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Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Background: People living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking., Methods: We examined levels of immune activation and exhaustion markers on CD8 + T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay., Findings: The level of intact HIV proviral DNA was comparable between the two groups (P = 0.29). The levels of activation and exhaustion markers PD-1 (P = 0.0019), TIGIT (P = 0.0222), 2B4 (P = 0.0015), CD160 (P = 0.0015), and CD38 + /HLA-DR + (P = 0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421., Interpretation: Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials., Funding: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Published by Elsevier B.V.)

Background: Once-weekly isoniazid with rifapentine (HP) for 3 months is a recommended treatment for latent tuberculosis infection in persons with HIV. HP reduces exposures of certain antiretroviral medications, resulting in limited options for the concomitant use of these therapies. Here, we examined the pharmacokinetics (PK), safety, and tolerability of darunavir/cobicistat with HP., Methods: This was an open-label, fixed sequence, two-period crossover study in persons without HIV. Participants received darunavir 800 mg/cobicistat 150 mg once-daily alone for 4 days, then continued darunavir/cobicistat once-daily for days 5-19 with HP coadministration on days 5, 12, and 19. Intensive PK assessments were performed on days 4, 14, and 19. PK parameters were determined using noncompartmental methods. Geometric mean ratios with 90% confidence intervals (CIs) were calculated and compared between phases using mixed-effects models., Results: Thirteen participants were enrolled. Two withdrew after day 4, and one withdrew after day 14. Of the 3 withdrawals, 2 were attributed to drug-related adverse events. Darunavir area under the concentration-time curve, maximum concentrations (Cmax), and concentrations at 24 hours postdose (C24h) were reduced by 71%, 41%, and 96% ∼48-72 hours after HP administration (day 14), respectively, and 36%, 17%, and 89% with simultaneous HP administration (day 19), respectively. On day 14, 45% of the predose and 73% of C24h concentrations were below the darunavir EC50 (0.055 µg/mL)., Conclusions: Darunavir exposures were significantly decreased with HP coadministration. Temporal relationships between HP coadministration and the extent of induction or mixed inhibition/induction of darunavir metabolism were apparent. Coadministration of darunavir/cobicistat with 3HP should be avoided., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

While the coronavirus disease 2019 (COVID-19) pandemic continues to present global challenges, sufficient time has passed to reflect on lessons learned and use those insights to inform policy and approaches to prepare for the next pandemic. In May 2022, the Duke Clinical Research Institute convened a think tank with thought leaders from academia, clinical practice, the pharmaceutical industry, patient advocacy, the National Institutes of Health, the US Food and Drug Administration, and the Centers for Disease Control and Prevention to share, firsthand, expert knowledge of the insights gained from the COVID-19 pandemic and how this acquired knowledge can help inform the next pandemic response. The think tank focused on pandemic preparedness, therapeutics, vaccines, and challenges related to clinical trial design and scale-up during the early phase of a pandemic. Based on the multi-faceted discussions, we outline 10 key steps to an improved and equitable pandemic response., Competing Interests: Potential conflicts of interest. A. F. H. reports contracts with Pfizer and Merck and consulting fees from Merck. B. L. is an employee of and owns stock in Moderna and reports support for travel to a meeting from Moderna. C. W. W. reports consulting fees from Arena Pharmaceuticals, BioFire, FHI Clinical, Giner, Karius, and SeLux Diagnostics; grants or contracts (paid to institution) from Defense Advanced Research Projects Agency, National Institutes of Health (NIH)-Antibacterial Resistance Leadership Group/National Institute of Allergy and Infectious Diseases/NIH Vaccine and Treatment Evaluation Units/National Institute of Mental Health/National Institute of General Medical Sciences, Sanofi, Najit, the Centers for Disease Control and Prevention (CDC), Patient-Centered Outcomes Research, United States Army Medical Research Acquisition Activity, Department of Defence, Abbott, and Pfizer; support for attending meetings and/or travel from the American Society for Microbiology (ASM); participation on a data and safety monitoring board (DSMB) or advisory board for IDbyDNA, Janssen, Regeneron, Roche Molecular Sciences; a leadership or fiduciary role for ASM and the American Society of Tropical Medicine and Hygiene; being employed by Duke University, Durham Veterans Affairs Hospital, Biomeme, and Equity/Founder of Predigen, Inc; and planned, issued, or pending patents for biomarkers for the molecular classification of bacterial infection, methods to diagnose and treat acute respiratory infections, gene expression signatures useful to predict or diagnose sepsis and methods of using the same, host-based molecular signatures of human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 (coronavirus disease 2019 [COVID-19]), methods of identifying infectious disease and assays for identifying infectious disease, and nasopharyngeal protein biomarkers of acute respiratory virus infection and methods of using same. H. C. and S. C. B. are employees of and hold or may hold stock in AstraZeneca. J. W. reports being an employee of and owns stock/stock options in and received equipment, materials, drugs, medical writing, gifts, and other services from Johnson & Johnson and, as CMO, has been deposed in litigation; patents issued that do not relate to the current article (available on request); and a role on the Brooklyn College Cancer Center Advisory Board, a Brooklyn College Foundation Trustee, and on the Fellowships at Auschwitz for the Study of Professional Ethics, Academic Committee. J. R. D. is an employee and shareholder in Eli Lilly and Company. L. H. C. reports consulting fees from Regeneron for the NFL Players Association and grants or contracts from NIH for PCORI. L. S. reports stock/stock options in Novartis. L. R. is an employee of and owns stock/stock options in and received support for attending meetings and/or travel from Bayer AG. M. S. reports consulting fees from AbbVie, Assembly Bio, Antios, Arbutus, Gilead Sciences, Precision Bio, and GSK for scientific advisory boards and participation on a DSMB for Gilead Sciences and AbbVie and a role as editor of the Journal Viral Hepatitis. O. V. is an employee of Boehringer Ingelheim. P. P. has a patent pending for sotrovimab and is an employee and shareholder of Vir Biotechnology. S. N. reports consulting fees from Pardes Biosciences, Theratechnologies, and Silverback Therapeutics; stock/stock options in Vir Biotechnology; grants or contracts (paid to institution) from Gilead Sciences and AbbVie; participation on an advisory board for Vir Biotechnology, a DSMB for Personal Health Insights, Inc; and serving on an event adjudication committee for Bristol–Myers Squibb/PRA. M. A. M. reports consulting fees from Abcam; stock/stock options in Grid Therapeutics; a role as an advisory board member for GSK Belimumab Pregnancy Registry; and funding to Duke from NIAD (U01 AI151378): Centers for Research in Emerging Infectious Disease (CREID) Network Coordinating Center, HHS 75N93019C00050: Duke Collaborative Influenza Vaccine Innovation Centers (CIVICs) A: Vaccine Center, HHS 75N93019C00054: Duke CIVICs C: Clinical Core, U19 AI144177: A Global Syphilis Vaccine Targeting Outer Membrane Proteins Of Treponema pallidum, 2P01 AI089618: Structure-Function Analysis Of Infection- And Vaccine-Induced B Cell Repertoires. S. E. T. reports royalties from UptoDate; grants or contracts (paid to institution) from the CDC; payment or honoraria (to author) from the Infectious Disease Society of America (IDSA) and Emerson Hospital; support from DCRI to attend the meeting upon which this article was based. L. R. B. is involved in human immunodeficiency virus (HIV) and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network, COVID Vaccine Prevention Network, International AIDS Vaccine Initiative, Crucell/Janssen, Moderna, Military HIV Research Program, the Gates Foundation, and Harvard Medical School. reports participation on a DSMB for NIH and AMDAC Committee for the FDA (research funded by the NIH, Welcome Trust, and the Gates Foundation). R. T. G. reports a leadership or fiduciary role on the NIH COVID Treatment Guidelines Panel and IDSA COVID Treatment Guidelines Panel. R. G. reports grants (to institution) from NIH/NIAID, book chapter royalties from Elsevier, and section editor royalties from UpToDate. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIV KGD ) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIV KGD was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC 50 of 130 femtomolar. When cells were exposed to HIV KGD IN-containing recombinant HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142. X-ray crystallographic analyses revealed that GRL-142 interacts with NLS's putative sequence (DQAEHLK) and sterically blocks the nuclear transport of GRL-142-bound HIV KGD 's PIC. Highly INSTI-resistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to GRL-142, suggesting that NLS-targeting agents would serve as salvage therapy agents for highly INSTI-resistant variant-harboring individuals. The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.