Prenatal efavirenz exposure is independently associated with maternal, but not fetal CYP2B6 genotype.

OBJECTIVES: Understanding the influence of fetal and maternal genetics on prenatal drug exposure could potentially improve benefit-risk evaluation. In this study, we investigated the impact of two functional polymorphisms in CYP2B6 on prenatal exposure to efavirenz. METHODS: Dried blood spot (DBS) samples were collected from HIV-positive pregnant women ( n  = 112) and their newborns ( n  = 107) at delivery. They were genotyped for single nucleotide polymorphisms in CYP2B6. Efavirenz was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Significant correlations were observed in efavirenz concentration between maternal and newborn ( r  = 0.46, R2  = 0.21, P  < 0.001), and maternal and cord ( r  = 0.83, R2  = 0.68, P  < 0.001) samples. Median (interquartile range) newborn plasma-to-maternal plasma and cord-to-maternal plasma ratios were 0.85 (0.03-3.49) and 0.78 (0.23-1.96), respectively. Newborn efavirenz concentration in DBS varied significantly based on composite maternal CYP2B6 genotype: fast ( CYP2B6 516GG and 983TT, n  = 26), 747 ng/ml (602-1060); intermediate ( CYP2B6 516GT or 983TC n  = 50), 1177 ng/ml (898-1765); and slow ( CYP2B6 516GT and 983TC or 516TT or 983CC, n  = 14), 3094 ng/ml (2126-3812). Composite newborn CYP2B6 genotype was, however, not significantly associated with prenatal exposure. Efavirenz concentration in newborn stratified as fast ( n  = 25), intermediate ( n  = 36), and slow metabolizers ( n  = 19) from prenatal exposure was 999.7 (774-1285), 1240 (709-1984), and 1792 ng/ml (1201-3188), respectively. CONCLUSION: The clinical relevance of the observed influence of maternal genetics on prenatal efavirenz exposure requires further investigation.

Clinical, pharmacological, and qualitative characterization of drug-drug interactions in pregnant women initiating HIV therapy in Sub-Saharan Africa.

BACKGROUND: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. METHODS: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure. RESULTS: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028). CONCLUSIONS: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.

Lack of antiviral activity of probenecid in vitro and in Syrian golden hamsters.

OBJECTIVES: Antiviral interventions are required to complement vaccination programmes and reduce the global burden of COVID-19. Prior to initiation of large-scale clinical trials, robust preclinical data to support candidate plausibility are required. This work sought to further investigate the putative antiviral activity of probenecid against SARS-CoV-2. METHODS: Vero E6 cells were preincubated with probenecid, or control media for 2 h before infection (SARS-CoV-2/Human/Liverpool/REMRQ0001/2020). Probenecid or control media was reapplied, plates reincubated and cytopathic activity quantified by spectrophotometry after 48 h. In vitro human airway epithelial cell (HAEC) assays were performed for probenecid against SARS-CoV-2-VoC-B.1.1.7 (hCoV-19/Belgium/rega-12211513/2020; EPI_ISL_791333, 2020-12-21) using an optimized cell model for antiviral testing. Syrian golden hamsters were intranasally inoculated (SARS-CoV-2 Delta B.1.617.2) 24 h prior to treatment with probenecid or vehicle for four twice-daily doses. RESULTS: No observable antiviral activity for probenecid was evident in Vero E6 or HAEC assays. No reduction in total or subgenomic RNA was observed in terminal lung samples (P > 0.05) from hamsters. Body weight of uninfected hamsters remained stable whereas both probenecid- and vehicle-treated infected hamsters lost body weight (P > 0.5). CONCLUSIONS: These data do not support probenecid as a SARS-CoV-2 antiviral drug.

Preferences and feasibility of long-acting technologies for treatment of hepatitis C virus in low- and middle-income countries: A survey of providers and policymakers.

Long-acting technologies (LATs) for hepatitis C virus (HCV) are under development as a strategy to improve linkage to care, treatment adherence and outcomes. We conducted a survey of HCV treatment prescribers and HCV policymakers in low- and middle-income countries (LMICs) regarding acceptability and feasibility of HCV LATs. We included one-time intramuscular injection, subdermal implant and transdermal patch as potential LAT options. We surveyed participants regarding optimal health system and patient characteristics, concerns, potential barriers, overall feasibility and preferences for HCV LAT as compared to daily oral medication. Overall, 122 providers and 50 policymakers from 42 LMICs completed the survey. Among providers, 93% (113/122) expressed willingness to prescribe LAT and 72% (88/120) of providers preferred LAT if provided at comparable efficacy, safety and cost as current oral treatments. Of providers preferring HCV LAT to daily oral medication, 67% (59/88) preferred injection, 24% (21/88) preferred patch and 9% (8/88) preferred implant. Only 20% (24/122) would prescribe LAT if it were more costly than oral treatment. In regression analysis, no provider characteristics were associated with preference for LAT over oral treatment. Policymakers reported high likelihood that LAT would be included in treatment guidelines (42/50; 84%) and national drug formularies (39/50; 78%) if efficacy, safety and cost were similar to oral treatment. HCV LATs could advance progress to HCV elimination in LMICs by diversifying treatment options to improve treatment coverage and outcomes. Provider preferences from LMICs are a critical consideration in the development of HCV LATs to ensure its early and equitable availability in LMICs.

Millimeter-Wave and High-Resolution Infrared Spectroscopy of 3-Furonitrile.

The rotational spectrum of 3-furonitrile has been collected from 85 to 500 GHz, spanning the most intense rotational transitions observable at room temperature. The large dipole moment imparted by the nitrile substituent confers substantial intensity to the rotational spectrum, enabling the observation of over 5600 new rotational transitions. Combined with previously published transitions, the available data set was least-squares fit to partial-octic, distorted-rotor A- and S-reduced Hamiltonian models with low statistical uncertainty (σfit < 0.031 MHz) for the ground vibrational state. Similar to its isomer 2-furonitrile, the two lowest-energy vibrationally excited states of 3-furonitrile (ν17, ν24), which correspond to the in-plane and out-of-plane nitrile bending vibrations, form an a- and b-axis Coriolis-coupled dyad. Rotationally resolved infrared transitions (30-600 cm-1) and over 4200 pure rotational transitions for both ν17 and ν24 were fit to a partial-octic, Coriolis-coupled, two-state Hamiltonian with low statistical uncertainty (σfit rot < 0.045 MHz, σfit IR < 6.1 MHz). The least-squares fitting of these vibrationally excited states provides their accurate and precise vibrational frequencies (ν17 = 168.193 164 8 (67) cm-1 and ν24 = 169.635 831 5 (77) cm-1) and seven Coriolis-coupling terms (Ga, GaJ, GaK, Fbc, FbcK, Gb, and Fac). The two fundamental states exhibit a notably small energy gap (1.442 667 (10) cm-1) and an inversion of the relative energies of ν17 and ν24 compared to those of the isomer 2-furonitrile. The rotational frequencies and spectroscopic constants of 3-furonitrile that we present herein provide a sufficient basis for conducting radioastronomical searches for this molecule across the majority of the frequency range available to current radiotelescopes.

Millimeter-wave and high-resolution infrared spectroscopy of the low-lying vibrational states of pyridazine isotopologues.

The gas-phase rotational spectrum from 8 to 750 GHz and the high-resolution infrared (IR) spectrum of pyridazine (o-C4H4N2) have been analyzed for the ground and four lowest-energy vibrationally excited states. A combined global fit of the rotational and IR data has been obtained using a sextic, centrifugally distorted-rotor Hamiltonian with Coriolis coupling between appropriate states. Coriolis coupling has been addressed in the two lowest-energy coupled dyads (ν16, ν13 and ν24, ν9). Utilizing the Coriolis coupling between the vibrational states of each dyad and the analysis of the IR spectrum for ν16 and ν9, we have determined precise band origins for each of these fundamental states: ν16 (B1) = 361.213 292 7 (17) cm-1, ν13 (A2) = 361.284 082 4 (17) cm-1, ν24 (B2) = 618.969 096 (26) cm-1, and ν9 (A1) = 664.723 378 4 (27) cm-1. Notably, the energy separation in the ν16-ν13 Coriolis-coupled dyad is one of the smallest spectroscopically measured energy separations between vibrational states: 2122.222 (72) MHz or 0.070 789 7 (24) cm-1. Despite ν13 being IR inactive and ν24 having an impractically low-intensity IR intensity, the band origins of all four vibrational states were measured, showcasing the power of combining the data provided by millimeter-wave and high-resolution IR spectra. Additionally, the spectra of pyridazine-dx isotopologues generated for a previous semi-experimental equilibrium structure (reSE) determination allowed us to analyze the two lowest-energy vibrational states of pyridazine for all nine pyridazine-dx isotopologues. Coriolis-coupling terms have been measured for analogous vibrational states across seven isotopologues, both enabling their comparison and providing a new benchmark for computational chemistry.

Precise Equilibrium Structure of Benzene.

Recent advances in gas-phase structure determination afford outstanding agreement between the CCSD(T)/cc-pCVTZ-corrected semi-experimental (reSE) equilibrium structures and their corresponding best theoretical estimates (BTEs) of the equilibrium structures (re) based upon corrections to the CCSD(T)/cc-pCV5Z geometries for the aromatic heterocycles pyrimidine and pyridazine. Herein, that same analysis is extended to the fundamental aromatic molecule benzene, using published experimental spectroscopic data for a total of 11 available isotopologues. The incorporation of rotational constants from all of these isotopologues and CCSD(T) corrections to address the impacts of both the vibration-rotation interaction and electron-mass distribution results in a highly precise and accurate reSE structure. The CCSD(T)/cc-pCV5Z optimized geometry has been further corrected to address a finite basis set, untreated electron correlation, relativistic effects, and a breakdown of the Born-Oppenheimer approximation. This analysis achieves outstanding agreement between the re (BTE) and reSE structural parameters of benzene to a highly satisfying level (0.0001 Å), an agreement that surpasses our recently published structures of the aforementioned nitrogen-substituted benzene analogues. The D6h geometry of benzene is now known to an unprecedented precision: RC-C = 1.3913 (1) Å and RC-H = 1.0809 (1) Å. The mutual agreement between theory and experiment presented in this work validates both, substantially resolving all discrepancies between the reSE and theoretical re structures available in the literature.

Using Dynamic Oral Dosing of Rifapentine and Rifabutin to Simulate Exposure Profiles of Long-Acting Formulations in a Mouse Model of Tuberculosis Preventive Therapy.

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have antituberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We used a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that have utility beyond latent tuberculosis infection.

Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study.

Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir's characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.

PDGFRα/Sca-1 Sorted Mesenchymal Stromal Cells Reduce Liver Injury in Murine Models of Hepatic Ischemia-Reperfusion Injury.

Liver transplantation is an effective therapy, but increasing demand for donor organs has led to the use of marginal donor organs with increased complication rates. Mesenchymal stromal cells (MSC) pleiotropically modulate aberrant immune-mediated responses and represent a potential therapy to target the inflammation seen post-transplant with marginal donor livers. To avoid the confounding effects of xenotransplantation seen in studies with human MSC, a PDGFRα/Sca-1 (PaS) sorted MSC population was used which was analogous to human MSC populations (LNGFR+Thy-1+VCAM-1Hi). PaS MSC are a well-described population that demonstrate MSC properties without evidence of clonal mutation during expansion. We demonstrate their anti-inflammatory properties herein through their suppression of T-lymphocyte proliferation in vitro and secretion of anti-inflammatory cytokines (IL-10 and OPG) after stimulation (P = .004 and P = .003). The MDR2-/- model of biliary injury and hepatic ischemia-reperfusion (HIR) injury models were used to replicate the non-anastomotic biliary complications seen following liver transplantation. Systemic MSC therapy in MDR2-/- mice led to reduced liver injury with an increase in restorative macrophages (5913 ± 333.9 vs 12 597 ± 665.8, P = .002, n = 7) and a change in lymphocyte ratios (3.55 ± 0.37 vs 2.59 ± 0.139, P = .023, n = 17), whereas subcutaneous administration of MSC showed no beneficial effect. MSC also reduced cell death in the HIR model assessed by Periodic acid-Schiff (PAS) staining (91.7% ± 2.8 vs 80.1% ± 4.6, P = .03). Systemically administered quantum dot-labeled MSC were tracked using single-cell resolution CryoViz imaging which demonstrated their sequestration in the lungs alongside retention/redistribution to injured liver tissue. MSC represent a potential novel therapy in marginal organ transplantation which warrants further study.

Screening for Prediabetes and Diabetes in a National Network of Federally Qualified Health Centers: An Observational Study.

BACKGROUND: In 2021, the U.S. Preventive Services Task Force (USPSTF) recommended screening for prediabetes and diabetes among adults aged 35-70 years with overweight or obesity. Studying dysglycemia screening in federally qualified health centers (FQHCs) that serve vulnerable patient populations is needed to understand health equity implications of this recommendation. OBJECTIVE: To investigate screening practices among FQHC patients who would be eligible according to the 2021 USPSTF recommendation. DESIGN: Retrospective cohort study analyzing electronic health records from a national network of 282 FQHC sites. PARTICIPANTS: We included 183,329 patients without prior evidence of prediabetes or diabetes, who had ≥ 1 office visit from 2018-2020. MAIN MEASURES: Screening eligibility was based on age and measured body mass index (BMI). The primary outcome, screening completion, was ascertained using hemoglobin A1c or fasting plasma glucose results from 2018-2020. KEY RESULTS: Among 89,543 patients who would be eligible according to the 2021 USPSTF recommendation, 53,263 (59.5%) were screened. Those who completed screening had higher BMI values than patients who did not (33.0 ± 6.7 kg/m2 vs. 31.9 ± 6.2 kg/m2, p < 0.001). Adults aged 50-64 years had greater odds of screening completion relative to younger patients (OR 1.13, 95% CI: 1.10-1.17). Patients from racial and ethnic minority groups, as well as those without health insurance, were more likely to complete screening than White patients and insured patients, respectively. Clinical risk factors for diabetes were also associated with dysglycemia screening. Among patients who completed screening, 23,588 (44.3%) had values consistent with prediabetes or diabetes. CONCLUSIONS: Over half of FQHC patients who would be eligible according to the 2021 USPSTF recommendation were screened. Screening completion was higher among middle-aged patients, those with greater BMI values, as well as vulnerable groups with a high risk of developing diabetes. Future research should examine adoption of the 2021 USPSTF screening recommendation and its impact on health equity.

Exosomes as perioperative therapeutics to limit organ injury.

Perioperative organ injury is a frequent and major complication for the ∼240 million people undergoing surgery worldwide annually. Ischaemic preconditioning is a powerful technique that reduces organ injury in experimental models of heart, lung, gut, brain, and kidney ischaemia-reperfusion injury. However, ischaemic preconditioning has been a challenge to translate into clinical practice. We describe how utilising isolated pre-conditioned exosomes (secreted vesicles containing many cell-survival mediators), some of the translational hurdles of ischaemic preconditioning can be overcome. Delivery of exosomes in the perioperative period could become a promising new therapeutic strategy to prevent perioperative organ injury.

Carbon Condensation via [4 + 2] Cycloaddition of Highly Unsaturated Carbon Chains.

We present computational studies of reaction pathways for alkyne/polyyne dimerization that represent plausible early steps in mechanisms for carbon condensation. A previous computational study of the ring coalescence and annealing model of C60 formation revealed that a 1,4-didehydrobenzocyclobutadiene intermediate (p-benzyne derivative) has little to no barrier to undergoing an unproductive retro-Bergman cyclization, which brings into question the relevance of that reaction pathway. The current study investigates an alternative model, which proceeds through an initial [4 + 2] cycloaddition instead of a [2 + 2] cycloaddition. In this pathway, the problematic intermediate is avoided, with the reaction proceeding via a (potentially) more kinetically stable tetradehydronaphthalene derivative. The computational studies of the [2 + 2] and [4 + 2] model systems, with increasing alkyne substitutions, reveal that the para-benzyne diradical of the [4 + 2] pathway has a significantly greater barrier to ring opening than the analogous intermediates of the [2 + 2] pathway and that alkyne substitution has little effect on this important barrier. These studies employ spin-flip, time-dependent density functional theory (SF-TDDFT) to provide suitable treatment of open-shell diradical intermediates.

Millimeter-Wave and High-Resolution Infrared Spectroscopy of 2-Furonitrile─A Highly Polar Substituted Furan.

The rotational spectrum of 2-furonitrile (2-cyanofuran) has been obtained from 140 to 750 GHz, capturing its most intense rotational transitions at ambient temperature. 2-Furonitrile is one of two isomeric cyano-substituted furan derivatives, both of which possess a substantial dipole moment due to the cyano group. The large dipole of 2-furonitrile allowed over 10 000 rotational transitions of its ground vibrational state to be observed and least-squares fit to partial octic, A- and S-reduced Hamiltonians with low statistical uncertainty (σfit = 40 kHz). The high-resolution infrared spectrum, obtained at the Canadian Light Source, allowed for accurate and precise determination of the band origins of its three lowest-energy fundamental modes (ν24, ν17, and ν23). Similar to other cyanoarenes, the first two fundamental modes (ν24, A″, and ν17, A', for 2-furonitrile) form an a- and b-axis Coriolis-coupled dyad. More than 7000 transitions from each of these fundamental states were fit to an octic A-reduced Hamiltonian (σfit = 48 kHz), and the combined spectroscopic analysis determines fundamental energies of 160.1645522 (26) cm-1 and 171.9436561 (25) cm-1 for ν24 and ν17, respectively. The least-squares fitting of this Coriolis-coupled dyad required 11 coupling terms, Ga, GaJ, GaK, GaJJ, GaKK, Fbc, FbcJ, FbcK, Gb, GbJ, and FacK. Using both the rotational and high-resolution infrared spectra, a preliminary least-squares fit was obtained for ν23, providing its band origin of 456.7912716 (57) cm-1. The transition frequencies and spectroscopic constants provided in this work, when combined with theoretical or experimental nuclear quadrupole coupling constants, will provide the foundation for future radioastronomical searches for 2-furonitrile across the frequency range of currently available radiotelescopes.

Relating CYP2B6 genotype and efavirenz resistance among post-partum women living with HIV with high viremia in Uganda: a nested cross-sectional study.

BACKGROUND: We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV who started on antiretroviral therapy during pregnancy and with high viremia during post-partum. METHODS: This was a cross-sectional study of women with viral loads greater than 1000 copies/ml who were at least 6 weeks postpartum. Sanger sequencing was used to detect resistant mutations, as well as host genotyping, and efavirenz resistance was compared among the metabolizer genotypes. RESULTS: Over the course of one year (July 2017-July 2018), 322 women were screened, with 110 (34.2%) having viral loads of 1000 copies/ml and 62 having whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. Efavirenz resistance according to metabolizer genotype was; 47% in slow, 34% in extensive and 28% in intermediate metabolizers, but the difference was not statistically significant due to the small sample size. CONCLUSIONS: There was no statistically significant difference in EFV resistance between EFV metabolizer genotypes in women who started antiretroviral therapy during pregnancy and had high viremia in the postpartum period. However, a numerical trend was discovered, which calls for confirmation in a large, well-designed, statistically powered study.

Expression of CYP2B6 Enzyme in Human Liver Tissue of HIV and HCV Patients.

Background and Objectives: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections present significant public health challenges worldwide. The management of these infections is complicated by the need for antiviral and antiretroviral therapies, which are influenced by drug metabolism mediated by metabolic enzymes and transporters. This study focuses on the gene expression of CYP2B6, CYP3A4, and ABCB1 transporters in patients with HIV, HCV, and HIV/HCV co-infection, aiming to assess their potential association with the choice of therapy, patohistological and clinical parameters of liver damage such as the stage of liver fibrosis, serum levels of ALT and AST, as well as the grade of liver inflammation and other available biochemical parameters. Materials and Methods: The study included 54 patients who underwent liver biopsy, divided into HIV-infected, HCV-infected, and co-infected groups. The mRNA levels of CYP2B6, CYP3A4, and ABCB1 was quantified and compared between the groups, along with the analysis of liver fibrosis and inflammation levels. Results: The results indicated a significant increase in CYP2B6 mRNA levels in co-infected patients, a significant association with the presence of HIV infection with an increase in CYP3A4 mRNA levels. A trend towards downregulation of ABCB1 expression was observed in patients using lamivudine. Conclusions: This study provides insight into gene expression of CYP2B6 CYP3A4, and ABCB1 in HIV, HCV, and HIV/HCV co-infected patients. The absence of correlation with liver damage, inflammation, and specific treatment interventions emphasises the need for additional research to elucidate the complex interplay between gene expression, viral co-infection, liver pathology, and therapeutic responses in these particular patients population.

A Holistic Review of the Preclinical Landscape for Long-Acting Anti-infective Drugs Using HIV as a Paradigm.

Lack of predictive preclinical models is a key contributor to the steep attrition rate in drug development. Successful clinical translation may be higher for new chemical entities or existing approved drugs reformulated for long-acting (LA) administration if preclinical studies designed to identify any new uncertainties are predictive of human exposure and response. In this review, we present an overview of standard preclinical assessments deployed for LA formulations and delivery systems, using human immunodeficiency virus LA therapeutics preclinical development as a paradigm. Key progress in the preclinical development of novel LA antiretrovirals formulations and delivery systems are summarized, including bispecific broadly neutralizing monoclonal antibody and small molecule technologies for codelivery of multiple drugs with disparate solubility properties. There are new opportunities to take advantage of recent developments in tissue engineering and 3-dimensional in vitro modeling to advance preclinical modeling of anti-infective activity, developmental and reproductive toxicity assessment, and to apply quantitative modeling and simulation strategies. These developments are likely to drive the progression of more LA anti-infective drugs and multipurpose technologies into clinical development in the coming years.

Prospects for Long-Acting Treatments for Hepatitis C.

In 2019, more than 4 years after the widespread availability of safe, oral, curative treatments, an estimated 58 million people were living with hepatitis C virus infections (PLWHC). Additional tools may enable those not yet reached to be treated. One such tool could be long-acting parenteral formulations of HCV treatments, which may allow PLWHC to be diagnosed and cured in a single encounter. Although existing highly effective oral medications might be formulated as long-acting parenteral treatments, pharmacological, regulatory, patent, and medical challenges have to be overcome; this requires the concerted efforts of PLWHC, researchers, funding agencies, industry, the World Health Organization, and other stakeholders.

The LEAP Process: Streamlining the Development of Long-Acting Products and Formulations for Infectious Diseases.

Developing long-acting products and formulations for infectious diseases is a nontrivial undertaking that is frequently classified as high risk and low reward by the pharmaceutical industry. The Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP) was founded in 2015 with the support of the National Institutes of Health to encourage, promote, and accelerate the development of such products. Assessment methodology for any new proposal brought to this group is part of a framework-the LEAP Process-that includes a landscape analysis of what is currently available in the public domain. This is followed by in silico modeling and simulation offered as a service to the relevant scientific community. A variety of preclinical and clinical outcome metrics are applied to each new agent as part of a continuous feedback loop to improve product characteristics. This allows us to catalog knowledge gaps and barriers that can be addressed by engaged stakeholders. Results are communicated in scientific articles, reviews, and position papers. This undertaking serves to de-risk discovery, development, and implementation by bridging the gaps between academic, regulatory, and industrial investigators, and by engaging those in the community who will be the eventual users of these medicines. The LEAP Process has supported formulations now approved for human immunodeficiency virus, as well as products in clinical and preclinical development for tuberculosis and hepatitis viruses B and C.

Potential Impact of Long-Acting Products on the Control of Tuberculosis: Preclinical Advancements and Translational Tools in Preventive Treatment.

A key component of global tuberculosis (TB) control is the treatment of latent TB infection. The use of long-acting technologies to administer TB preventive treatment has the potential to significantly improve the delivery and impact of this important public health intervention. For example, an ideal long-acting treatment could consist of a single dose that could be administered in the clinic (ie, a "1-shot cure" for latent TB). Interest in long-acting formulations for TB preventive therapy has gained considerable traction in recent years. This article presents an overview of the specific considerations and current preclinical advancements relevant for the development of long-acting technologies of TB drugs for treatment of latent infection, including attributes of target product profiles, suitability of drugs for long-acting formulations, ongoing research efforts, and translation to clinical studies.