending on their grade of ultrasound experience. In the future, the chosen approach should be tested in practical scientific examination settings.

The challenging pathway towards the identification of SARS-CoV-2/COVID-19 therapeutics.

The development of therapeutic agents against SARS-CoV-2/COVID-19  faces numerous barriers and a multidisciplinary approach to evaluating drug efficacy and toxicity is essential. Experimental and preclinical data should be integrated into a comprehensive analysis, where drug potency, the timing of therapy initiation, drug combinations, variability in systemic and local drug exposure and short- and long-term toxicities represent fundamental factors for the rational identification of candidates and prioritization of clinical investigations. Although the identification of SARS-CoV-2 therapeutics is a priority, rigorous and transparent methodologies are crucial to ensure that accelerated research programmes result in high-quality and reproducible findings.

Drug interactions: a review of the unseen danger of experimental COVID-19 therapies.

As global health services respond to the coronavirus pandemic, many prescribers are turning to experimental drugs. This review aims to assess the risk of drug-drug interactions in the severely ill COVID-19 patient. Experimental therapies were identified by searching ClinicalTrials.gov for 'COVID-19', '2019-nCoV', '2019 novel coronavirus' and 'SARS-CoV-2'. The last search was performed on 30 June 2020. Herbal medicines, blood-derived products and in vitro studies were excluded. We identified comorbidities by searching PubMed for the MeSH terms 'COVID-19', 'Comorbidity' and 'Epidemiological Factors'. Potential drug-drug interactions were evaluated according to known pharmacokinetics, overlapping toxicities and QT risk. Drug-drug interactions were graded GREEN and YELLOW: no clinically significant interaction; AMBER: caution; RED: serious risk. A total of 2378 records were retrieved from ClinicalTrials.gov, which yielded 249 drugs that met inclusion criteria. Thirteen primary compounds were screened against 512 comedications. A full database of these interactions is available at www.covid19-druginteractions.org. Experimental therapies for COVID-19 present a risk of drug-drug interactions, with lopinavir/ritonavir (10% RED, 41% AMBER; mainly a perpetrator of pharmacokinetic interactions but also risk of QT prolongation particularly when given with concomitant drugs that can prolong QT), chloroquine and hydroxychloroquine (both 7% RED and 27% AMBER, victims of some interactions due to metabolic profile but also perpetrators of QT prolongation) posing the greatest risk. With management, these risks can be mitigated. We have published a drug-drug interaction resource to facilitate medication review for the critically ill patient.

Correction: Undergraduate Medical Competencies in Digital Health and Curricular Module Development: Mixed Methods Study.

[This corrects the article DOI: 10.2196/22161.].

Undergraduate Medical Competencies in Digital Health and Curricular Module Development: Mixed Methods Study.

BACKGROUND: Owing to an increase in digital technologies in health care, recently leveraged by the COVID-19 pandemic, physicians are required to use these technologies appropriately and to be familiar with their implications on patient care, the health system, and society. Therefore, medical students should be confronted with digital health during their medical education. However, corresponding teaching formats and concepts are still largely lacking in the medical curricula. OBJECTIVE: This study aims to introduce digital health as a curricular module at a German medical school and to identify undergraduate medical competencies in digital health and their suitable teaching methods. METHODS: We developed a 3-week curricular module on digital health for third-year medical students at a large German medical school, taking place for the first time in January 2020. Semistructured interviews with 5 digital health experts were recorded, transcribed, and analyzed using an abductive approach. We obtained feedback from the participating students and lecturers of the module through a 17-item survey questionnaire. RESULTS: The module received overall positive feedback from both students and lecturers who expressed the need for further digital health education and stated that the field is very important for clinical care and is underrepresented in the current medical curriculum. We extracted a detailed overview of digital health competencies, skills, and knowledge to teach the students from the expert interviews. They also contained suggestions for teaching methods and statements supporting the urgency of the implementation of digital health education in the mandatory curriculum. CONCLUSIONS: An elective class seems to be a suitable format for the timely introduction of digital health education. However, a longitudinal implementation in the mandatory curriculum should be the goal. Beyond training future physicians in digital skills and teaching them digital health's ethical, legal, and social implications, the experience-based development of a critical digital health mindset with openness to innovation and the ability to assess ever-changing health technologies through a broad transdisciplinary approach to translate research into clinical routine seem more important. Therefore, the teaching of digital health should be as practice-based as possible and involve the educational cooperation of different institutions and academic disciplines.

[Economic aspects of digitalization in orthopedics and trauma surgery]. / Ökonomische Aspekte der Digitalisierung in Orthopädie und Unfallchirurgie.

INTRODUCTION: In addition to the advantages for patients and physicians, the progression of digitalization will also have economic implications for healthcare systems in toto worldwide. The integration of digital innovations enables healthcare institutions to transform their current activities and processes and to create a new form of patient care. IMPORTANT ECONOMIC TOPICS OF DIGITALIZATION: Using digital applications process optimization can be achieved by increased efficiency and therefore a reduction in costs in the healthcare system. Improved processes can in turn achieve an increase in quality in the treatment of patients. Simultaneously, a duplication of investigations can be avoided through digital interfaces and the communication among the healthcare professions involved can be improved, which would result in a conservation of resources. Finally, these influences can lead to more precision in medicine, acceleration of healing processes and represent an advantage for all parties involved. PERSPECTIVES: Economic redistribution due to digitalization of medicine will become increasingly apparent in the future. Ethical considerations as well as data protection will be important topics. At the same time investments and digital innovations must be sponsored by the government and industry. Scientific studies are necessary to secure the evidence of new methods for practice in orthopedics and trauma surgery.

[Digitalization in orthopedics and trauma surgery: current status of clinical and practical aspects 2020]. / Digitalisierung in Orthopädie und Unfallchirurgie: Stand 2020 in Klinik und Praxis.

This article deals with the current state mid-2020 in the clinical and practical aspects from the perspective of orthopedics and trauma surgery. The risks, difficulties, potentials and options are discussed in detail. The following topics are specifically debated: infrastructure of telematics, apps and mobile health, online video consultation, electronic medical records and data protection. The advantages and disadvantages and the current state of each topic in the special case of orthopedics and trauma surgery are discussed. Additionally, seven meaningful examples from the field of digital applications are named. A survey of members of the Professional Association of Orthopedic and Trauma Surgeons (BVOU) is described and analyzed. In a concluding perspective the current hurdles and future topics that need clarification are addressed.

[Potential of digitalization in undergraduate and postgraduate medical education and training in orthopedics and trauma surgery]. / Potenzial der Digitalisierung in Aus­, Fort- und Weiterbildung in Orthopädie und Unfallchirurgie.

INTRODUCTION: In its digital agenda the German Federal Government pursues the ambitious objective to facilitate digital competence and perform research into digital learning and teaching processes. Considerable investments are to be concentrated into the future viability of education, academic research and digitalization. As far as academic teaching and further education are concerned, not only in the field of orthopedics and trauma surgery, three aspects can be identified: digital organization, digital competence and digital tools. DIGITAL APPLICATIONS: New formats, such as the elective subject digital health of the Charité in Berlin, enable digital competences to be mediated in a multimodal and interdisciplinary way. With the help of a newly developed app the University of Essen provides teachers and students with mobile and flexible access to information on lectures in terms of content and organization. Especially because of transparency, high legal compliance and predictability, the digital logbook for the resident training program promises a real innovation for trainees in the further training reformation. Augmented and virtual reality play a crucial role in the imparting of practical skills and interconnect high-tech with classical craftsmanship. Digital training course formats have significantly gained in importance and are meanwhile well-established tools for efficient advanced medical training. OUTLOOK: If orthopedic and trauma surgeons take an active role in the process of digitalization of teaching, they can take part in decisions, adequately prepare the colleagues of tomorrow, optimize patient care, encourage innovations and altogether improve the discipline even more.

[Computer-assisted decision-making for trauma patients]. / Computerassistierte Entscheidungsfindung beim Traumapatienten.

BACKGROUND: In the management of trauma patients in the resuscitation room many time-pressured and critical decisions must continuously be made in complex situations. Even experienced teams frequently make errors in this context. Computer-assisted decision-making systems can predict critical situations based on patient data continuously acquired online. Based on the calculated predictions these systems can suggest the next steps in managing the patient. This review summarizes the current literature on computer-assisted decision-making in the management of trauma patients. OBJECTIVE: A literature review summarizing existing concepts and applications of computer-assisted decision-making support for the management of trauma patients. METHODS: Narrative review article based on an analysis of literature in the German and English languages from the last 10 years. RESULTS: There exist numerous computer-assisted decision-making systems in the field of trauma care. Several studies could show that computer-assisted decision-making can improve the outcome in the preclinical setting, the resuscitation room and in the intensive care unit. For further validation and implementation of these systems, information technological barriers have to be overcome, existing systems need to be adapted to current data protection regulations and large multicenter studies are necessary. CONCLUSION: Computer-assisted decision-making can help to improve the management of trauma patients; however, before a ubiquitous implementation a number of technological and legislative barriers have to be overcome.

Potentials of Digitalization in Sports Medicine: A Narrative Review.

Digital transformation is becoming increasingly common in modern life and sports medicine, like many other medical disciplines, it is strongly influenced and impacted by this rapidly changing field. This review aims to give a brief overview of the potential that digital technologies can have for health care providers and patients in the clinical practice of sports medicine. We will focus on mobile applications, wearables, smart devices, intelligent machines, telemedicine, artificial intelligence, big data, system interoperability, virtual reality, augmented reality, exergaming, or social networks. While some technologies are already used in current medical practice, others still have undiscovered potential. Due to the diversity and ever changing nature of this field, we will briefly review multiple areas in an attempt to give readers some general exposure to the landscape instead of a thorough, deep review of one topic. Further research will be necessary to show how digitalization applications could best be used for patient treatments.

Predicting Drug-Drug Interactions Between Rifampicin and Long-Acting Cabotegravir and Rilpivirine Using Physiologically Based Pharmacokinetic Modeling.

BACKGROUND: Cabotegravir and rilpivirine are 2 long-acting (LA) antiretrovirals that can be administered intramuscularly; their interaction with rifampicin, a first-line antituberculosis agent, has not been investigated. The aim of this study was to simulate and predict drug-drug interactions (DDIs) between these LA antiretroviral agents and rifampicin using physiologically based pharmacokinetic (PBPK) modeling. METHODS: The designed PBPK models were qualified (according to European Medicines Agency guidelines) against observed data for oral formulations of cabotegravir, rilpivirine, and rifampicin. Induction potential of rifampicin was also qualified by comparing the DDI between oral cabotegravir and oral rilpivirine with rifampicin. Qualified PBPK models were utilized for pharmacokinetic prediction of DDIs. RESULTS: PBPK models predicted a reduction in both area under the curve (AUC0-28 days) and trough concentration (Ctrough, 28th day) of LA cabotegravir of 41%-46% for the first maintenance dose coadministered with 600 mg once-daily oral rifampicin. Rilpivirine concentrations were predicted to decrease by 82% for both AUC0-28 days and Ctrough, 28th day following the first maintenance dose when coadministered with rifampicin. CONCLUSIONS: The developed PBPK models predicted the theoretical effect of rifampicin on cabotegravir and rilpivirine LA intramuscular formulations. According to these simulations, it is likely that coadministration of rifampicin with these LA formulations will result in subtherapeutic concentrations of both drugs.

Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV infection and psychiatric disorders: An integrated analysis.

Although direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection are highly efficacious and safe, treatment initiation is often limited in patients with neuropsychiatric disorders due to concerns over reduced treatment adherence and drug-drug interactions. Here, we report adherence, efficacy, safety and patient-reported outcomes (PROs) from an integrated analysis of registrational studies using the pangenotypic DAA regimen of glecaprevir and pibrentasvir (G/P). Patients with chronic HCV genotypes 1-6 infection with compensated liver disease (with or without cirrhosis) receiving G/P for 8, 12 or 16 weeks were included in this analysis. Patients were classified as having a psychiatric disorder based on medical history and/or co-medications. Primary analyses assessed treatment adherence, efficacy (sustained virologic response at post-treatment week 12; SVR12), safety and PROs. Among 2522 patients receiving G/P, 789 (31%) had a psychiatric disorder with the most common diagnoses being depression (64%; 506/789) and anxiety disorders (27%; 216/789). Treatment adherence was comparably high (>95%) in patients with and without psychiatric disorders. SVR12 rates were 97.3% (768/789; 95% CI = 96.2-98.5) and 97.5% (1689/1733; 95% CI = 96.7-98.2) in patients with and without psychiatric disorders, respectively. Among patients with psychiatric disorders, SVR12 rates remained >96% by individual psychiatric diagnoses and co-medication classes. Overall, most adverse events (AEs) were mild-to-moderate in severity with serious AEs and AEs leading to G/P discontinuation occurring at similarly low rates in both patient populations. In conclusion, G/P treatment was highly efficacious, well-tolerated and demonstrated high adherence rates in patients with chronic HCV infection and psychiatric disorders.

Real-world safety and effectiveness of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C virus genotype 1- and 4-infected patients with diverse comorbidities and comedications: A pooled analysis of post-marketing observational studies from 13 countries.

Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment-naïve or -experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post-treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off-label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow-up data at post-treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2-96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b-infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro-esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post-baseline Grade 3-4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real-world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real-world setting.

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.