BACKGROUND:Broadly neutralizing antibodies (bNAbs) are a promising treatment option for children with HIV-1, but their long-term impact on virologic, immunologic, and clinical outcomes is unknown. METHODS:The Tatelo Study investigated dual bNAbs as an alternative to standard antiretroviral treatment (ART) in children. Children received bNAb-only treatment for 24 weeks (or until detectable viremia ≥400 copies/mL occurred) and were followed initially through 24 weeks after restarting ART. We continued follow-up from 24 to 96 weeks post-bNAb intervention to identify the long-term clinical, immunologic, and viral reservoir outcomes. RESULTS:Median age at the start of long-term follow-up was 4.9 years (range 3.4, 6.8 years). From 23.0 to 43.6 weeks post-bNAb intervention, all 25 children transitioned to dolutegravir-based ART; 3 (12%) had a single episode of HIV-1 RNA ≥ 40 copies/mL after starting the DTG-based regimen and re-suppressed with adherence counseling on the same regimen. There were no grade 3 or 4 events, and no child died. Absolute CD4 cell counts remained stable at 96 weeks post-bNAb intervention (median: 1130 cells/mm3, IQR: 840, 1249 cells/mm3), and clinical biomarkers (serology, qualitative HIV DNA) were stable. At last available sampling, only 8 (32%) participants had detectable intact provirus (5 had rebounded during the bNAb-only intervention phase), with a low median HIV-1 DNA in PBMCs of 0.39 log10 (range 0.1 to 3.8 log10) copies/106 cells. CONCLUSIONS:There was no long-term impact on safety, clinical, immunologic, or virologic outcomes after bNAb-only treatment, including for children who rebounded during the intervention. These findings support further bNAb treatment trials in children. CLINICAL TRIALS REGISTRATION:Clinicaltrials.gov, NCT03707977, https://clinicaltrials.gov/.

The occurrence of virological failure in a subset of individuals is an inevitable aspect of antiretroviral treatment, and historically has been primarily influenced by suboptimal adherence to oral therapies. The risk of selecting 1- or 2-class human immunodeficiency virus (HIV) drug resistance is influenced by the composition of the regimen, differing significantly depending on the intrinsic barrier to resistance of the regimen. HIV resistance emergence during treatment can be viewed as a regimen-related adverse effect that warrants equal consideration in clinical trials alongside virological and safety endpoints. Antiretroviral regimens demonstrating non-inferiority and showing similar rates of virological failure can nonetheless differ in terms of HIV emergent resistance. We propose the development of a systematic framework to categorize emergent HIV drug resistance in clinical trials. Standardizing the evaluation of resistance in clinical trials and its reporting to regulatory agencies will facilitate an improved understanding of regimen-specific resistance risks and better inform clinical decision making.

PURPOSE:SARS-CoV-2 infection continues to impact global health, particularly among high-risk vulnerable individuals. With the loss of federal funding for SARS-CoV-2 management, hospitals will need to budget appropriately for antivirals like remdesivir, which has demonstrated effectiveness in reducing mortality. We evaluated the economic impact realized by hospitals for patients hospitalized for SARS-CoV-2 infection and initiated on remdesivir therapy. METHODS:We conducted a retrospective analysis using data compiled in the Premier Healthcare Database from January 2023 to February 2024. Propensity score matching was used to compare remdesivir-treated (RDV) and untreated (No RDV) groups. The mortality rate, hazard ratios associated with remdesivir use, and hospitalization costs were assessed overall and among the elderly (age ≥65 years). We also conducted a cost-effectiveness analysis to assess the economic value of remdesivir treatment. RESULTS:Among 25,498 hospitalized patients, the mortality rate in the RDV group was lower than in the No RDV group (6.2% versus 8.1%), with a greater reduction in the elderly (6.9% versus 9.0%). Remdesivir significantly reduced mortality risk by approximately 25% overall and among the elderly. Each life saved was realized at a minimal increase in average hospitalization costs ($18,329 in the RDV group versus $14,845 in the No RDV group). Remdesivir was a cost-effective treatment option at a willingness-to-pay threshold of $25,000 overall and among the elderly. CONCLUSIONS:Our evaluation provides contemporaneous evidence of benefits and costs associated with management of individuals hospitalized for SARS-CoV-2 infection. Initiation of remdesivir was associated with minimal incremental hospitalization costs for lives saved as compared to not initiating remdesivir. Hospital pharmacy leadership can utilize this real-world evidence to appropriately budget for remdesivir treatment.

Broadly neutralizing antibodies (bnAbs) are evaluated as possible alternatives to standard antiretroviral treatment (ART) for maintaining control of HIV-1 replication and may enhance immune responses to reduce or control the viral reservoir. However, the immunological and virological effects of bnAbs in infants and children are unknown. We conducted a detailed analysis of proviral reservoir dynamics and antiviral immune responses in a unique group of young children from Botswana who started ART at birth and then stopped standard ART while receiving the bnAbs 10-1074 and VRC01-LS in a subsequent clinical trial. No quantitative changes in frequencies of proviral sequences were observed during bnAb treatment, but selection of genome-intact proviruses in transcriptionally repressive heterochromatin regions occurred in some study participants. Fasterviral rebound following standard ART cessation was linked to elevated proportions of KIR2DL1-positive NK cells. In contrast, delayed viral rebound and more limited viral reservoir size were associated with elevated proportions of NKG2A-positive NK cells and with the HLA-B-21M signal peptide polymorphism. HIV-specific T cell responses were low in all study participants and unrelated to viral reservoir sizes or clinical outcomes following ART interruption. These results suggest that, in young children, specific NK cell subsets and KIR-HLA interactions might be linked to HIV-1 rebound kinetics after substitution of standard ART with bnAbs.

Despite the success of antiretroviral therapy, a subset of people with HIV experience low-level viraemia (LLV), a challenging condition with inconsistent definitions and management across settings. We conducted a scoping review of the literature and developed international consensus recommendations through a modified Delphi process involving a multidisciplinary panel of experts. Available evidence shows wide variability in definitions of persistent LLV, most commonly encompassing repeated viral loads between 50 and 1000 copies per mL. Outcomes associated with LLV are heterogeneous. Despite associations between LLV at 50-200 copies per mL and virological failure of more than 1000 copies per mL, resistance emergence or adverse clinical outcomes are inconsistent; stronger evidence links LLV of 200-1000 copies per mL to these endpoints. Based on these findings, we propose a pragmatic management framework that includes prompt confirmation of LLV, assessment of adherence and drug interactions, consideration of resistance testing (especially at viral loads of 200-1000 copies per mL), a broader clinical evaluation, individualised treatment optimisation (according to viral load strata, the genetic barrier to resistance of current and potential antiretroviral regimens, and the HIV resistance profile), and individual prevention strategies for viral loads of 200-1000 copies per mL. This international guidance aims to support clinicians in identifying when LLV requires action, reduce variability in clinical practice, and inform management strategies across diverse health-care settings.

BACKGROUND:Doravirine is a non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) designed to address the limitations of other NNRTIs, particularly resistance due to common RT substitutions including K103N, Y181C, and G190A. METHODS:This report summarizes the development of genotypic and phenotypic resistance to doravirine through week 192 of the DRIVE-FORWARD (NCT02275780) and DRIVE-AHEAD (NCT02403674) phase 3 studies in adults with previously untreated HIV-1. Participants were randomized (1:1) to the doravirine or comparator regimen (darunavir/ritonavir or efavirenz) for 96 weeks (double-blind phase), followed by 96 weeks of the doravirine regimen (open-label extension). Resistance was evaluated in participants with protocol-defined virologic failure (PDVF; nonresponse or rebound) or treatment discontinuation (d/c) for other reasons and HIV-1 RNA >400 copies/mL. RESULTS:Of 747 participants randomized to doravirine, 51 (34 PDVF, 17 d/c) met resistance-testing criteria. Doravirine resistance-associated mutations (RAMs) were detected in 12/51 participants, by week 48 in 9/12, with phenotypic resistance to doravirine in 10. Of 502 participants who switched from comparator to doravirine, 9 (6 PDVF, 3 d/c) met resistance-testing criteria: Doravirine RAMs were detected in 4/9, conferring phenotypic resistance to doravirine in 3. The most common doravirine RAMs were V106A/I/M and F227C. Common RAMs observed with other NNRTIs (K103N, Y181C, K101E, E138K, and G190A) were not detected in any participant who met resistance-testing criteria. CONCLUSIONS:In DRIVE-FORWARD and DRIVE-AHEAD, the development of resistance to doravirine was uncommon (genotypic 1.3%; phenotypic 1.0%) and occurred mainly during the first 48 weeks of treatment. Overall, the RAMs observed with doravirine were distinct from those of other NNRTIs.

Effective monitoring of HIV treatment remains constrained by limited access to affordable, sensitive, and user-friendly viral load diagnostics, particularly in resource-limited settings. To address this critical gap, a fully automated, point-of-care device was developed that integrates microfluidic sample processing with ultrasensitive bioluminescence-based viral load detection. Upon simple sample loading, the system automates all steps, capturing multiple HIV subtypes with antibody-coated magnetic beads without fold-change, amplifying bioluminescence via enzyme cascades, and quantifying viral load using a low-cost optical sensor. Analytical validation using 87 HIV-spiked plasma samples confirmed a 95 copies per mL detection limit and reliable quantification of viral loads. Clinical testing with 53 patient samples demonstrated 95% sensitivity and 100% specificity, exceeding the performance of currently available POC assays. The assay can be completed within 65 minutes at a cost of less than $3 per test, further supporting its feasibility for widespread implementation. The platform's ease of use and robust performance across different user experience levels support its potential for expanding access to ART monitoring and improving HIV management worldwide.

The central illustration displays the flow of study participants and the results of the primary endpoint. The individual baseline and follow-up MDS TBR are presented as red (LDMTX) or blue (Placebo) slope charts, along with the mean and standard deviation from each group at week 0 and week 24. A waterfall plot displays the absolute change in MDS TBR for each individual participant, colored by treatment group. An example of an FDG PET study of a subject with HIV who has heightened arterial inflammation that persists over time. HIV: Human immunodeficiency virus, 18F-FDG: 18F-Fluorodeoxyglucose, LDMTX: Low dose Methotrexate, PET: Positron Emission Tomography, CT: Computed Tomography, MDS: Most diseased segment, TBR: Tissue to Background.

Digital nucleic acid assays, known for their high sensitivity and specificity, typically rely on fluorescent readouts and expensive and complex nanowell manufacturing, which constrain their broader use in point-of-care (POC) application. Here, we introduce an alternative digital molecular diagnostics, termed dCRISTOR, by seamlessly integrating deactivated Cas9 (dCas9)-engineered micromotors, extraction-free loop-mediated isothermal amplification (LAMP), low-cost bright field microscopy, and deep learning-enabled image processing. The micromotor, composed of a polystyrene sphere attached to a magnetic bead, incorporates a dCas9 ribonucleoprotein complex. The presence of human immunodeficiency virus-1 (HIV-1) RNA in a sample results in the formation of large-sized amplicons that can be specifically captured by the micromotors, reducing their velocity induced by an external magnetic field. The micromotor is propelled by an external magnetic field, which eliminates the need for chemical fuels, reducing system complexity, and allowing for precise control over micromotor movement, enhancing accuracy and reliability. A convolutional neural network classification-based multiobject tracking algorithm, CNN-MOT, accurately measures the change in micromotor motion, facilitating the binary digital assay format ("1" or "0") for simplified result interpretation without user bias. Incorporating an extraction-free LAMP assay streamlines the dCRISTOR workflow, enabling qualitative HIV-1 detection in spiked plasma (n = 21) that demonstrates 100% sensitivity and specificity and achieves a limit of detection (LOD) of 0.96 copies/μL. The assay also achieved 100% correlation with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in clinical patient samples (n = 9). The dCRISTOR assay, a label-free digital nucleic acid testing system that eliminates the need for fluorescence readouts, absorbance measurements, or expensive manufacturing processes, represents a substantial advancement in digital viral RNA diagnostics.

Bioluminescence holds notable promise as a modality in diagnostics due to its high signal-to-noise ratio and absence of incident radiation. However, challenges arise from rapid signal decay and reduced enzyme activity when linked to targeting molecules, limiting its reliability in point-of-care diagnostic applications. Here we introduce the luminescence cascade-based sensor (LUCAS) assay, an enzyme cascade system capable of detecting analytes with ultrahigh sensitivity and prolonged bioluminescence. Utilizing a sequential enzymatic reaction, our assay achieves a greater than 500-fold increase in bioluminescence signal and maintains an 8-fold improvement in signal persistence compared to conventional bioluminescence assays. Implemented on a portable, fully automated device designed for point-of-care settings, our system facilitates rapid (<23 min) sample-to-answer analysis of viruses without an external power supply. Its accuracy surpasses 94

BACKGROUND:Definitions of virological failure and treatment discontinuation for long-acting injectable (LAI) cabotegravir and rilpivirine antiretroviral therapy are inconsistent in clinical practice and observational studies, which complicates interpretation and implementation of findings. The CONSENSUS-LAI study aimed to establish consistent definitions of virological failure and treatment discontinuation to enhance evidence transferability and support optimal clinical outcomes. METHODS:The study had two phases. Phase 1 was an international online survey exploring existing definitions of virological and treatment discontinuation, conducted between April 25 and July 1, 2024. Eligible participants were health-care professionals working in infectious disease or sexual health services who had provided care to at least ten people living with HIV in the past 6 months, had prescribed LAI cabotegravir and rilpivirine in clinical trials or clinical practice, and were able to give informed consent. Participants were recruited via social media and mailing lists of medical specialist societies. Phase 2 was a Delphi process, in which a panel of experts, selected to ensure representation from all six WHO regions, scored leading definitions from phase 1 on a 9-point Likert scale. The proposed definitions were scored according to four validity criteria: clarity, usability in the expert's setting, appropriateness across clinical purposes, and applicability across relevant population groups. Revisions were suggested in iterative rounds until consensus was reached. Consensus was predefined as at least 75% of experts agreeing or strongly agreeing (scores 7-9) with the validity criteria. FINDINGS:386 LAI cabotegravir and rilpivirine prescribers across 28 countries completed the survey, revealing 15 definitions for virological failure on LAI cabotegravir and rilpivirine and nine for treatment discontinuation. 52 experts participated in the Delphi process. Consensus agreement on both definitions was reached after two rounds for all validity criteria. For virological failure, the consensus definition was as follows: (a) viral load 200 copies or more per mL or more on two occasions 2-4 weeks apart, or (b) a single viral load of more than 1000 copies per mL, and/or (c) emergent resistance, in the context of timely injections and prior suppression of less than 200 copies per mL, OR (d) unable to suppress viral load to less than 200 copies per mL on continuous therapy. For treatment discontinuation the consensus definition was as follows: people on LAI cabotegravir and rilpivirine who have missed two consecutive injections and have not taken oral bridging in the interim, irrespective of reason for discontinuation. INTERPRETATION:The consensus definitions provide a foundation for aligning practice and evaluating patient outcomes. Further validation of the viral load threshold for virological failure and the optimal viral load retesting window is required. FUNDING:ViiV Healthcare.

Enzyme-linked immunosorbent assays (ELISA) are recognized for their accuracy and versatility in disease diagnostics. However, conventional ELISA protocols rely on laboratory equipment, trained personnel, and established infrastructure, restricting their use to complex clinical environments, making them impractical for at-home diagnostics. Here, VISTA, a disposable, electricity-free microfluidic chip designed for immunoassay-based point-of-care diagnostic applications is reported. VISTA enables a bubbling immunoassay-based assay to be completed, sample-to-result, in under 45 min in non-laboratory settings. Using pressure-driven microfluidics, the device manipulates antibody-conjugated magnetic beads and platinum nanoparticles to execute a streamlined semiautomated immunoassay process with minimal user input. VISTA consolidates all steps, including sample processing and reagent addition, into a single, low-cost cartridge with user-friendly features to ensure proper operation. It pairs with an AI-enabled smartphone application, utilizing an adversarial neural network, that automatically interprets assay results from a smartphone image, eliminating the need for specialized expertise. The device's capability is demonstrated through the bubbling immunoassay to detect SARS-CoV-2 N antigen and HCV core antigen directly from 52 patient samples. VISTA's sensitivity is on par with lab-based ELISAs and surpasses conventional point-of-care technologies, detecting viral loads less than 104 copies mL-1. This solution provides sensitive and cost-effective diagnostics, ideal for use in low-resource settings.

Background Integrase strand transfer inhibitors (INSTIs) have been associated with excess weight gain in people living with HIV compared to other antiretroviral agents. The mechanisms that underlie these effects are not well defined. Thus, we aimed to examine the effects of switching to INSTI-containing regimens on clinical metabolic parameters. Setting A secondary analysis of a prospective cohort study in which people living with HIV on a stable efavirenz-based regimen were switched to a cobicistat-boosted elvitegravir or raltegravir-containing regimen. Participants remained on the NRTI backbone of tenofovir disoproxil fumarate and emtricitabine. Methods Frozen plasma samples from 19 participants were used to determine concentrations of leptin, adiponectin, insulin and lactate at baseline and 8 weeks post-switch. Fasting lipids and blood glucose not reported in the initial study were obtained to examine metabolic changes. Anthropometric data including height and weight were abstracted from the medical record. Results Participants switched from efavirenz to cobicistat-boosted elvitegravir without change in tenofovir disoproxil fumarate/emtricitabine backbone showed a 20% increase in HOMA-IR after 8 weeks (1.84 vs 2.24, p < .05), due mostly to increases in fasting insulin. This increase occurred independent of weight gain in the cohort as whole (83.4 vs 85.9 kg, pre vs post, p = .04), but was linked to increases in circulating lactate. Conclusions Participants switched to an INSTI-based regimen tended to gain weight, and those switched to cobicistat-boosted elvitegravir had increases in markers of insulin resistance and elevation in plasma lactic acid compared to raltegravir, suggesting that elvitegravir may promote metabolic perturbations in people living with HIV.

An increasing number of people with HIV (PWH) are failing treatment without HIV drug resistance in the drug target region. While sub-optimal adherence is likely the cause of treatment failure in many PWH, resistance emerging at noncanonical (HIV drug resistance mutations occurring outside the drug target site) drug target sites is also plausible. Noncanonical drug resistance mechanisms have been identified for integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs. Overall, they may act by restoring viral fitness caused by mutations in the drug target sites, enhance resistance when occurring with mutations at the drug target sites, independently cause resistance even in the absence of drug resistant mutations (DRMs) at the drug target site, and prime the emergence of resistant variants with DRMs at drug target sites. However, the clinical relevance of non-canonical HIV drug resistance mechanisms beyond in vitro and small in vivo studies is still needed and could include the assessment of such mechanisms in clinical trials and implementation studies. This information would be vital in guiding effective management of PWH with viral nonsuppression despite good adherence as well as informing public health surveillance strategies.

In May 2022, the most widespread outbreak of sustained transmission of mpox outside of countries historically affected countries in Western and Central Africa occurred. We aimed to examine the personal and clinical experiences of international healthcare workers (HCWs) during this public health emergency. We conducted an international cross-sectional survey study between August and October 2022, examining the experiences and perceptions of HCWs clinically involved in the 2022 mpox response. Respondents were recruited via an international network of sexual health and HIV clinicians responding to mpox and promoted through clinical associations and social media. Survey domains included: clinical workload; preparedness; training and support at work; psychological well-being and vaccination. 725 multi-national healthcare workers across 41 countries were included in the analysis. 91% were physicians specialised in Sexual Health or Infectious Diseases; with 34% (n = 247) of all respondents involved in mpox policy. A substantial proportion of respondents (n = 296, 41%) reported working longer hours during the mpox outbreak, with no concomitant removal of other clinical responsibilities. 30% (n = 218) of respondents reported that they had never heard of mpox before the outbreak and over 25% of the respondents reported that they had misdiagnosed someone initially. This culminated in a high prevalence of moral distress at thirty percent. Less than 9% of HCWs in the region of the Caribbean, Central America and South America had been offered a vaccine as compared to almost one-third in the other regions. Where offered, there were high levels of uptake across all regions. The findings highlight a critical need for addressing the profound gaps in HCW knowledge about re-emerging diseases with pandemic potential. Strengthening the resilience of global health systems and prioritising internationally coordinated approaches to global vaccine deployment is imperative.

The occurrence of virological failure in a subset of individuals is an inevitable aspect of antiretroviral treatment, and historically has been primarily influenced by suboptimal adherence to oral therapies. The risk of selecting 1- or 2-class human immunodeficiency virus (HIV) drug resistance is influenced by the composition of the regimen, differing significantly depending on the intrinsic barrier to resistance of the regimen. HIV resistance emergence during treatment can be viewed as a regimen-related adverse effect that warrants equal consideration in clinical trials alongside virological and safety endpoints. Antiretroviral regimens demonstrating non-inferiority and showing similar rates of virological failure can nonetheless differ in terms of HIV emergent resistance. We propose the development of a systematic framework to categorize emergent HIV drug resistance in clinical trials. Standardizing the evaluation of resistance in clinical trials and its reporting to regulatory agencies will facilitate an improved understanding of regimen-specific resistance risks and better inform clinical decision making.

BACKGROUND:Simple clinical markers may predict favorable outcomes in pediatric HIV treatment and cure trials. We report findings for biomarker combinations evaluated during the broadly neutralizing antibodies (bNAbs)-only step of the Tatelo Study in Botswana. METHODS:Twenty-five children who were on ART since birth received up to 24 weeks of bNAb-only treatment (VRC01LS+10-1074). Suppression was defined as maintaining HIV RNA<400 copies/mL. HIV qualitative DNA and HIV RNA were performed every 1-2 weeks and enzyme immunosorbent assay (EIA) every 4-8 weeks. RESULTS:The median age of children at study entry was 3.7 years (IQR 3.1-4.4). At the start of bNAb-only treatment, 13/25 (52%) had negative qualitative DNA, 17/25 (68%) had negative EIA, and 10/25 (40%) were negative for both. Nine of 13 (69%) with negative qualitative DNA remained suppressed compared with 2/12 (17%) with positive or indeterminate qualitative DNA (OR 11.3, 95% CI 1.7-76.9). Nine of 17 (53%) with negative EIA remained suppressed compared with 2/8 (25%) with positive EIA (OR 3.4, 95% CI 0.5-21.7). Combining biomarkers, 8/10 (80%) who were negative/negative remained suppressed, compared with 3/15 (20%) with any other pattern (OR 16.0, 95% CI 2.2-118.3). In the visit immediately prior to viral rebound, HIV RNA target detection occurred in 1/14 (7%) of failures. CONCLUSION:At the start of bNAb-only treatment, negative qualitative DNA, and especially negative/negative DNA and EIA, have potential to predict maintenance of viral suppression among children on dual bNAbs. HIV RNA target detection below the assay limit did not prove to be a clinically useful biomarker in the visits preceding failure.

Background:T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods:This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/μL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results:Five men were enrolled (median CD4+ count, 911 cells/μL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions:One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.