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Traumatic heterotopic ossification (HO) of the lower extremity is relatively rare but is of major importance in clinical practice. They are defined as posttraumatic abnormal formations of bone within soft tissue outside of the skeletal system. This article describes the clinical case of a 31-year-old male patient who suffered 2 traumatic events within 12 months—a gunshot wound in the lumbar spine/gluteal region followed by a severe traumatic brain injury with intracranial hemorrhage in a traffic accident as a pedestrian. Clinically, the patient was bedridden because of complete stiffening of the lumbar spine, both hip joints, and the left knee joint. After preoperative diagnosis, 3 surgical ablations of the HO were performed on both the hip joints and the left knee joint. In addition, physiotherapeutic exercise, postoperative nonsteroidal anti-inflammatory drug administration (25 mg of indomethazine for 6 weeks, 3 times a day), and perioperative radiation with 7 Gy for each operation were advised. After 4 years of follow-up, the patient showed significant improvement. In HO treatment, prophylactic local radiotherapy (pre- and postoperative radiation with a local single dose of 7 Gy) and postoperative administration of nonsteroidal anti-inflammatory drugs are often recommended. For therapeutic purposes, surgical resection is still indicated for pronounced cases.

Hintergrund: Im Verlauf der COVID-19-Pandemie haben offizielle Schutzmaßnahmen traditionelle Präsenzfortbildungen zum Erliegen gebracht. Für das Fach Orthopädie und Unfallchirurgie (O&U) gibt es bisher bezüglich der Angebots- und Nachfragesituation von E‑Learning per Webinar im Kontext der COVID-19-Pandemie keine belastbaren Zahlen. Fragestellung: Das Ziel der vorliegenden Arbeit ist die quantitative Beschreibung von Angebot und Nachfrage deutschsprachiger Online-Fortbildungen mit Webinar-Charakter aus der Orthopädie und Unfallchirurgie (O&U) im zeitlichen Zusammenhang mit der COVID-19-Pandemie. Material und Methoden: Über gängige Suchmaschinen wurden deutschsprachige, nichtkommerzielle, editierte und wissenschaftlich fundierte Fortbildungen in Form von Webinaren im Bereich O&U von Anbietern mit Sitz in Deutschland identifiziert und interviewt. Ergebnisse: Alle 4 eingeschlossenen Anbieter (AO Online Campus, BVOU Study Club, OU TO GO, WebDGU) nahmen an den strukturierten Interviews teil und stimmten einer Offenlegung der Teilnehmerzahlen zu. Das Angebot von Webinaren stieg im zeitlichen Zusammenhang mit der COVID-19-Pandemie an. Ebenfalls erhöhten sich bei allen 4 Anbietern die Teilnehmerzahlen. Diskussion: Während OU TO GO und der BVOU Study Club bereits vor der Pandemie auf E‑Learning-Formate spezialisiert waren, wurde das Kursangebot der AO durch den neu etablierten AO online Campus erweitert und WebDGU ganz neu konzipiert. Eine Limitation der Studie ist die exklusive Ausrichtung auf Webinare und nichtkommerzielle Anbieter. Die Ergebnisse lassen auf positive Entwicklungen in O&U im Bereich E‑Learning hoffen. Graphic abstract:

Digitalisierung nimmt einen kontinuierlich wachsenden Stellenwert in der Medizin ein. Prozesse werden optimiert, Daten digital erfasst, analysiert und archiviert. Wenngleich in Deutschland noch ein vergleichsweise großer Aufholbedarf existiert, befinden wir uns auf einem soliden Weg. Mit der Etablierung des European Health Data Space (EHDS) wird in Brüssel ein Meilenstein für den sicheren Austausch von Daten gesetzt. Digitalisierung beinhaltet das Potenzial für umfangreiche Prozessoptimierung. Während derzeit ein Gros der Arbeitszeit deutscher Ärzte von Bürokratie verschlungen wird, kann ein relevanter Anteil dieser Arbeit durch digitale Lösungen effizienter erledigt werden. Die Digitalisierung ersetzt nicht den Arzt, sondern unterstützt ihn, zum Wohle des Patienten. Zahlreiche Wege sowie damit verbundene Transport- und Logistikkosten sind vermeidbar bzw. durch digitale Ergänzungen und neue Darreichungsformen auf digitalem Wege adressierbar. Dies schont Ressourcen, spart Zeit und optimiert die Versorgung. Die Offenheit und Affinität von Ärzten und Patienten für das Thema hängen bedeutend von der Digital Health Literacy, d. h. dem Verständnis und Wissen zum Thema, ab. Kontinuierlich Ängste abzubauen und Akzeptanz zu steigern, ist das Ziel der kommenden Jahre. Zudem bedarf es relevanter Investitionen in die technische Grundausstattung auf Soft- und Hardwareseite.

This article provides an overview of the potentials and vast areas of digital applications in the field of sports medicine.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.

Modern health systems have to respond to a wide variety of catastrophic scenarios, from natural disasters to terror attacks. It is reasonable to already start educational approaches for physicians in this field at medical school level. An approach combining civilian disaster medicine and military deployment medicine can be beneficial both for clinical strategies and in undergraduate teaching.

IntroductionMilitary surgeons must be prepared to care for severe and complex life-threatening injuries rarely seen in the civilian setting. Typical civilian training and practice do not provide adequate exposure to the broad set of surgical skills required. The German Bundeswehr Medical Service has developed and refined the War Surgery Course (WSC) to meet this training gap. This article describes the recent experience with this readiness curriculum.MethodsRun annually since 1998, WSC consists nowadays of 5 days with 20 theoretical modules. Four sessions with standardised practical skills training use a live tissue porcine model, and the recently added cadaver-based Advanced Surgical Skills for Exposure in Trauma course. Sixteen military surgeons who participated in the WSC in January 2016 completed a survey of their self-rated readiness for 114 predefined emergency skills before and after completion, and provided an overall evaluation of the course.ResultsSelf-assessed readiness improved significantly over baseline for all areas covered in both the practical skills and theoretical knowledge portions of the WSC curriculum. Additionally, all participants rated the course as important and universally recommended it to other military surgeons preparing for missions.ConclusionsThe WSC course format was well received and perceived by learners as a valuable readiness platform. Ongoing evaluation of this course will enable data-driven evolution to ensure a maximum learning benefit for participants. With the increasing multinational nature of modern military missions, surgeons’ training should follow international standards. Continuing evolution of military surgical training courses should further encourage the sharing and adoption of best educational practices.

Digital learning (e-learning) has become a firm part of surgical undergraduate education. However, there is still a lack in analyzing e-learning tools in experimental settings without potentially biasing curricular influences. This study should compare students’ learning outcome with podcasts versus book texts under laboratory conditions in the field of orthopedics.

Long-acting injectable antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 study was done to characterise the safety, acceptability, and pharmacokinetic and pharmacodynamic profile of long-acting rilpivirine.

ABSTRACTEfavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxin in vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available published in vitroand in vivodata. The effect of the CYP2B6c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above the in vitrotoxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above the in vitrotoxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of the CYP2B6genotype, particularly in those with impaired blood-brain barrier integrity.

The use of antiretrovirals as pre-exposure prophylaxis (PrEP) is highly efficacious in HIV prevention. The World Health Organization recently recommended Truvada®(Gilead Sciences, Inc.) or tenofovir disoproxil fumarate (TDF) for high-risk individuals, with limited data for single-agent TDF PrEP in men who have sex with men (MSM). We report two cases of TDF PrEP failure in MSM who had received long-term TDF for hepatitis B infection and had therapeutic levels of drug immediately after HIV acquisition. Rapid antiretroviral intensification at diagnosis of acute HIV infection failed to limit immune dysfunction or prevent the establishment of a viral reservoir.

ABSTRACTA long-acting injectable form of rilpivirine (RPV) is being evaluated in clinical trials for the prevention of HIV infection. Preclinical testing was undertaken to define RPV pharmacokinetic (PK) and pharmacodynamic (PD) activities in ectocervical and colonic tissue treated in vitro. Tenfold dilutions of RPV were added to the basolateral medium of polarized ectocervical and colonic explant tissues. To half the explants, HIV-1BaLwas applied to the apical tissue surface. After culture overnight, all the explants were washed and the RPV in the explants not exposed to HIV was quantified using a validated liquid chromatography-mass spectrometry assay. For efficacy, explants exposed to HIV remained in culture, and supernatants were collected to assess viral replication using a p24 enzyme-linked immunosorbent assay. The data were log10transformed, and PK/PD correlations were determined using GraphPad Prism and SigmaPlot software. The application of RPV to the basolateral medium at 10 μM and 1 μM was effective in protecting ectocervical and colonic tissues, respectively, from HIV infection. When the RPV in paired ectocervical and colonic explant tissues was quantified, significant inverse linear correlations (P< 0.001) between p24 and RPV concentrations were obtained; more viral replication was noted at lower drug levels. Using a maximum effect model, RPV concentrations of 271 nM in ectocervical tissue and 45 nM in colonic tissue were needed to achieve a 90% effective concentration (EC90). These data demonstrate that RPV can suppress HIV infection in mucosal tissue but that higher levels of RPV are needed in female genital tract tissue than in gastrointestinal tract tissue for protection.

Use of ‘party drugs’, a particular set of recreational drugs used in the context of ‘ChemSex’, is frequent among MSM living with HIV. A recently published observational study showed that more than half of HIV-infected MSM interviewed reported use of illicit substances in the previous 3 months, with frequent concomitant use of three or more drugs. These substances are a combination of ‘club drugs’ (methylenedioxymethamphetamine, gamma-hydroxybutyrate, ketamine, benzodiazepine) and drugs that are more specifically used in a sexualized context (methamphetamine, mephedrone, poppers and erectile dysfunction agents). Although formal data on pharmacokinetic or pharmacodynamic interactions between recreational drugs and antiretroviral agents are lacking, information regarding potentially toxic interactions can be theorized or sometimes conclusions may be drawn from case studies and cohort observational studies. However, the risk of coadministering party drugs and antiretrovirals should not be overestimated. The major risk for a drug–drug interaction is when using ritonavir-boosting or cobicistat-boosting agents, and maybe some nonnucleoside reverse transcriptase inhibitors. Knowledge of the metabolic pathways of ‘party drugs’ may help in advising patients on which illicit substances have a high potential for drug–drug interactions, as this is not the case for all.

ABSTRACTPharmacokinetic (PK) data describing a prolonged time course of antiretrovirals in plasma and peripheral blood mononuclear cells (PBMCs) are important for understanding and managing late or missed doses and to assess the appropriateness of compounds for preexposure prophylaxis (PrEP). This study aimed to evaluate the PK of coformulated tenofovir disoproxil fumarate (DF), emtricitabine, and rilpivirine in plasma and of the intracellular (IC) anabolites tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in healthy volunteers up to 9 days after drug cessation. Individuals received daily tenofovir DF-emtricitabine-rilpivirine (245/200/25 mg) for 14 days. Drug intake was stopped, and serial sampling occurred prior to the final dose and up to 216 h (9 days) after stopping drug intake. Concentrations were quantified and PK parameters calculated. Eighteen volunteers completed the study. The terminal elimination plasma half-lives for tenofovir and emtricitabine over 216 h (geometric mean [90% confidence interval]) were higher than those seen over 0 to 24 h (for tenofovir, 31 h [27 to 40 h] versus 13.3 h [12.5 to 15.1 h]; for emtricitabine, 41 h [36 to 54 h] versus 6.4 h (5.9 to 7.6 h]). Model-predicted IC half-lives (0 to 168 h) were 116 h (TFV-DP) and 37 h (FTC-TP). The plasma rilpivirine concentration at 216 h was 4.5 ng/ml (4.2 to 6.2 ng/ml), and half-lives over 0 to 216 h and 0 to 24 h were 47 h (41 to 59 h) and 35 h (28 to 46 h), respectively. These data contribute to our understanding of drug behavior following treatment interruption; however, adherence to therapy should be promoted. Validated plasma and IC target concentrations are necessary to allow interpretation with respect to sustained virus suppression or HIV prevention. (The trial was conducted in accordance with the Declaration of Helsinki [EudraCT 2012-002781-13].)

Efavirenz (EFV) is one of the preferred components of first-line antiretroviral treatment. EFV is characterized by a long plasma half-life (40–55 hours) with large interpatient variability, which raises the potential for individualization of therapy. Analyses of EFV levels in plasma require specialized facilities (cold storagetransport) which, in resource-limited settings, can be problematic; dried blood spots (DBS)-EFV measurements thus provide a cheap easy alternative for therapeutic drug monitoring. Our aim was to develop and validate a liquid chromatography–mass spectrometry method to quantify EFV in DBS collected as part of clinical trials in resource-limited settings.

Background CYP3A4 induction by efavirenz (EFV) persists after drug cessation; we assessed the pharmacokinetics (PK), efficacy and safety of maraviroc (MVC) administered to HIV-infected individuals switching from EFV-containing therapy.Methods Patients with R5-tropic virus and suppressed viral load on two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus EFV switched EFV to MVC 600 mg twice daily for 14 days, and then to MVC 300 mg twice daily. Following screening, three intensive PK visits were performed (sampling was pre-dose and 1, 2, 4, 6, 8 and 12 h post-dose): day 1 (VISIT 1, MVC 600 mg twice daily), day 14 (VISIT 2, steady-state MVC 600 mg twice daily) and day 28 post regimen switch (VISIT 3, steady-state MVC 300 mg twice daily); MVC trough concentration (Ctrough) was determined 3, 6 and 10 days following regimen switch and viral loads up to week 24. MVC PK parameters on visits 1 and 2 and MVC Ctroughon day 6 were compared to visit 3 (reference) via geometric mean ratios (GMR) and 95% CIs.Results Twelve males completed the study. MVC PK parameters at visit 1 versus visit 3 were: GMR and 95% CI 12-h area under the curve (AUC0–12) 1.25 (1.00, 1.58); Cmax1.64 (1.16, 2.31); Ctrough0.61 (0.46, 0.80). Visit 2 MVC PK parameters were significantly higher than visit 3: GMR and 95% CI AUC0–122.31 (1.84, 2.90); Cmax2.42 (1.87, 3.12); Ctrough2.25 (1.74, 2.91). MVC was well tolerated with no grade 3/4 adverse events; all subjects maintained viral suppression to the end of the study.Conclusions The EFV induction effect necessitated increased MVC dose to 600 mg twice daily following switch and persisted for approximately one week after EFV cessation. This is less than the 2-week induction observed when switching EFV to etravirine and highlights the importance of studying different tail interactions. Higher dose MVC was well tolerated. All measured MVC Ctroughconcentrations exceeded wild-type 90% inhibitory concentration.

Efavirenz-based antiretroviral therapy is recommended for prevention of mother-to-child transmission of HIV with two programmatic options: lifelong therapy for all women or treatment until cessation of breastfeeding. However, the risk of HIV resistance emerging after discontinuing efavirenz-based antiretroviral therapy is unclear. We review present knowledge surrounding the emergence of resistance after stopping efavirenz-based antiretroviral regimens.

The CYP3A422 (c.522-191 C>T; rs35599367) single nucleotide polymorphism has been associated with lower CYP3A4 mRNA expression and activity. We investigated the association of CYP3A422 with the pharmacokinetics of lopinavir through a population pharmacokinetic approach. The minor allele frequency for CYP3A422 was 0.035, and seven of 375 patients had a combination of CYP3A422 and SLCO1B1521T>C alleles. Lack of information on the ethnicity in this cohort should be considered as a limitation. However, in the final model, the population clearance was 5.9 lh and patients with CYP3A42222 had 53 (P=0.023) lower clearance compared with noncarriers. In addition, the combined effect of CYP3A422 with SLCO1B1521T>C (previously shown to be associated with lopinavir plasma concentration) was analysed. We observed a 2.3-fold higher lopinavir trough concentration (Ctrough) in individuals with CYP3A42222, a 1.8-fold higher Ctroughwith SLCO1B1521CC and a 9.7-fold higher Ctroughin individuals homozygous for both single nucleotide polymorphisms, compared with noncarriers. A simulated dose-reduction scenario showed that 200100 mg lopinavirritonavir was adequate to achieve therapeutic concentration in individuals with CYP3A42222 alone or in combination with SLCO1B1521CC. These data further our understanding of the genetic basis for variability in the pharmacokinetics of lopinavir.

Within the last decade, e-learning has gained a consistent place in surgical teaching. However, as the use of new programs is often voluntary, more information on the implications of the data regarding user acceptance and knowledge with mandatory use is desirable, especially in the context of the long-term developments of courses.

ABSTRACTRifampin is a potent inducer of cytochrome P450 (CYP) enzymes and transporters. Drug-drug interactions during tuberculosis treatment are common. Induction by rifapentine and rifabutin is understudied. Rifampin and rifabutin significantly induced CYP3A4(80-fold and 20-fold, respectively) in primary human hepatocytes. The induction was concentration dependent. Rifapentine induced CYP3A4 in hepatocytes from 3 of 6 donors. Data were also generated for ABCB1, ABCC1, ABCC2, organic anion-transporting polypeptide 1B1 (OATP1B1), and OATP1B3. This work serves as a basis for further study of the extent to which rifamycins induce key metabolism and transporter genes.

ABSTRACTRilpivirine is a nonnucleoside reverse transcriptase inhibitor approved for treatment of HIV-1 infection in antiretroviral-naive adult patients. Potential interactions with drug transporters have not been fully investigated. Transport by and inhibition of drug transporters by rilpivirine were analyzed to further understand the mechanisms governing rilpivirine exposure and determine the potential for transporter-mediated drug-drug interactions. The ability of rilpivirine to inhibit or be transported by ABCB1 was determined using ABCB1-overexpressing CEMVBL100cells and Caco-2 cell monolayers. The Xenopus laevisoocyte heterologous protein expression system was used to clarify if rilpivirine was either transported by or inhibited the function of influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A2, SLC22A6, and SLC22A8. The ability of rilpivirine to inhibit or be transported by SLC22A1 was determined using SLC22A1-expressing KCL22 cells. Rilpivirine showed higher accumulation in SLC22A1-overexpressing KCL22 cells than control cells (27% increase, P= 0.03) and inhibited the functionality of SLC22A1 and SLC22A2 transport with 50% inhibitory concentrations (IC50s) of 28.5 μM and 5.13 μM, respectively. Inhibition of ABCB1-mediated digoxin transport was determined for rilpivirine, which inhibited digoxin transport in the B-to-A direction with an IC50of 4.48 μM. The maximum rilpivirine concentration in plasma in patients following a standard 25-mg dosing regimen is around 0.43 μM, lower than that necessary to substantially inhibit ABCB1, SLC22A1, or SLC22A2 in vitro. However, these data indicate that SLC22A1 may contribute to variability in rilpivirine exposure and that interactions of rilpivirine with substrates of SLC22A1, SLC22A2, or ABCB1 may be possible.

HIV lipodystrophy (HIVLD), associated with combination antiretroviral therapy (cART), leads to metabolic and cardiovascular diseases. Nuclear receptors play a central role in lipid homoeostasis and drug disposition; their genetic variants may predispose an individual to the development of HIVLD. DNA samples obtained from cART-treated HIV-positive patients with (HIVLD; 124) and without (HIVLD−; 56) HIVLD were genotyped for 77 single nucleotide polymorphisms in nine nuclear receptor genes. Statistical analysis was carried out using Haploview software and by logistic regression. Three single nucleotide polymorphisms in RXR(rs2134095, rs113471, rs2194899) and its haplotypes (HIVLD, 54; HIVLD−, 40.6; P=0.02) showed significant association with HIVLD. Multivariate analysis identified time since diagnosis (P=0.001) and carriage of the RXRhaplotype (P=0.02) to be independently associated with HIVLD. Genetic variation in RXR, a common binding partner of nuclear receptors that modulate lipid homoeostasis and drug disposition, may contribute to the development of HIVLD in cART-treated HIV patients. These results need replication in other cohorts.

ABSTRACTAtazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO4. HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25mmol/liter received 125 mg daily of ZnSO4as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO4was well tolerated. Statistically significant declines in total bilirubin Cmaxand AUC0–24of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubin Cmaxand AUC0–24of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for Ctrough, Cmax, and AUC0–24were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO4decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO4supplementation may be useful in management of ATV-related HBR in selected patients.

To investigate the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine during rifampicin intake and after stopping rifampicin.

The group of infections known as the neglected tropical diseases (NTDs) collectively affect one billion people worldwide, equivalent to one-sixth of the world's population. The NTDs cause severe physical and emotional morbidity, and have a profound effect on cycles of poverty; it is estimated that NTDs account for 534 000 deaths per year. NTDs such as soil-transmitted helminth infections and the vector-borne protozoal infections leishmaniasis and trypanosomiasis occur predominantly in the most economically disadvantaged and marginalized communities. It is estimated that all low-income countries harbour at least five of the NTDs simultaneously. NTDs are neglected because they do not individually rank highly in terms of mortality data, and because they affect populations with little political voice. There is considerable geographic overlap between areas with high prevalence of NTDs and HIV, raising the possibility of complex polypharmacy and drug–drug interactions. Antiretrovirals pose a particularly high risk for potential drug–drug interactions, which may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering plasma or tissue concentrations of co-prescribed drugs. Elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. The aim of this paper is to review the currently available data on interactions between antiretrovirals and drugs used in the management of NTDs. It is intended to serve as a resource for policy makers and clinicians caring for these patients, and to support the recent WHO 2020 Roadmap and the 2012 London Declaration on NTDs.

Here, we report suboptimal efavirenz exposure in an obese patient treated with the standard 600 mg dose. Tripling the dose allowed attainment of therapeutic efavirenz concentrations. We developed an in vitro–in vivoextrapolation model to quantify dose requirements in obese individuals. Obesity represents a risk factor for antiretroviral therapy underdosing.

Background The organic anion transporting polypeptides (OATP)/SLCO family represents an important class of hepatic drug uptake transporters that mediate the sodium independent transport of a diverse range of amphipathic organic compounds, including the protease inhibitors. The SLCO1B1521T>C (rs4149056) single nucleotide polymorphism (SNP) has been consistently associated with reduced transport activity in vivo, and we previously showed an association of this polymorphism with lopinavir plasma concentrations. The aim of this study was to develop a population pharmacokinetic (PK) model to quantify the impact of 521T>C.Methods A population PK analysis was performed with 594 plasma samples from 375 patients receiving lopinavir/ritonavir. Non-linear mixed effects modelling was applied to explore the effects of SLCO1B1521T>C and patient demographics. Simulations of the lopinavir concentration profile were performed with different dosing regimens considering the different alleles.Results A one-compartment model with first-order absorption best described the data. Population clearance was 5.67 l/h with inter-patient variability of 37%. Body weight was the only demographic factor influencing clearance, which increased 0.5 l/h for every 10 kg increase. Homozygosity for the C allele was associated with a 37% lower clearance, and 14% for heterozygosity, which were statistically significant.Conclusions These data show an association between SLCO1B1521T>C and lopinavir clearance. The association is likely to be mediated through reduced uptake by hepatocytes leading to higher plasma concentrations of lopinavir. Further studies are now required to confirm the association and to assess the influence of other polymorphisms in the SLCO family on lopinavir PK.

Raltegravir (RAL) is the first in class integrase inhibitor and is licensed for administration at 400 mg twice daily. RAL pharmacokinetics are characterized by high interpatient variability and recently RAL plasma exposure has been correlated with efficacy. RAL is primarily metabolized by glucuronidation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A128 considered to be the main genetic variant associated with decreased UGT1A1 expression. This study investigated variability in RAL trough plasma concentrations (Ctrough) in the clinical setting, the effect of UGT1A128 and concomitant antiretrovirals.

ABSTRACTRaltegravir shows marked pharmacokinetic variability in patients, with gastrointestinal pH and divalent-metal binding being potential factors. We investigated raltegravir solubility, lipophilicity, pKa, and permeativity in vitroto elucidate known interactions with omeprazole, antacids, and food, all of which increase gastric pH. Solubility of raltegravir was determined at pH 1 to 8. Lipophilicity of raltegravir was determined using octanol-water partition. Raltegravir pKawas determined using UV spectroscopy. The effects of pH, metal salts, and omeprazole on the cellular permeativity of raltegravir were determined using Caco-2 monolayers. Cellular accumulation studies were used to determine the effect of interplay between pH and ABCB1 transport on raltegravir accumulation. Samples were analyzed using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) or scintillation counting. Raltegravir at 10 mM was partly insoluble at pH 6.6 and below. Raltegravir lipophilicity was pH dependent and was reduced as pH was increased from 5 to 9. The pKaof raltegravir was 6.7. Raltegravir cellular permeativity was heavily influenced by changes in extracellular pH, where apical-to-basolateral permeativity was reduced 9-fold (P< 0.05) when apical pH was increased from 5 to 8.5. Raltegravir cellular permeativity was also reduced in the presence of magnesium and calcium. Omeprazole did not alter raltegravir cellular permeativity. Cellular accumulation of raltegravir was increased independently by inhibiting ABCB1 and by lowering extracellular pH from pH 8 to 5. Gastrointestinal pH and polyvalent metals can potentially alter the pharmacokinetic properties of raltegravir, and these data provide an explanation for the variability in raltegravir exposure in patients. The evaluation of how divalent-metal-containing products, such as multivitamins, that do not affect gastric pH alter raltegravir pharmacokinetics in patients is now justified.

ABSTRACTThere is interest in evaluating the efficacy of lower doses of certain antiretrovirals for clinical care. We determined here the bioequivalence of plasma lamivudine (3TC) and intracellular 3TC-triphosphate (3TC-TP) concentrations after the administration of two different doses. ENCORE 2 was a randomized crossover study. Subjects received 3TC at 300 and 150 mg once daily for 10 days (arm 1; n= 13) or vice versa (arm 2; n= 11), separated by a 10-day washout. Pharmacokinetic (PK) profiles (0 to 24 h) were assessed on days 10 and 30. Plasma 3TC and 3TC-TP levels in peripheral blood mononuclear cells were quantified by high-performance liquid chromatography-tandem mass spectrometry. Within-subject changes in PK parameters (the area under the concentration-time curve from 0 to 24 h [AUC0-24], the trough concentration of drug in plasma at 24 h [C24], and the maximum concentration of drug in plasma [Cmax]) were evaluated by determining the geometric mean ratios (GMRs) adjusted for study arm, period, and intra-individual variation. Regimens were considered bioequivalent if the 90% confidence interval (90% CI) fell within the range of 0.8 to 1.25. A total of 24 subjects completed the study. The GM (90% CI) 3TC AUC0-24), expressed as ng·h/ml, for the 300- and 150-mg doses were 8,354 (7,609 to 9,172) and 4,773 (4,408 to 5,169), respectively. Bioequivalence in 3TC PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC0-24, C24, and Cmaxwere 0.57 (0.55 to 0.60), 0.63 (0.59 to 0.67), and 0.56 (0.53 to 0.60), respectively. The GM (90% CI) 3TC-TP AUC0-24values (pmol·h/106cells) for the 300- and 150-mg doses were 59.5 (51.8 to 68.3) and 44.0 (38.0 to 51.0), respectively. Bioequivalence in 3TC-TP PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC0-24, C24, and Cmaxwere 0.73 (0.64 to 0.83), 0.82 (0.68 to 0.99), and 0.70 (0.61 to 0.82), respectively. We found that 3TC at 150 mg is not bioequivalent to the standard regimen of 300 mg, indicating that saturation of cytosine phosphorylation pathways is not achieved at a dose of 150 mg.

Nevirapine exhibits marked interpatient variability in pharmacokinetics. CYP2B6 activity and demographic factors are important, but there are a few data on drug transporters for nevirapine. ABCC10 (MRP7) is an efflux transporter highly expressed in liver, intestine, and peripheral blood cells. We investigated whether nevirapine is a substrate for ABCC10 and whether genetic variants contribute to variability in nevirapine plasma concentrations.

Background Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily.Methods HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs.Results A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (Ctrough) and maximum concentration (Cmax), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, Ctroughand Cmax, respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir.Conclusions There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP Ctroughwas significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.

HIV resides within anatomical ‘sanctuary sites’, where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Suboptimal anti-retroviral concentrations in the genital tract may result in compartmentalized viral replication, selection of resistant mutations and possible re-entry of wild-type/resistant virus into the systemic circulation. Therefore, achieving adequate antiretroviral exposure in the genital tract has implications for the prevention of sexual and vertical transmission of HIV.Penetration of antiretrovirals in the genital tract is expressed by accumulation ratios derived from the measurement of drug concentrations in time-matched seminal plasma/cervicovaginal fluid and plasma samples. Penetration varies by gender and may be drug (as opposed to class) specific with high interindividual variability. Concentrations in seminal plasma are highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of newer agents, raltegravir and maraviroc, is moderate (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide). In the female genital tract, the nucleoside analogues exhibit high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists between individuals and study centres. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, demonstrate effective accumulation in cervicovaginal secretions (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir).

HIV resides within anatomical ‘sanctuary sites’ where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Widespread implementation of antiretroviral therapy has seen a significant decline in the incidence of mother-to-child transmission (MTCT) of HIV. In addition to suppression of maternal plasma/genital viral loads, antiretroviral agents that cross the placenta and achieve adequate concentrations in the fetal compartment may exert a greater prophylactic effect.Penetration of antiretrovirals in the fetal compartment is expressed by accumulation ratios derived from the measurement of drug concentrations in paired maternal plasma and umbilical cord samples. The nucleoside analogues and nevirapine accumulate extensively in cord blood and in the surrounding amniotic fluid, whereas the protease inhibitors (PIs) exhibit low-to-moderate placental accumulation. Early data suggest that high placental/neonatal concentrations are achieved with raltegravir, but to a lesser extent with etravirine and maraviroc (rank order of accumulation: raltegravir/nucleoside reverse transcriptase inhibitor [tenofovir > zidovudine/lamivudine/emtricitabine/stavudine/abacavir] > non-nucleoside reverse transcriptase inhibitor [nevirapine > etravirine] > PI > maraviroc/enfuvirtide). More comprehensive in vivopharmacokinetic data are required to justify the potential use of these agents as safe and effective options during pregnancy.

ABSTRACTThe object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC50] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC50for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.

ABSTRACTNonlinear mixed-effects modeling was applied to explore the relationship between lopinavir and ritonavir concentrations over 72 h following drug cessation and also to assess other lopinavir and ritonavir dosing strategies compared to the standard 400-mg–100-mg twice-daily dose. Data from 16 healthy volunteers were included. Possible covariates influencing lopinavir and ritonavir pharmacokinetics were also assessed. Data were modeled first separately and then together by using individually predicted ritonavir pharmacokinetic parameters in the final lopinavir model. The model was evaluated by means of a visual predictive check and external validation. A maximum-effect model in which ritonavir inhibited the elimination of lopinavir best described the relationship between ritonavir concentrations and lopinavir clearance (CL/F). A ritonavir concentration of 0.06 mg/liter was associated with a 50% maximum inhibition of the lopinavir CL/F. The population prediction of the lopinavir CL/Fin the absence of ritonavir was 21.6 liters/h (relative standard error, 14.0%), and the apparent volume of distribution and absorption rate constant were 55.3 liters (relative standard error, 10.2%) and 0.57 h−1(relative standard error, 0.39%), respectively. Overall, 92% and 94% of the observed concentrations were encompassed by the 95% prediction intervals for lopinavir and ritonavir, respectively, which is indicative of an adequate model. Predictions of concentrations from an external data set (HIV infected) (n= 12) satisfied predictive performance criteria. Simulated lopinavir exposures at lopinavir-ritonavir doses of 200 mg-150 mg and 200 mg-50 mg twice daily were 38% and 65% lower, respectively, than that of the standard dose. The model allows a better understanding of the interaction between lopinavir and ritonavir and may allow a better prediction of lopinavir concentrations and assessments of different dosing strategies.

Although highly active antiretroviral therapy (HAART) has been hugely beneficial in the treatment of HIV, HIV lipodystrophy (HIVLD) associated with HAART isaserious adverse effect, with long-term consequences including metabolic disturbances and an increased risk of atherosclerotic disease. Although HIVLD is clearly related to the drug regimen, individual susceptibility also plays a role. We hypothesized that variation in genes regulating adipogenesis, and in those implicated in inherited forms oflipodystrophy, may predispose to the development of HIVLD.

ABSTRACTAtazanavir (ATV) plasma concentrations are influenced by CYP3A4 and ABCB1, which are regulated by the pregnane X receptor (PXR; NR1I2). PXR expression is correlated with CYP3A4 in liver in the absence of enzyme inducers. The PXRsingle nucleotide polymorphism (SNP) 63396C→T (rs2472677) alters PXR expression and CYP3A4 activity in vitro, and we previously showed an association of this polymorphism with unboosted ATV plasma concentrations. The aim of this study was to develop a population pharmacokinetic analysis to quantify the impact of 63396C→T and diurnal variation on ATV clearance. A population analysis was performed with 323 plasma samples from 182 randomly selected patients receiving unboosted ATV. Two hundred fifty-nine of the blood samples were collected at random time points, and 11 patients had a full concentration-time profile at steady state. Nonlinear mixed effects modeling was applied to explore the effects of PXR63396C→T, patient demographics, and diurnal variation. A one-compartment model with first-order absorption and lag time best described the data. Population clearance was 19.7 liters/h with interpatient variability or coefficient of variation (CV) of 21.5%. Homozygosity for the T allele for PXR63396 was associated with a 17.0% higher clearance that was statistically significant. Evening dosing was associated with 34% higher bioavailability than morning dosing. Patient demographic factors had no effect on ATV clearance. These data show an association of PXR63396C→T and diurnal variation on unboosted ATV clearance. The association is likely to be mediated through an effect on hepatic PXR expression and therefore expression of its target genes (e.g., CYP3A4, SLCO1B1, and ABCB1), which are known to be involved in ATV clearance.

Organic anion transporting polypeptides (OATPs) are emerging as major determinants of pharmacokinetics for numerous drugs, with the 1B1 isoform-mediating hepatic uptake. The 521 T>C polymorphism has been correlated earlier with higher plasma concentrations of several drugs and the aim of this study was to determine whether this polymorphism influences trough concentrations of maraviroc.

ABSTRACTThe identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir. Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by ABCB1 was studied with CEM, CEMVBL100, and Caco-2 cells. Transport by uptake transporters was assessed by using a Xenopus laevisoocyte expression system, peripheral blood mononuclear cells, and primary renal cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM, CEMVBL100, and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression systems but not by other transporters studied. The Kmand Vmaxfor SLC22A6 transport were 150 μM and 36 pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentration-dependent manner. Raltegravir inhibited 1 μM tenofovir with a 50% inhibitory concentration (IC50) of 14.0 μM, and tenofovir inhibited 1 μM raltegravir with an IC50of 27.3 μM. Raltegravir concentrations were not altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics.