Drug information

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Other Names
GS-5423, 3BNC117-LS, 3BNC117-LS-J, (long-acting forms of 3BNC117)
Drug Class
Broadly Neutralizing Antibodies
Registry Number
1412902-17-0 (CAS)
Organization
Rockefeller University, Gilead Sciences
Phase of Development

3BNC117 is in Phase 2 development as a broadly neutralizing antibody for HIV treatment. (3BNC117 is also being developed for HIV prevention.)

(Compound details obtained from ChemIDplus Advanced,1 Nature article,2 Treatment Action Group website,Gilead Sciences press release,4 and Treatment Action Group Pipeline Report 20215)

Pharmacology

Pharmacology

Mechanism of Action: Broadly neutralizing antibody (bNAb). 3BNC117 is a recombinant human IgG1 kappa monoclonal antibody cloned from an HIV-infected viremic controller. It is a next-generation bNAb that targets the CD4 binding site on HIV envelope gp160.2,6

Next-generation HIV bNAbs are naturally occurring antibodies with potent neutralizing activity against a broad array of HIV strains. The utility of bNAbs is being researched for both HIV prevention and treatment/cure. By binding to sites on HIV envelope and through Fc receptor interactions, bNAbs can potentially 1) inhibit cell-free and cell-to-cell viral entry, 2) induce cellular phagocytosis and destruction by macrophages or antibody dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells, and 3) promote the maturation and activity of dendritic cells.6–9 Because it is difficult to induce in vivo generation of bNAbs using conventional vaccination techniques, bNAbs may need to be given by passive transfer, whereby a bNAb is directly administered to an individual.6,10

3BNC117 and long-acting versions of 3BNC117 (called 3BNC117-LS and 3BNC117-LS-J) are being developed for HIV prevention and/or as a possible component to HIV treatment or cure.3,5

Half-life (T½): A Phase 1 study (NCT02018510) investigated a single intravenous (IV) infusion of 3BNC117 at four different dose levels (1, 3, 10, and 30 mg/kg) in adults with and without HIV and found that the average half-life of 3BNC117 was approximately 9 days in the HIV-infected group and 17 days in the HIV-uninfected group.10 In a Phase 2a trial (NCT02446847) of multiple IV infusions of 3BNC117 (30 mg/kg) in adults with HIV, the half-life of 3BNC117 ranged from 14.1 days in adults receiving four doses of 3BNC117 to 19.6 days in adults receiving two doses of 3BNC117.2

The half-life of 3BNC117-LS relative to 3BNC117 was measured in a study of macaques administered single IV infusions. 3BNC117-LS was found to have a median half-life of 2.8 weeks, an increase of 2.0-fold when compared to the half-life of 3BNC117 (median 1.4 weeks).11

Resistance: HIV has developed resistance to 3BNC117 in both a Phase 1 (NCT02018510) and 2a (NCT02446847) trial of 3BNC117.2,10 In the Phase 1 study, high-level resistance to 3BNC117 developed in some, although not all, participants by 28 days after a single 3BNC117 dose.10

In the Phase 2a study, eight out of 13 participants with HIV had rebound viruses that were more resistant to 3BNC117 when compared to pre-infusion viruses. In the majority of participants, viral rebound occurred at high 3BNC117 concentrations. Of eight participants who had sequence analysis performed on rebound viruses, six participants had viral genotypes indicating resistance to 3BNC117. Notably, five out of eight participants had rebound viruses that appeared to arise from a single reactivated virus from the latent reservoir. In all but two participants, rebound viruses did not demonstrate increased resistance to the investigational bNAb 10-1074.2

Select Clinical Trials

Select Clinical Trials

Study Identifier: NCT02588586
Sponsor: Rockefeller University
Phase: Phase 2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety of 3BNC117 and its ability to delay or prevent viral rebound during a treatment interruption of ART.
Study Population:

  • Participants were adults with HIV who had HIV RNA <50 copies/mL for at least 12 months while on ART and had HIV RNA <20 copies/mL at screening.
  • Participants had CD4 counts >500 cells/mm3 and nadir CD4 counts >200 cells/mm3.12


Study Identifier: NCT02446847
Sponsor: Rockefeller University
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this open-label, dose-escalation study was to evaluate the safety and pharmacokinetics of 3BNC117 and its ability to delay or prevent viral rebound during a treatment interruption of ART.
Study Population:

  • Participants were adults with HIV who had HIV RNA <50 copies/mL for at least 12 months while on ART and had HIV RNA <20 copies/mL at screening.
  • Participants had CD4 counts >500 cells/mm3 and nadir CD4 counts ≥200 cells/mm3.
  • Participants had 3BNC117-sensitive viruses.2,13

Selected Study Results: Results published in the Nature (2016) journal showed that 3BNC117 was safe and well tolerated. 3BNC117 was effective in delaying viral rebound following an analytical treatment interruption of ART.2


Study Identifiers: ROADMAP; NCT02850016
Sponsor: Rockefeller University
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to compare the efficacy of the latency-reversing agent romidepsin plus 3BNC117 to the efficacy of romidepsin alone on delaying or preventing viral rebound during a treatment interruption of ART.
Study Population:

  • Participants were adults with HIV who had been on ART for at least 18 months.
  • Participants on a PI- or NNRTI-based ART regimen or on a cobicistat-containing regimen were willing to switch to an INI-based regimen prior to enrollment.
  • Participants had HIV RNA <50 copies/mL for at least 12 months and had CD4 counts >500 cells/mm3 at screening.14,15

Selected Study Results: Results published in The Lancet Microbe (2022) showed that romidepsin plus 3BNC117 and romidepsin administered alone had no substantial effect on reducing latent HIV reservoir size in participants on suppressive ART. Additionally, romidepsin plus 3BNC117, compared to romidepsin administered alone, was not effective in delaying the time to viral rebound during analytical treatment interruption. The observed time to viral rebound was not clinically meaningful in either group.15


Study Identifiers: eCLEAR; NCT03041012
Sponsor: Aarhus University Hospital
Phase: 1b/2a
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether the early administration of romidepsin and/or 3BNC117 in treatment-naive individuals who are initiating ART can reduce the time to viral suppression, limit the size of the latent HIV reservoir, and delay the time to viral rebound during an analytical treatment interruption of ART.
Study Population:

  • Participants have HIV but have never received ART.
  • Participants have CD4 counts >200 cells/mm3 prior to study entry.16,17

Selected Study Results: Results presented at CROI 2022 showed that 3BNC117 administered to participants initiating ART led to faster viral load decline during the second phase of viral decay (10–24 days after ART initiation) and significantly enhanced the elimination of infected cells, as compared to what was observed in participants receiving ART only. After one year, latent HIV reservoir size was reduced from baseline in all treatment groups, with the greatest reduction seen in those receiving 3BNC117 plus ART. Among participants who had 3BNC117-sensitive virus, 80% maintained viral control during treatment interruption of ART. In contrast, among participants who had 3BNC117-resistant virus or did not receive 3BNC117, only 20% maintained viral control during treatment interruption.17


Study Identifiers: TITAN; NCT03837756
Sponsor: University of Aarhus
Phase: 2a
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of the TLR9 agonist lefitolimod plus the bNAbs 3BNC117 and 10-1074 in delaying the time to re-initiation of ART during a treatment interruption of ART.
Study Population:

  • Participants are adults with HIV who have been on ART for at least 18 months.
  • Participants have had HIV RNA <50 copies/mL for at least 15 months and have CD4 counts >500 cells/mm3 at screening.
  • Participants have HIV that is sensitive to 3BNC117 and 10-1074.18


Study Identifier: NCT03719664
Sponsor: Frontier Biotechnologies Inc.
Phase: 2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to determine an optimal dosage of 3BNC117 and the HIV fusion inhibitor albuvirtide and evaluate the safety and efficacy of this combination as long-acting maintenance treatment.
Study Population:

  • Participants are adults with HIV who have been receiving oral ART for the last 24 weeks.
  • Participants have been on a stable ART regimen for the past 4 weeks prior to screening and during the time between the screening visit and first treatment visit.
  • Participants have at least two alternative antiretroviral drug options available.
  • Participants have had HIV RNA <50 copies/mL within the 24 weeks prior to screening and at screening.
  • Participants have CD4 counts >300 cells/mm3 at screening.19


Study Identifiers: RIO; NCT04319367
Sponsor: Imperial College London
Phase: 2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to determine whether the combination of the two long-acting bNAbs 3BNC117-LS and 10-1074-LS can prevent viral rebound after a treatment interruption of ART.
Study Population:

  • Participants are adults with HIV who had previously been diagnosed with primary HIV infection and who had started ART during the primary HIV infection stage.
  • Participants have been receiving continuous suppressive ART for at least 1 year.
  • Participants have had undetectable HIV RNA for at least 1 year and have CD4 counts >500 cells/mm3. Participants have nadir CD4 counts >350 cells/mm3.
  • Participants show no evidence of viral insensitivity to either 10-1074 or 3BNC117.20


Study Identifier: NCT04819347
Sponsor: Frontier Biotechnologies Inc.
Phase: 2
Status: See the ClinicalTrials.gov record for this study’s status.
Study Purpose: The purpose of this open-label study is to evaluate the safety of combination therapy with albuvirtide plus 3BNC117 and determine whether this combination can control viral load levels after an analytical treatment interruption of ART.
Study Population:

  • Participants are adults with HIV on a stable ART regimen who initiated ART either within 6 months of primary HIV infection (cohort 1) or after 6 months of primary HIV infection (cohort 2).
  • Participants have had HIV RNA <50 copies/mL for at least 12 months prior to screening and have HIV RNA <20 copies/mL at screening.
  • Participants have CD4 counts >500 cells/mm3.21


Study Identifier: NCT04560569
Sponsor: Frontier Biotechnologies Inc.
Phase: 2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the safety and efficacy of combination therapy with albuvirtide plus 3BNC117 in participants with multidrug-resistant HIV.
Study Population
:

  • Participants are adults with HIV who have received ART for at least 6 months. Participants have been on a failing ART regimen for at least 8 weeks prior to screening or had treatment failure within the past 8 weeks of screening and are off therapy.
  • Participants have HIV that is resistant to at least one ARV drug from at least three different ARV drug classes and have difficulty in constructing a viable suppressive regimen. Participants must have at least one potential approved ARV drug available which can be used as part of an optimized background regimen.
  • Participants have had HIV RNA >200 copies/mL within the last 3 months prior to screening and have HIV RNA ≥1,000 copies/mL at screening.22


Additional studies evaluating 3BNC117 for HIV treatment have been or are being conducted, including the following early-phase trials of 3BNC117 and 10-1074:

  • NCT03526848: A Phase 1 study evaluating whether 3BNC117 and 10-1074 can control viral rebound in adults with HIV during a treatment interruption of ART. This study is ongoing, but not recruiting participants.23
  • NCT03571204: A Phase 1 study that evaluated whether 3BNC117 and 10-1074 can control viral load levels in individuals with HIV who are currently not receiving ART and in individuals with HIV who stop ART during a treatment interruption. This study has been completed.24
  • NCT03554408: A Phase 1 study that investigated the safety and pharmacokinetics of 10-1074-LS when given alone and when given in combination with 3BNC117-LS in adults with and without HIV. This study has been completed.25
  • BEAT-2 (NCT03588715): A Phase 1 study evaluating whether peginterferon alfa-2b plus 3BNC117 and 10-1074 can control viral rebound and reduce the latent HIV reservoir in adults with HIV during a treatment interruption of ART. This study is ongoing, but not recruiting particpants.26
  • NCT04250636: A Phase 1 study that will evaluate the safety, pharmacokinetics, and antiviral activity of single infusions of both 3BNC117-LS and 10-1074-LS in adults with HIV who are off ART. This study has been completed.27
  • NCT04811040: A Phase 1b study evaluating the safety and efficacy of 3BNC117-LS (GS-5423) and 10-1074-LS (GS-2872) in combination with the investigational capsid inhibitor lenacapavir in controlling viral load levels in virologically suppressed adults with HIV. This study is ongoing, but not recruiting participants.28

Adverse Events

Adverse Events

NCT02446847:
In this Phase 2a trial investigating multiple infusions of 3BNC117 in 13 individuals with HIV, most adverse events (AEs) that occurred during the study were transient and mild. Some participants experienced modest drops in CD4 counts during viral rebound, but most had their counts return to baseline by Week 12. Acute retroviral syndrome was not reported in any participants during rebound.2

ROADMAP (NCT02850016):
In this Phase 1b/2a trial, 11 participants were enrolled to receive romidepsin plus 3BNC117 and nine participants were enrolled to receive romidepsin alone. There were 109 reactogenicity AEs and 131 nonreactogenicity AEs reported. A total of 237 AEs occurred, the majority of which were Grade 1. Sixty-four (27.4%) of the AEs were at least possibly related to romidepsin or 3BNC117. The most common AEs were nausea (87%), headache (37%), fatigue (32%), malaise (42%), chills (26%), and vomiting (37%). After receiving romidepsin, two participants experienced QTc prolongation, which resolved by 1 week after infusion.14,29,30

eCLEAR (NCT03041012):
In the Phase 1b/2a eCLEAR study, 60 participants were enrolled to receive ART only; ART plus 3BNC117; ART plus romidepsin; or a combination of ART, 3BNC117, and romidepsin. The majority of AEs that occurred during the trial were mild and unrelated to study treatment.17

Drug Interactions

Drug Interactions

Drug-drug interactions associated with 3BNC117 are currently unknown.

References

References

  1. United States National Library of Medicine. ChemIDplus Advanced: 3BNC117. https://chem.nlm.nih.gov/chemidplus/rn/1412902-17-0. Accessed April 25, 2022
  2. Scheid JF, Horwitz JA, Bar-On Y, et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature. 2016;535(7613):556-560.
  3. Treatment Action Group website. Research toward a cure trials. https://www.treatmentactiongroup.org/cure/trials/. Accessed April 25, 2022
  4. Gilead Sciences: press release, dated January 9, 2020. Gilead Sciences licenses portfolio of HIV antibodies from The Rockefeller University. https://www.gilead.com/news-and-press/press-room/press-releases/2020/1/gilead-sciences-licenses-portfolio-of-hiv-antibodies-from-the-rockefeller-university. Accessed April 25, 2022
  5. Jefferys R. HIV vaccines & passive immunization. Treatment Action Group Pipeline Report 2021. https://www.treatmentactiongroup.org/wp-content/uploads/2021/07/pipeline_2021_HIV_vaccine_final.pdf. Accessed April 25, 2022
  6. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest. 126(2):415-423.
  7. Jefferys R, Jacobson J. Therapeutic vaccines and immune-based therapies. CUREiculum: HIV/AIDS and cure basics – Module 12. PowerPoint presentation available on the AIDS Vaccine Advocacy Coalition (AVAC) website. https://www.avac.org/sites/default/files/u16/Theraeutic_Vaccine_Module_June.pptx. Accessed April 25, 2022
  8. Bruel T, Guivel-Benhassine F, Amraoui S, et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun. 2016;7:10844.
  9. Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13:31-37.
  10. Caskey M Klein F, Lorenzi JC, et al. 3BNC117 a broadly neutralizing antibody suppresses viremia in HIV-1-infected humans. Nature. 2015;522(7557):487-491.
  11. Gautam R, Nishimura Y, Gaughan N, et al. A single injection of crystallizable fragment domain- modified antibodies elicits durable protection from SHIV infection. Nat Med. 2018;24(5):610-616.
  12. Rockefeller University. An open label, Phase 2 study of the safety and antiretroviral activity of 3BNC117 in HIV-infected individuals on combination antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 26, 2015. NLM Identifier: NCT02588586. https://clinicaltrials.gov/ct2/show/NCT02588586. Accessed April 25, 2022
  13. Rockefeller University. A Phase 2, open label study of the safety, antiretroviral activity and pharmacokinetics of 3BNC117 during a short analytical treatment interruption in HIV-infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 17, 2015. NLM Identifier: NCT02446847. https://clinicaltrials.gov/ct2/show/NCT02446847. Accessed April 25, 2022
  14. Rockefeller University. A Phase 2a, randomized study of romidepsin with or without 3BNC117 to evaluate the effects on the HIV-1 reservoir (ROADMAP). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 26, 2016. NLM Identifier: NCT02850016. https://clinicaltrials.gov/ct2/show/NCT02850016. Accessed April 25, 2022
  15. Gruell H, Gunst JD, Cohen YZ, et al. Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial. Lancet Microbe. 2022;3(3):e203-e214. doi:10.1016/S2666-5247(21)00239-1
  16. Aarhus University Hospital. Early administration of latency reversing therapy and broadly neutralizing antibodies to limit the establishment of the HIV-1 reservoir during initiation of antiretroviral treatment - a randomized controlled trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 20, 2017. NLM Identifier: NCT03041012. https://clinicaltrials.gov/ct2/show/NCT03041012. Accessed April 25, 2022
  17. Gunst JD, Pahus MH, Rosás-Umbert M, et al. The impact of 3BNC117 and romidepsin treatment at ART initiation on HIV-1 persistence. International AIDS Society (IAS) Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2022. https://www.natap.org/2022/CROI/croi_54.htm. Accessed April 25, 2022
  18. University of Aarhus. Combining a TLR9 agonist with broadly neutralizing antibodies for reservoir reduction and immunological control of HIV infection: an investigator-initiated randomized, placebo-controlled, Phase IIa trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 7, 2019. NLM Identifier: NCT03837756. https://clinicaltrials.gov/ct2/show/NCT03837756. Accessed April 25, 2022
  19. Frontier Biotechnologies Inc. A Phase 2, multicenter, three-part study to establish the dosage, safety and antiviral activity of combination therapy with albuvirtide and 3BNC117 as long-acting maintenance therapy in virologically suppressed subjects with HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 22, 2018. NLM Identifier: NCT03719664. https://clinicaltrials.gov/ct2/show/NCT03719664. Accessed April 25, 2022
  20. Imperial College London. A randomised placebo controlled trial of ART plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) vs ART plus placebo in treated primary HIV infection on viral control off ART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 2, 2020. NLM Identifier: NCT04319367. https://clinicaltrials.gov/ct2/show/NCT04319367. Accessed April 25, 2022
  21. Frontier Biotechnologies Inc. The Phase 2, two arms, one site, safety and antiviral activity of combination therapy with albuvirtide and 3BNC117 in virologically suppressed subjects with HIV-1 infection after analytical treatment interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 22, 2021. NLM Identifier: NCT04819347. https://clinicaltrials.gov/ct2/show/NCT04819347. Accessed April 25, 2022
  22. Frontier Biotechnologies Inc. A multicenter, two-arm, 24-week study of albuvirtide in combination with 3BNC117 in patients with multi-drug resistant (MDR) HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 17, 2020. NLM Identifier: NCT04560569. https://clinicaltrials.gov/ct2/show/study/NCT04560569. Accessed April 25, 2022
  23. Rockefeller University. An open label, randomized study of the safety and antiretroviral activity of 3BNC117 and 10-1074 in HIV-infected individuals on combination antiretroviral therapy and during analytical treatment interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 3, 2018. NLM Identifier: NCT03526848. https://clinicaltrials.gov/ct2/show/NCT03526848. Accessed April 25, 2022
  24. National Institute of Allergy and Infectious Diseases (NIAID). An exploratory study of combination therapy with 3BNC117 and 10-1074 in HIV-infected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 22, 2018. NLM Identifier: NCT03571204. https://clinicaltrials.gov/ct2/show/NCT03571204. Accessed April 25, 2022
  25. Rockefeller University. A Phase 1, dose escalation, first-in-human study of the safety and pharmacokinetics of the subcutaneous and intravenous administration of 10-1074-LS alone and in combination with 3BNC117-LS in HIV-infected and HIV-uninfected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 31, 2018. NLM Identifier: NCT03554408. https://clinicaltrials.gov/ct2/show/NCT03554408. Accessed April 25, 2022
  26. Luis Montaner. Pilot study on innate activation and viral control in HIV-infected adults undergoing an analytical treatment interruption after administration of pegylated interferon alpha 2b with broadly HIV-1 neutralizing antibodies (3BNC117, 10-1074). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 30, 2018. NLM Identifier: NCT03588715. https://clinicaltrials.gov/ct2/show/NCT03588715. Accessed April 25, 2022
  27. Rockefeller University. An open label, single arm study of the safety, pharmacokinetics and antiretroviral activity of the combination of 3BNC117-LS and 10-1074-LS in viremic HIV-infected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 30, 2020. NLM Identifier: NCT04250636. https://clinicaltrials.gov/ct2/show/NCT04250636. Accessed April 25, 2022
  28. Gilead Sciences. A Phase 1b randomized, blinded, proof-of-concept study to evaluate the safety and efficacy of broadly neutralizing antibodies (bNAbs) GS-5423 and GS-2872 in combination with capsid inhibitor lenacapavir (GS-6207) in virologically suppressed adults with HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 19, 2021. NLM Identifier: NCT04811040. https://clinicaltrials.gov/ct2/show/NCT04811040. Accessed April 25, 2022
  29. Gruell H, Cohen YZ, Gunst JD, et al. A randomized trial of the impact of 3BNC117 and romidepsin on the HIV-1 reservoir. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, MA. Abstract 38. https://www.croiconference.org/abstract/a-randomized-trial-of-the-impact-of-3bnc117-and-romidepsin-on-the-hiv-1-reservoir/. Accessed April 25, 2022
  30. Søgaard OS. A randomized trial of the impact of 3BNC117 and romidepsin on the HIV-1 reservoir. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, MA. http://www.croiwebcasts.org/console/player/44589?mediaType = slideVideo&. Accessed April 25, 2022

Last Reviewed: April 25, 2022