• ACTG to Present Data on Investigational New COVID-19 Treatment at IDWeek 2021

    September 29, 2021 Alexis Sexton Spotlight

    The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, which recently expanded its focus to include evaluating outpatient treatment for COVID-19, today announced that Teresa H. Evering, M.D., M.S., a co-lead investigator (with Eric S. Daar, M.D.) for BRII-196/BRII-198 in the ACTIV-2 study of Outpatient Monoclonal Antibodies and Other Therapies, will present data for the monoclonal antibody combination at the virtual IDWeek 2021 conference, taking place September 29 – October 3, 2021.

    As SARS-CoV-2, the virus that causes COVID-19, continues to spread, there remains a significant need to develop safe and effective therapeutics that prevent severe disease,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles (UCLA). “This presentation demonstrates that BRII-196/BRII-198 was safe, well-tolerated, and demonstrated a significant reduction in the risk of hospitalization and death among adults with mild to moderate COVID-19 who were high risk of progressing to severe disease. We are excited to present data highlighting a new therapeutic with the potential to help attenuate the impact of this pandemic.”

    BRII-196 and BRII-198 (developed by Brii Biosciences) were derived from antibodies isolated from people who had recovered from COVID-19. Administered as two separate infusions as a one-time dose, they target two different parts of SARS-CoV-2. In an interim analysis, the combination demonstrated a 78 percent reduction in the combined endpoint of hospitalization and death compared with placebo in 837 non-hospitalized participants with COVID-19 who were at high risk of clinical progression. In the ACTIV-2 arm receiving BRII-196/BRII-198, there were 12 hospitalizations and one death, compared to 45 hospitalizations and nine deaths in the arm receiving placebo [2.4 vs. 11.1 percent, relative risk 0.22 (95% CI: 0.05, 0.86), P=0.00001]. Grade 3 or higher adverse events (AEs) were observed less frequently among BRII-196/BRII-198 participants than placebo (3.8 percent vs. 13.4 percent), with no severe infusion reactions or drug-related serious AEs. Notably, the clinical benefit was similar among participants who entered the study after having five or fewer days of symptoms and those who had experieinced symptoms for more than five days.

    Between January and July 2021, ACTIV-2 enrolled participants from sites in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines who were randomized to receive either BRII-196/BRII-198 or placebo. The median participant age was 49 years; 51 percent of participants were female, 17 percent were Black, and 49 percent were Hispanic. In this interim analysis, 71 percent of participants had a day 28 visit and 97 percent had a day seven visit.

    ACTIV-2 is a randomized, blinded, controlled adaptive platform that allows promising therapies to be added and removed over the course of the study to efficiently test a variety of new agents against placebo within the same trial infrastructure. In addition to studying the safety and efficacy of investigational therapies, ACTIV-2 also aims to determine whether they can decrease viral shedding, thereby potentially preventing transmission of SARS-CoV-2.

    ACTIV-2 is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), which also funds the ACTG. ACTIV-2 is part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program to create a coordinated research strategy that prioritizes and speeds development of the most promising treatments and vaccines. It also receives support from the Federal COVID Response – Therapeutics, the U.S. government’s multi-agency effort to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. The phase 3 trial is a continuation of the phase 2 trial in which BRII-196/BRII-198 met study-defined safety and efficacy criteria.

    ACTIV-2 is led by Kara Chew, M.D., M.S., UCLA and Davey Smith, M.D., University of California San Diego (protocol chairs) and David Alain Wohl, M.D., University of North Carolina (UNC) and Dr. Daar, Lundquist Institute at Harbor-UCLA Medical Center (vice-chairs), and supported by Dr. Currier and Joseph J. Eron, M.D., UNC (ACTG Co-Chair).

    For more information about ACTIV-2, please visit www.riseabovecovid.orgwww.actgnetwork.org, or clinicaltrials.gov.

    To read the full press release click here.

  • ACTG Announces Graduation of Novel Polyclonal Antibody Therapy SAB-185 to Phase 3 Study in ACTIV-2

    September 27, 2021 Alexis Sexton Spotlight

    The AIDS Clinical Trials Group (ACTG), the largest global HIV research   network, which recently expanded its focus to include evaluating outpatient treatment for COVID-19, today announced that SAB-185, a novel polyclonal antibody therapy, has demonstrated safety and efficacy in phase 2 that meet the criteria for graduation to phase 3 in the ACTIV-2 Outpatient Monoclonal Antibodies and Other Therapies Trial (ACTG A5401). SAB-185 is the second agent to graduate to phase 3 in ACTIV-2, which is evaluating multiple investigational agents to treat early, symptomatic COVID-19 in non-hospitalized individuals. The combination monoclonal antibody treatment BRII-196/BRII-198 graduated to phase 3 in May 2021 and recently reported positive data. For more information about the trial, please visit the study website.

    SAB-185 (developed by SAB Biotherapeutics), is the first polyclonal antibody (a treatment containing a variety of targeted, highly potent antibodies) to be evaluated in ACTIV-2. SAB-185 is made by Tc Bovines™ that have been genetically engineered to make fully human antibodies. Once the bovines develop an immune response and generate antibodies against the spike protein on the surface of SARS-CoV-2 (the virus that causes COVID-19), their plasma is collected, and the antibodies are separated out and purified.

    “The graduation of SAB-185 from phase 2 to phase 3 in ACTIV-2 is an important milestone as we evaluate a variety of potential treatments for people who have COVID-19 but aren’t sick enough to be hospitalized, “said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles (UCLA). “We are thrilled that, per the study protocol, the interim analysis of phase 2 data from participants receiving SAB-185 demonstrated sufficient safety and efficacy to justify advancement to phase 3.”

    The phase 2 study of SAB-185 evaluated two doses, both of which met pre-defined criteria for graduation to phase 3. Evaluations are ongoing to determine which of these doses will advance to phase 3. The planned phase 3 study will evaluate the safety and efficacy of SAB-185 to prevent hospitalization and death in non-hospitalized adults with COVID-19. The study will enroll 1,200 participants at high risk of progressing to severe COVID-19. Half of the participants will receive SAB-185 and half will receive casirivimab and imdevimab, Regeneron’s combination monoclonal antibody treatment. Both will be administered as an intravenous infusion.

    ACTIV-2 is a randomized, blinded, controlled adaptive platform that allows promising therapies to be added and removed over the course of the study to efficiently test a variety of new agents within the same trial infrastructure.

    “We are pleased to advance a second agent to phase 3 in the ACTIV-2 study,” said Babafemi Taiwo, M.B.B.S., Professor of Medicine and Chief of Infectious Diseases at Northwestern University and lead investigator of SAB-185 in ACTIV-2. “We are especially enthusiastic about the first polyclonal antibody therapy being evaluated in ACTIV-2. Because it contains a diverse mix of antibodies, SAB-185 can simultaneously attack SARS-CoV-2 at different points, rendering it a very promising treatment option.”

    ACTIV-2 is led by Kara W. Chew, M.D., M.S., UCLA and Davey Smith, M.D., University of California, San Diego (protocol chairs) and David Alain Wohl, M.D., University of North Carolina (UNC) and Eric S. Daar, M.D., Lundquist Institute at Harbor-UCLA Medical Center (vice-chairs) and supported by Dr. Currier and ACTG Co-Chair Joseph J. Eron, M.D., UNC.

    ACTIV-2 is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), which also funds the ACTG. ACTIV-2 is part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program to create a coordinated research strategy that prioritizes and speeds development of the most promising treatments and vaccines. It also receives support from the Federal COVID Response-Therapeutics, the U.S. government’s multi-agency effort to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics.

    For more information about ACTIV-2, please visit www.riseabovecovid.orgwww.actgnetwork.org, or clinicaltrials.gov.

    To read the full press release click here.

  • ACTG announces data from ACTIV-2 study, demonstrating benefit of BRII-196 and BRII-198 in non-hospitalized participants with COVID-19

    August 26, 2021 Alexis Sexton Spotlight

    The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, which has expanded its focus to include evaluating outpatient treatment for COVID-19, today announced positive data for the monoclonal antibody combination therapy BRII-196/BRII-198 from the ACTIV-2 study of Outpatient Monoclonal Antibodies and Other Therapies. In an interim analysis of the phase 3 evaluation of BRII-196/BRII-198, the combination demonstrated a 78 percent reduction in the combined endpoint of hospitalization and death compared with placebo in more than 800 non-hospitalized COVID-19 participants who were at high risk of clinical progression.

     

    BRII-196 and BRII-198 (developed by Brii Biosciences) were derived from antibodies isolated from people who had recovered from COVID-19. Administered as two separate infusions as a one-time dose, they target two different parts of SARS-CoV-2 (the virus that causes COVID-19). In the ACTIV-2 group receiving BRII-196/BRII-198, there were 12 hospitalizations and one death, compared to 45 hospitalizations and nine deaths among the group receiving placebo. There were no safety concerns.

     

    This interim analysis of this fully enrolled study included 837 participants who were at high risk of progressing to severe COVID-19, including being age 60 or older, being a current smoker, or having one of the following conditions: chronic lung, kidney, or liver disease; obesity; hypertension; cardiovascular disease; diabetes; or current cancer or immunosuppression. Participants were enrolled within 10 days of COVID-19 symptom onset across six countries (United States, Argentina, South Africa, Brazil, Philippines, and Mexico). Nearly two-thirds of participants had follow-up through 28 days following treatment.

     

    “The ACTG is very excited to announce such positive data from the ACTIV-2 study, particularly as we continue to see cases of COVID-19 skyrocket as a result of the Delta variant,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles (UCLA). “These data offer very convincing evidence of the clinical benefit of the combination of BRII-196/BRII-198 among people at high risk of progressing to severe COVID-19.”

     

    Today’s data were revealed by the ACTIV-2 Data Safety Monitoring Board (DSMB) based on an interim analysis of the trial. The DSMB recommended that the study continue in a blinded manner for longer term follow-up, and all participants continue to be followed.

     

    The study will ultimately evaluate the clinical efficacy of BRII-196/BRII-198 by SARS-CoV-2 variants. Participants were enrolled during a period when a number of variants of concern were circulating, including Alpha, Beta, Gamma, and Delta. Current in vitro pseudovirus testing data suggest that BRII-196/BRII-198 is active against all major SARS-CoV-2 variants, including the Delta variant. In addition, ACTIV-2 will conduct analyses to better understand the clinical benefits of BRII-196/BRII-198 treatment among participants who received it within five days compared to within six to 10 days of symptom onset.

     

    “The recent surge in COVID-19 hospitalizations and deaths serves as a stark reminder of the importance of early treatment for this devastating illness,” said Teresa H. Evering, M.D., M.S., Weill Cornell Medicine, co-lead investigator of BRII-196/BRII-198 in ACTIV-2.

     

    “These data suggest that BRII-196/BRII-198 will be a potent new treatment option for COVID-19,” said Eric S. Daar, M.D., Lundquist Institute at Harbor-UCLA Medical Center, co-lead investigator of BRII-196/BRII-198 in ACTIV-2. “ACTIV-2 will provide us with vital insights that will help clinicians make real-world treatment decisions for the many people who continue to be affected by COVID-19.”

     

    ACTIV-2 is a randomized, blinded, controlled adaptive platform that allows promising therapies to be added and removed over the course of the study to efficiently test a variety of new agents against placebo within the same trial infrastructure. In addition to studying the safety and efficacy of investigational therapies, ACTIV-2 also aims to determine whether they can decrease viral shedding, thereby potentially preventing transmission of SARS-CoV-2.

     

    ACTIV-2 is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), which also funds the ACTG. ACTIV-2 is part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program to create a coordinated research strategy that prioritizes and speeds development of the most promising treatments and vaccines. It also receives support from the Federal COVID Response – Therapeutics, the U.S. government’s multi-agency effort to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. The phase 3 trial was a continuation of the phase 2 trial in which BRII-196/BRII-198 met study-defined safety and efficacy criteria.

     

    ACTIV-2 is led by Kara W. Chew, M.D., M.S., UCLA and Davey Smith, M.D., University of California, San Diego (protocol chairs) and David Alain Wohl, M.D., University of North Carolina (UNC) and Dr. Daar (vice-chairs) and supported by Dr. Currier and Joseph J. Eron, M.D., UNC (ACTG Co-Chair).

     

    For more information about ACTIV-2, please visit www.riseabovecovid.orgwww.actgnetwork.org, or clinicaltrials.gov.

    To read the full press release click here.

  • ACTG Network Solicits for Membership to its Science Committees

    August 25, 2021 Alexis Sexton Spotlight

    This is a solicitation for nominations to the ACTG’s leadership, science, laboratory, and resource committees. See below that the nomination process is automated and that nominations must be submitted through the ACTG website.

    For the science committees, the ACTG is seeking qualified clinical and laboratory investigators with expertise relevant to the area of research who are willing to commit the time necessary to serve on the Transformative Science Groups (TSGs) and other committees, including the Scientific Agenda Steering Committee (SASC). Interested investigators with appropriate expertise need not be affiliated with a funded ACTG Clinical Trials Unit (CTU) or Clinical Research Site (CRS) and/or have previous involvement with ACTG studies, except for the SASC positions.

    • International investigators and junior investigators are strongly encouraged to submit their names in nomination to science committees appropriate to their interests.
    • International site personnel are strongly encouraged to submit their names in nomination to committees appropriate to their interests and experience.

    For the leadership, laboratory, and resource committees, the nomination and election process is open to both domestic and international investigators and staff at funded ACTG-affiliated CTUs and CRSs. Unlike for the science committees, investigators and staff at sites not affiliated to the ACTG are not eligible for nomination to those committees, given the nature of the work for the committees.

    Current members of committees for whom a second term is permitted and who are interested in serving a second term must submit a nomination packet.

    VACANCIES:

    The detailed listing of position vacancies for the different committees is available on the ACTG Committee Nomination web site at https://nomination.mis.s-3.net/ and is also attached to this memorandum for your convenience. The listing also specifies who is eligible for the positions, term duration, number of conference calls per month and meetings per year, and a brief description of duties and responsibilities of the positions.

    To see the full list of vacancies you may also click here.

    NOMINATION PROCESS:

    Nominations and required accompanying materials must be submitted online at https://nomination.mis.s-3.net/ by Monday, September 20.

    The individual position descriptions for the vacancies specify who may submit a nomination and when self-nominations are acceptable with the appropriate documentation.

    Nominees must submit all required documents and acknowledge their willingness to serve. The list of required documents, also available on the website, is as follows:

    • Nomination letter outlining the candidate’s qualifications, relevant expertise, experience, and accomplishments pertinent to the position
    • Letter of support from the nominee’s CRS Leader or CTU PI for non-investigator positions; the letter of support from the CTU PI or CRS Leader is not necessary for investigator positions or if the nomination letter is from the nominee’s CRS Leader or CTU PI
    • NIH biosketch (template available at http://grants.nih.gov/grants/forms/biosketch.htm and on the ACTG member web site) or a resume or curriculum vitae for resource committee members.

    SELECTION PROCESS:
    The ACTG’s Voting Members will review nominations to the ACTG Executive Committee (AEC) and Performance Evaluation Committee. The AEC will vote on membership of the Scientific Agenda Steering Committee. Nominations for all other committees will be distributed to the relevant committee for review and selection. The AEC will review and determine whether to endorse the selections made by the respective committees. Following the AEC review, the nominees will be notified of the election outcome. Once the committees have advised nominees of the outcome, the AEC will broadly announce the selections and post the results to the ACTG web site.

    INQUIRIES

    Questions regarding the nomination process should be directed to the ACTG Network Coordinating Center at ACTGCommitteeNominations@dlhcorp.com.

    We look forward to receiving your nominations.

  • Small Clinical Trials Advancing HIV Remission and Cure – Due September 1, 2021

    August 13, 2021 Alexis Sexton Spotlight

    Request for Applications

    Small Clinical Trials Advancing HIV Remission and Cure

    The AIDS Clinical Trials Group (ACTG) Network in collaboration with the NIAID Division of AIDS (DAIDS) has developed a new pathway for the conduct of small experimental trials that aim to advance efforts related to HIV remission and cure utilizing the infrastructure of the ACTG Network.  It is anticipated these studies will be small ( < 30 participants)  and will involve 1-3 clinical research sites experienced at these types of trials. The trials will by nature be intensive and may include specialized assays or procedures, thus making them unsuitable for the ACTG’s larger multi-site studies. Concepts selected for development will be managed by the ACTG’s newly-created Small Clinical Trials Unit (SCTU) with dedicated clinical trial specialists and statistical support. The studies will be conducted at ACTG sites, and the efforts will be coordinated with the ACTG’s Reservoirs, Remission, and Cure Transformative Science Group (Cure TSG). This mechanism is open broadly to investigators with interest in experimental science clinical trials addressing questions important to the HIV cure agenda, and proposing investigators do not need to be affiliated with the ACTG.

    Successful applicants will work with the ACTG SCTU to finalize protocol development and implementation, which will be overseen by the Cure TSG steering committee. The submitting investigator may serve as the study’s chair; additional team members with experience working at ACTG sites will be added to the protocol team. DAIDS will be the sponsor if the study requires an IND/IDE.

    To the extent possible, the ACTG will support all primary endpoint laboratory assays in the currently funded specialty laboratories or through contract laboratories. Secondary, exploratory, and specialized assays can be performed by the applicant but will not be routinely funded by the ACTG. This RFA will not fund assay development. Excess samples will be saved in the ACTG specimen repository and will be available to investigators, both internal and external to the ACTG, for work outside the objectives of the original trial via a standard ACTG request and review process.

    The ACTG Statistical Data Center (SDAC) will lead the analyses of primary endpoint data. Analyses of secondary and exploratory endpoints will be conducted in collaboration with the proposing investigators’ statistical experts and SDAC.

    Applications must demonstrate clear linkage to the DAIDS and ACTG scientific agendas. Examples of areas of particular scientific interest to include but are not limited to:

    • Quantification and characterization of HIV reservoirs and their decay on current antiretroviral therapy or in response to experimental therapies
    • Mechanisms of HIV persistence, immune control and/or immune escape.
    • Therapeutic vaccination to enhance immune clearance of HIV-infected cells
    • Immune-based therapies to clear virus expressing cells and/or control HIV reservoirs
    • Novel therapies to induce HIV expression and deplete HIV reservoirs including combination interventions

    Application Procedure

    • Applications should use PHS 398 forms and proposal format, except that the Research Plan is limited to 6 pages (single-spaced, 11 pt Times New Roman font). Applicants should include the following information in their proposals:
      • Prior and current experience with specific HIV remission and cure studies and a summary of past contributions to the field of HIV remission and cure.
      • Proposed scientific contributions to the ACTG and DAIDS agendas in the area of HIV cure and remission.
      • NIH-format biosketches for the PI/other key personnel.
      • Other Support for key personnel.
    • The grant format should include the following sections:
      • Background
      • Accomplishments
      • Innovation
      • Approach, – should contain the basic design of proposed clinical trial including rationale, hypotheses, objectives and outcomes, study population, intervention and analysis plan
      • Investigators

    A schedule of events may be included as the single appendix.

    Criteria for Evaluation

    Proposals will be evaluated on the basis of significance, originality, feasibility, and likely contribution to the HIV remission/cure agenda of the ACTG and DAIDS.

    Specific criteria will include:

    • Investigators: Are the investigators qualified to design, oversee and perform the proposed work, as judged by past accomplishments (publications; independent peer-reviewed support), and/or patient-oriented AIDS research, and experience working in regulated environment? Access to trainees and junior faculty as collaborators in the work should also be described.
    • Institutional Resources: Does the investigator have the resources and environment to conduct assays that will be done outside of the ACTG specialty or contract labs and participate in the statistical analysis? If the applicant proposes to utilize a non-ACTG laboratory, does the team have the capabilities and resources to meet ACTG standards (e.g. QA/QC, data management) and perform any specialized assays required by the concept proposal? Is the host institution committed to providing the necessary space and other infrastructure needed to complete the required work for the duration of the award?
    • Innovation: Will the study, if successful, advance efforts to understand HIV reservoirs and/or facilitate HIV remission/cure?
    • Approach: Does the concept propose a study focused on an area of scientific interest to the field of HIV reservoirs and/or HIV remission that is investigational and intensive, uses non-standard experimental endpoints, and/or requires specialized assays or procedures, thus making it unsuitable for the ACTG’s larger multi-site studies? If the study requires experimental interventions or devices, are they available to the investigator?

    Application Timelines

    This RFA has twice-yearly receipt dates on March 1st and September 1st.

    An optional Letter of Intent may be submitted by August 1st and April 1st that includes the principal investigator, other key investigators, investigator institution, tentative title of the proposal, primary hypotheses and intention to conduct specialized laboratory assays outside of the ACTG and contract laboratories.

    Release of solicitation:  July 12, 2021

    First application due date: September 1, 2021

    EXPECTED SUPPORT OF FUNDED APPLICATIONS

    1. The funded applications will generally receive an award of 3 years duration.
    2. The ACTG intends to fund up to 2 small clinical trial awards per year.
    3. The ACTG will provide protocol development support, clinical trials expertise, regulatory support, statistical and data support and the sites, staff and laboratory support need to conduct the trial.
    4. Primary and secondary endpoint assays conducted by the ACTG specialty labs or contract labs will be supported by the ACTG.
    5. Each awardee will receive core support of up to 25% FTE up to the NIH salary cap per year, direct costs. (This funding is to support the effort of the PI and other Key Personnel who will be directly involved in the development and conduct of the clinical trial and will be provided as part of protocol development and implementation as per ACTG standard operating procedures.)
    6. Assay performance work that is deemed essential to the trial and conducted outside of the ACTG or contract labs may be supported by the ACTG using a cost-reimbursement model, depending on the nature of the assays and the volume of work required.
    7. Support for exploratory assays is the responsibility of the proposing investigators.

    Application Submission and Questions

    Completed applications are to be submitted on or after August 15, 2021 to a portal available at:  https://actgnetwork.org/submit-a-proposal/.

    Questions about the RFA can be sent to ACTGLeadershipSupport@DLHCorp.com; Click here to view the FAQs (frequently asked questions and answers document).

  • ACTG launches study evaluating the effects of an ARV change among people living with HIV who experience excessive weight gain

    The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced the launch of the Do IT Study (Doravirine for Persons with Excessive Weight Gain on Integrase Inhibitors and Tenofovir Alafenamide), also known as A5391. The study will evaluate the effects of an antiretroviral (ARV) regimen change among people living with HIV who have experienced excessive weight gain when on a regimen that includes an integrase strand transfer inhibitor (INSTI) and tenofovir alafenamide/emtricitabine (TAF/FTC) or TAF/lamivudine (TAF/3TC).

    While weight gain is common following initiation of most ARV regimens, recent studies have shown greater incidences of weight gain with some of the newer medications, such as combination therapies that include the INSTI class of drugs and TAF/FTC or TAF/3TC. Recent studies have also shown that greater incidences of weight gain while on ARV therapy increases the risk of developing co-morbid conditions such as diabetes and other chronic conditions among people living with HIV, particularly in those who are overweight or obese.

    “Weight gain and the chronic conditions to which it often leads can have detrimental effects on the health and quality of life of people living with HIV,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “The ACTG is committed to undertaking research that optimizes ARV treatment and ensures optionality for people living with HIV.”

    A5391 is a phase 4, 48-week, open-label, randomized study to assess whether switching from the INSTIs bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL) with TAF/FTC or TAF/3TC to a new ARV regimen containing doravirine reduces weight gain or causes weight loss. Doravirine is a recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI); research suggests that individuals may gain less weight on NNRTI- and non-TAF-containing ARV regimens. The three arms of A5391 are:

    • Doravirine + TAF/FTC or TAF/3TC
    • Doravirine + tenofovir disoproxil fumarate (TDF)/FTC or TDF/3TC
    • Continuation with current BIC-, DTG-, or RAL with TAF/FTC or TAF/3TC

    A5391 will enroll a total of 222 adults living with HIV (74 per study arm) who have a body mass index (BMI) ≥27.5 kg/m2 and an unintentional weight gain of more than 10 percent of their body weight in the one to three years after starting an INSTI-containing regimen and TAF/FTC or TAF/3TC. Eligible participants must have also maintained virologic suppression for the 48 weeks prior to entry. All participants will be followed for 48 weeks to determine the effect of the medication switch on weight, body fat, blood glucose and metabolic health, and other parameters.

    The trial is now enrolling participants at ACTG clinical research sites in the United States and may add other sites in South America and Africa.

    “We are seeing an increase in chronic diseases linked to excess weight among people living with HIV,” said A5391 Protocol Chair John Koethe, M.D., Vanderbilt University Medical Center. “We expect to gain valuable insights from A5391, the first rigorously designed study to determine if a change in antiretroviral medications may benefit people who have experienced excessive weight gain on INSTIs and TAF.”

    A5391 is led by Dr. Koethe; Jordan Lake, M.D., M.Sc. (University of Texas Health Science Center); and Roy (Trip) Gulick, M.D., M.P.H. (Weill Cornell Medicine). It is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and by Merck & Company, which is also providing study medications. NIAID and collaborating NIH Institutes fund the ACTG. 

    “While the benefits of current HIV drugs are well-known and appreciated, we need better strategies to manage their side effects, including weight gain,” said Dr. Gulick. “We are hopeful that this study will inform the field in a way that benefits the overall health of people living with HIV.”

  • Solicitation for ACTG Science Committee Leadership Positions

    DEADLINE: August 18, 2021

    This memorandum is a solicitation for nominations to the leadership positions on most of the ACTG science committees including the Comorbidities, Cure, Hepatitis and TB Transformative Science Groups (TSGs) and for the Neurology and Women’s Health Collaborative Science Groups (CSGs). We anticipate that the global solicitation for other committee members will follow in late August. See below that the nomination process is automated and that nominations must be submitted through the ACTG website.

    VACANCIES:

    The detailed listing of leadership vacancies is available on the ACTG Committee Nomination web site at https://nomination.mis.s-3.net/  and is also attached. The listing also specifies who is eligible for the positions, term duration, number of conference calls per month and meetings per year, and a brief description of duties and responsibilities of the positions.

    Specifically, we are soliciting nominations for the available positions below.

    • Chair and Vice Chair of the Comorbidities TSG
    • Chair and Vice Chair of the Reservoirs Remission and Cure TSG
    • Chair and Vice Chair of the Hepatitis TSG
    • Chair and Vice Chair of the Tuberculosis TSG
    • Chair and Vice Chair of the Neurology Collaborative Science Group
    • Chair and Vice Chair of the Women’s Health Collaborative Science Group

    Eligible candidates include US and non-US ACTG investigators, as well, as experts in the field who are not ACTG members or affiliated with ACTG sites. We strongly encourage international investigators to apply and urge you to consider experts at your institution who may not currently be affiliated with the ACTG.

    Please note that elected chairs and vice chairs will be invited to attend the ACTG Leadership Retreat in Los Angeles, CA November 8-10, 2021. The meeting is currently planned to be in-person but there will be virtual access for those unable to travel to Los Angeles.

    FINANCIAL SUPPORT:

    Chairs and vice chairs of ACTG committees receive salary support and travel funds to attend ACTG meetings.

    NOMINATION PROCESS:

    Nominations and required accompanying materials must be submitted online at https://nomination.mis.s-3.net/ by August 18, 2021.

    Any ACTG member may submit a nomination. Self-nominations (from both ACTG and non-ACTG members) will be accepted with the appropriate documentation.

    Nominees must submit all required documents and acknowledge their willingness to serve. The list of required documents, also available on the website, is as follows:

    • Nomination letter outlining the candidate’s qualifications, relevant expertise, experience, and accomplishments pertinent to the position
    • One-page vision/strategic plan for the relevant research area
    • NIH biosketch (template available at http://grants.nih.gov/grants/forms/biosketch.htm)

    SELECTION PROCESS:
    The ACTG Executive Committee (AEC) will review the nominations and select the leaders. Following the selection, the AEC leadership will notify nominees of the election outcome. Once that notification process is completed, the AEC will broadly announce the selections and post the results to the ACTG web site.

    INQUIRIES:

    Interested investigators who would like to discuss the positions or have questions should contact us.

    Judy:   jscurrier@mednet.ucla.edu

    Joe:     joseph_eron@med.unc.edu

    Ian:      isanne@witshealth.co.za

    Direct questions regarding the nomination process to the ACTG Network Coordinating Center at

    ACTGCommitteeNominations@dlhcorp.com.

    We look forward to receiving your nominations.

  • ACTG announces publication of REPRIEVE sub-study in JAMA Network Open, providing insights into cardiovascular disease risk among people living with HIV

    The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced that findings from a sub-study of REPRIEVE (A5332/A5332s, an international clinical trial studying heart disease prevention in people living with HIV) have been published in the Journal of the American Medical Association Network Open (JAMA Network Open). The study found that approximately half of study participants, who were considered by traditional measures to be at low-to-moderate risk of future heart disease, had atherosclerotic plaque in their coronary arteries.

    While it is well-known that people living with HIV are at increased risk of cardiovascular events, including heart attacks and strokes, little is understood about the prevalence and extent of atherosclerosis in heart blood vessels and associated biological factors. The Mechanistic sub-study of REPRIEVE was designed to specifically identify factors that contribute to cardiovascular disease among people living with HIV.

    “This sub-study of REPRIEVE is seeking to better understand why people living with HIV develop heart disease, even when their HIV is well controlled and they don’t have many traditional risk factors,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “REPRIEVE is the largest study of cardiovascular disease among people living with HIV and this is an important early report that sets the stage for future important findings.”

    Today’s publication describes baseline data on 755 participants between the ages of 40 and 75 years old, who were enrolled at 31 sites across the United States. The sub-study used coronary CT angiography to assess the amount of plaque in participants’ coronary arteries and then correlated those findings with blood samples that measured inflammation and immune activation.

    Nearly half the participants (49 percent) had plaque in their coronary arteries, though the plaques were mostly seen in just a few areas of the coronary arteries. The presence of plaque was associated with a higher burden of risk factors, but also with higher levels of inflammation independent of traditional risk scores. In almost all individuals (97 percent), the plaque was mild and did not cause a narrowing of more than 50 percent of the coronary artery. While significant narrowing was rare, about one-quarter of participants (23 percent) had plaque with features that could potentially cause problems in the future (also known as vulnerable plaque).

    In the general population, epidemiologic studies have shown that future cardiovascular disease increases with higher ASCVD PCE (atherosclerotic cardiovascular disease pooled cohort equation) risk scores, an index of traditional risk. REPRIEVE recruited participants with low to moderate ASCVD risk and a low average 10-year risk score of 4.5 percent. The clinical significance of mild or even significant plaque in asymptomatic people with low cardiovascular risk is unknown, as is the effectiveness of statin therapy to prevent cardiovascular disease in this population. REPRIEVE will address these important questions by following these participants to determine if the plaque reported in the Mechanistic sub-study of REPRIEVE is clinically significant (whether it is related to future cardiovascular events), whether statin therapy can reduce plaque and markers of inflammation, and if statin therapy can reduce the incidence of heart attacks and strokes.

    “Heart disease is a major cause of illness and death among people living with HIV, including those with well-controlled HIV disease receiving antiretroviral treatment,” said Steven Grinspoon, M.D., Massachusetts General Hospital. “Until now, our understanding of coronary artery disease among people living with HIV has been very limited. These findings significantly expand our knowledge and provide important insights that will lay the foundation to ultimately help us better support the health and well-being of people living with HIV.”

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    About REPRIEVE

    REPRIEVE (the Randomized Trial to Prevent Vascular Events in HIV) has enrolled 7,770 people living with HIV at more than 100 sites in 12 countries around the world in collaboration with the ACTG and is led by Dr. Grinspoon and Michael Lu, M.D., M.P.H., Massachusetts General Hospital and Harvard Medical School; Pamela Douglas, M.D., Duke University; and Heather Ribaudo, Ph.D., Harvard School of Public Health. The Mechanistic sub-study of REPRIEVE was led by Dr. Grinspoon and Udo Hoffmann, M.D., M.P.H., Massachusetts General Hospital. REPRIEVE is supported by the National Institutes of Health’s (NIH) National Heart, Lung, and Blood Institute (NHLBI) and National Institute of Allergy and Infectious Diseases (NIAID) as well as by KOWA Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.

     

    To read the full press release click here.

  • ACTG announces Camostat will not advance to phase 3 in outpatient treatment study for COVID-19

    Los Angeles, Calif. – The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced that the Camostat treatment group of the COVID-19 outpatient treatment study, ACTIV-2 Outpatient Monoclonal Antibodies and Other Therapies Trial, will not move to phase 3. ACTIV-2 includes both phase 2 and phase 3 evaluations of multiple investigational agents for treating early COVID-19 in a single trial. For information about the trial, please visit the study website.

    Camostat, provided by Sagent Pharmaceuticals (a Nichi-Iko Group Company), is an orally administered protease inhibitor that was dosed as 200 mg every six hours for seven days. The Camostat arm of ACTIV-2 completed phase 2 enrollment with 224 participants on April 26, 2021. When the Therapeutic and Prevention Data and Safety Monitoring Board (DSMB) met on June 14, 2021 to review the data and determine whether Camostat would advance to phase 3, they determined that while there were no safety concerns, the phase 2 data failed to meet the criteria for graduation (which is based on demonstrating early changes in viral shedding or improvement in symptoms). Participants enrolled in phase 2 in the Camostat treatment group will continue to be followed per the ACTIV-2 protocol.

    ACTIV-2 is a randomized, blinded, controlled adaptive platform that allows promising therapies to be added and removed over the course of the study to efficiently test a variety of new agents against placebo within the same trial infrastructure. It is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), which also funds the ACTG. ACTIV-2 is part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program to create a coordinated research strategy that prioritizes and speeds development of the most promising treatments and vaccines. It also receives support from the Federal COVID Response-Therapeutics, the U.S. government’s multi-agency effort to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics.

     

    To see the complete press release click here.

  • ACTG launches phase 1 combination HIV cure study

    Los Angeles, Calif. – The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced the launch of A5386, a phase 1 HIV cure study evaluating two promising therapies. A5386 will study whether N-803 (a clinical-stage biologic also called Anktiva™) can control HIV alone or together with combination broadly neutralizing antibodies (bNAbs) after participants stop their antiretroviral therapy (ART) and they are carefully monitored.

    In pre-clinical and clinical research, N-803 (an IL-15 superagonist) has exhibited three activities that may help the immune system eliminate HIV reservoirs or control virus rebound. First, N-803 has been shown to reverse HIV latency (the process of no reproduction of HIV within long-lived cells in the immune system), allowing it to be detected by the immune system. Second, it activates NK cells and CD8+ T-cells, two elements of the immune system that specialize in killing virus-infected cells. Finally, it enables NK cells and CD8+ T-cells to move to lymphoid tissues where they will encounter and hopefully eliminate HIV-infected cells.

    The actions of bNAbs (or antibodies that neutralize different variants of HIV) are well-matched to that of N-803. bNAbs neutralize HIV that is produced upon reactivation, preventing new infections; target (label) HIV-infected cells for destruction by NK cells; and may act to boost CD8+ T-cell responses. A5386 will utilize an array of virologic and immunologic tests to evaluate the degree to which each of these expected activities are induced in study participants. Ultimately, the study will test whether this approach results in immune control of HIV when ART is paused with careful monitoring.

    “HIV cure clinical trials remain a fundamental element of the ACTG’s research agenda,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “A5386 is particularly exciting as it marries two of the approaches in the HIV cure research space with the most potential. We believe this study will provide important insights as we continue to pursue our ultimate goal of identifying a cure for HIV and making it available to the millions of people living with HIV around the world.”

    A5386 is a phase 1, open-label, randomized study evaluating the safety, tolerability, and efficacy of N-803 both with and without combination bNAbs. It will enroll 46 people living with HIV (23 in each study arm) whose virus has been suppressed by ART for approximately two years, including at least 30 percent cisgender women or transgender men. Participants will undergo leukapheresis (a medical procedure in which white blood cells, or leukocytes, are separated from the blood) to measure their HIV reservoirs and a subset will undergo optional lymph node fine needle aspirations to assess the effect of N-803 on lymphoid tissue. They will then be randomized to one of two arms: N-803 alone or N-803 with combination bNAbs. After receiving treatment, participants will stop taking ART and will be followed closely to monitor for signs that they need to restart ART. Most participants will be followed for approximately 100 weeks after receiving treatment.

    “Pre-clinical studies have shown that this approach enables the immune system to control viral replication and suggest that N-803 and bNAbs will have a complementary effect on each other,” said A5386 Protocol Vice-Chair Richard Brad Jones, Ph.D., Weill Cornell Medicine. “We hope A5386 will demonstrate whether this new approach can enable us to safely decrease the amount of participants’ HIV.”

    A5386 is led by Timothy Wilkin, M.D., M.P.H. (Weill Cornell Medicine), Marina Caskey, M.D., (The Rockefeller University) and Dr. Jones. It is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and N-803 is provided by ImmunityBio, Inc. NIAID and collaborating NIH Institutes fund the ACTG.

     

    To see the full press release click here.