Last month, the ACTG presented six oral and 27 poster presentations at CROI 2022. Highlights included findings on COVID-19 among people living with HIV, interactions between emergency contraception and TB treatment, and insights into neurocognitive and functional impairment among people living with HIV. Take a look at coverage on our social media pages to hear more from the presenters! Read more about all of our presentations HERE.
Congratulations to Dr. Sikhulile Moyo, PhD, MSC, MPH from our Gaborone CRWS in Botswana on being awarded the MLK Honoree International Humanitarian Service Award at the 32nd Annual Rev. Martin Luther King Jr. celebration last month! You can watch the recording of the live presentation HERE.
The ACTG would like to congratulate Amita Gupta, MD, MHS on being named the seventh director of Johns Hopkins Medicine's Division of Infectious Diseases! Dr. Gupta is a long time ACTG investigator, taking on many roles within the network. Most recently, she is the study chair on A5300 (MDR TB Feasilibility) and A5300B (MDR TB Households) and the vice chair on A5274 (Empiric TB Tx) and A5279 (BRIEF TB).You can read more HERE.
Patricia Reichelderfer (Sinclair) 1946 - 2022
By Bob Coombs, MD, PhD, and Mary Glenn Fowler, MD, MPH
Dr. Patricia Reichelderfer, PhD was a virologist will be remembered for her dedication to the Division of Allergy and Infectious Diseases (DAIDS)/ AIDS Clinical Trials Group (ACTG) virology laboratory program and her work supporting the health of women living with HIV, including working to establish a better understanding of HIV in the female genital tract.
She began her virology research working on influenza at the CDC and joined DAIDS after directing a clinical virology laboratory in Las Vegas, Nevada in the early 1990s. Her scientific enthusiasm and sense of humor enlightened the ACTG laboratorians’ efforts to meld a cohesive laboratory group that was integrated with the ACTG therapeutic protocols.
Pat fostered comradeship among many ACTG laboratory investigators during our early years through the judicious use of social gatherings at her home near Annapolis and sports activities (We remember the virology baseball games that Pat organized between the ACTG laboratorians and ACTG leadership!).
After joining DAIDS in 1991, one of Pat’s first tasks was to facilitate the transfer of the Virology Quality Assurance Program (VQA) from Baylor College of Medicine (then under Blaine Hollinger, MD) to Rush University Medical Center, under Jim Bremer, PhD. She had a unique passion for fostering the quality of the virology data generated from our clinical trials and embraced the early support for the retrovirology laboratory data management program (RLMP developed by DataWorks) and the later development of the laboratory data management system (LDMS), under Frontier Science and Research Foundation (FSTRF). This support was critical to the timely reporting of the domestic ACTG virology data and implementation of the ACTG international virology laboratory program.
Pat transferred from DAIDS to National Institute of Child Health and Human Development in 1998 and continued supporting for HIV research efforts in women’s health with the establishment of the WHIN (Women’s HIV Network) and investigations into genital tract HIV shedding. Pat maintained her interest in providing research funding support for women living with HIV who were connected with the adult and pediatric HIV treatment networks.
As a DAIDS project officer, Pat had a keen interest in connecting DAIDS and the ACTG laboratory investigators and she used her irreverent sense of humor to effectively bridge her role between government and science.
Pat will be remembered for her passionate dedication to supporting HIV virology research within the ACTG and other NIH network studies. May she rest in peace.
The Role of the ACTG on National Women & Girls HIV/AIDS Awareness Day
By Rosie Mngqibisa, MD, ChB, MPH and Risa Hoffman, MD, MPH, Chair and Vice Chair of the Women's Health CSG
ACTG’s Women’s Health Collaborative Science Group (WHCSG), works closely with the ACTG leadership and Transformative Science Groups (TSGs) to ensure that ACTG develops studies that address scientific questions that are important to the health of women living with HIV. The WHCSG also seeks to optimize recruitment, retention, and sex-specific analyses of women in clinical trials.
In honor of NWGHAAD and on behalf of the WHCSG, we would like to acknowledge the incredible work and advances that have been made in the treatment of people living with HIV and highlight the importance of the women’s health agenda. Women represent more than half of people living with HIV globally and the rates of HIV remain extremely high among young girls and women 15-24 years old. While there have been several gains in this field, there are critical gaps in our knowledge of various health issues that affect women(including transgender women, such as data on antiretroviral interactions with commonly used contraceptives and feminizing hormones; risks of developing premature co-morbidities, such as cardiovascular disease (ischaemic stroke), metabolic diseases (diabetes), bone disease (osteopenia), and neurocognitive impairment; and the effects of newer HIV therapeutics in pregnant and lactating women. Additionally, as women living with HIV age, the impact of perimenopause and menopause on health and wellness remains poorly understood.
We are honored to highlight some of the significant strides the WHCSG has made, through supporting the implementation and development of studies addressing these gaps, below.
Contraception: Effective contraception is critical in preventing unintended pregnancies in women living with HIV and women with TB. The ACTG has conducted several pharmacokinetic studies to assess interactions between antiretroviral therapy (ART), TB treatment and contraceptives. A5375 confirmed that doubling the dose of the emergency contraception levonorgestrel (a medication that taken very soon after unprotected sex to prevent a pregnancy from occurring in someone not already pregnant) achieves levels required for pregnancy prevention when taken with efavirenz-based ART or with rifampicin-containing TB therapy and marks an important step in offering contraceptive choice to women living with HIV and being treated for TB.
Aging/menopause: Women with HIV experience menopause earlier, have more severe menopausal symptoms, and are at higher risk of post-menopausal complications such as bone loss compared to women without HIV. The group is working to develop a study that will explore the use of treatments such as the transdermal estrogen patch versus escitalopram (an antidepressant) for menopausal symptoms and determine if they treatments will lead to a reduction in bone loss among women living with HIV. This study will address an understudied area of the women’s health agenda, and is an important step in providing insight into a possible way to improve quality of life and clinical outcomes for women aging with HIV.
Transgender Women: Transgender women are the fastest-growing population of people living with HIV in the United States and have an extremely high global prevalence of HIV, yet have been underrepresented in clinical trials of ART. A5403 (the GET IT RIgHT Study), while not yet open, will evaluate interactions between feminizing hormone therapy (17-b oestradiol) and several commonly used ART regimens in adult transgender women living with HIV. This study represents important progress in optimizing evidence-based ART for transgender women and has the potential to improve our ability to delivery safe and effective gender-affirming care.
These studies are a small subset of the exciting and important ongoing work of the ACTG. The WHCSG looks forward to the coming year and to continuing to support research that can close critical data gaps and improve health and wellness for women living with HIV.
Study Shows the Probiotic Visbiome ES is Safe But Has No Anti-inflammatory Benefit in People Living with HIV
A5350 was a randomized, double-blind, two-arm study designed to evaluate whether 24 weeks of the probiotic Visbiome Extra Strength (ES) therapy caused a significant change in inflammation levels and was safe and did not cause side effects people whose HIV was well-controlled on stable antiretroviral therapy. Visbiome ES was well tolerated with only mild to moderate gastrointestinal side effects, such as flatulence. The primary assessment was soluble CD14, a marker that has previously been associated with gut inflammation and bacteria crossing from the gut into the body. This inflammation has been associated with cardiovascular and other disease and increased mortality in people living with HIV. The study did not detect a difference in the change of this inflammation marker or several others after treatment with the probiotic compared to placebo. While researchers saw the changes in the gut bacteria expected after treatment with Visbiome ES (which are associated with healthy gut bacteria), there was no evidence of change in the leakiness of the gut or gut inflammation. As people living with HIV are living longer, there may be dietary interventions to help maintain health, but this study did not demonstrate any benefit of the probiotic Visbiome ES in people living with HIV who are on stable ART.
Integrative Multi-Omics Approach Reveals Serum Markers of Tuberculosis Among People with Advanced HIV
TB accounts for disproportionate morbidity and mortality among people living with HIV. Conventional methods of diagnosing TB, including smear microscopy and Xpert MTB/RIF, have lower sensitivity in people living with HIV. Novel high-throughput approaches, such as miRNAomics and metabolomics, may advance our ability to recognize subclinical and difficult-to-diagnose TB, especially in people who have advanced HIV. In an “omics” approach, complete identification and characterization of a class of biological molecules is attempted – e.g., miRNAomics seeks to characterize the abundance of all microRNAs (non-coding RNA molecules that regulate gene expression). In this study, we sought to evaluate if the use of a multi-omics approach in HIV/TB co-infection could further identify contributory pathways in the development of TB. We evaluated three different modalities in serum: cytokines/chemokines, microRNAs, and metabolites. We conducted a case-control study leveraging A5274 (REMEMBER), a multi-country, open-label randomized controlled trial comparing four-drug empiric standard TB treatment with isoniazid preventive therapy in people living with HIV initiating ART with CD4 counts <50 cells/mL. Cases of incident TB were site-matched with controls to identify serum microRNAs, cytokines/chemokines, and metabolites associated with the development of newly diagnosed TB in oeople living with HIV . We found higher TNFα and IP-10/CXCL10 in cases (p=0.011, p=0.0005) and higher MDC/CCL22 in controls (p=0.0072). A machine learning approach using the multi-omics data revealed that a metabolite/microRNA pair, gamma-glutamylthreonine and hsa-miR-215-5p, had the ability to accurately discriminate incident TB cases from controls with an area under the ROC curve of 0.965. hsa-miR-215-5p, which targets genes in the TGF-β signaling pathway, was downregulated in cases. Gamma-glutamylthreonine, a breakdown product of protein catabolism, was less abundant in cases.
To our knowledge, this is one of the first uses of a multi-omics approach to identify incident TB in severely immunosuppressed people living with HIV. These data provide insight into dysregulated immune pathways in people living with HIV who developed active TB disease despite receipt of TB prophylaxis or standard anti-TB treatment at the initiation of ART.
Eric Daar, MD, Harbor University of California Los Angeles Center CRS
Eric S. Daar, MD is an infectious diseases-trained clinician investigator who has focused his research and clinical work on HIV/AIDS. He is currently Chief of the Division of HIV Medicine at Harbor-UCLA Medical Center and Professor of Medicine at the David Geffen School of Medicine at UCLA. He received his undergraduate degree from UCLA and Medical Degree from the Georgetown University School of Medicine. He subsequently did his internal medicine residency and infectious diseases clinical and research fellowship at Cedars-Sinai Medical Center. After fellowship he was the Director of the AIDS and Immune Disorder Center and Chief of Division of Infectious Diseases at Cedars-Sinai prior to relocating to his current position in 2001.
Upon arriving at Harbor-UCLA, Dr. Daar took on the role of ACTG CRS lead at the site and has been active in both ACTG leadership and protocols. His research focus has been on optimization of antiretroviral therapy, as well as the pathogenesis of acute and chronic HIV infection. He has served on several ACTG committees, including the Executive Committee, SASC and as first Chair of the ARTS. He was Chair of A5202 and is currently chair of A5354, as well as being protocol investigator on several studies, including currently on A5324. Since the emergence of the COVID-19 pandemic, he has taken on role of Vice Chair of ACTIV-2/A5401, along with ACTIV-2b/c/A5405 and A5404. He is also a participant on the Coronavirus Prevention Network. On ACTIV-2 he was co-lead for BRII-196/BRII-198 which, in the phase 3 portion of study, recently was shown to reduce the risk of hospitalization and death among high-risk individuals with mild-to-moderate COVID-19 by 80%.
Dr. Daar has had editorial roles on numerous journals and served on a variety of professional organizations. He has been a member of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adult and Adolescents for many years. He has also been an inaugural member of the NIH COVID-19 Treatment guidelines panel.
Dr. Daar lives in Los Angeles and his wife Judy, who is Dean at the Salmon P. Chase College of Law at Northern Kentucky University. He has four sons who are spread across San Francisco, Philadelphia, and New York, and a granddaughter in San Francisco. He treasures time with family, coworkers at Harbor-UCLA and the UCLA CTU, as well as colleagues across the globe who are committed to addressing the needs of people living with HIV.
Family Clinical Research Unit CRS, Capet Town, South Africa
The Family Clinical Research Unit CRS (FAM CRS), located in Cape Town, South Africa, has been part of the ACTG since 2014 and has taken part in a number of studies including REPRIEVE, A5381, A5243, A5288, A5349, A5302, A5360, A5263, A5324, and A5375. The site has five teams that are involved in various studies. Each team consists of two to four doctors, a PI, three to five nurses, two counselors/adherence monitors, four pharmacists, two lab assistants, two data groups, one data manager, five drivers to help participants travel to and from the site, and administrative staff. The ACTG team works together to provide their participants with the best experience possible on site.
The most meaningful experience for the site has been seeing participants cured of hepatitis C on the MINMON (A5360) trial and providing access to medication that otherwise would not have been readily available. The FAM CRS has also been able to enroll adolescent participants who were previously enrolled in infant PACTG trials into adult ACTG trials, showcasing the site’s long-lasting involvement in personal patient care, as well as the fantastic progress that has been made in HIV care over the last 15 years.
Working on the REPRIEVE trial has been a major milestone for the FAM CRS, as it allows them to get to know and support their participants over a long period of time. The site staff have been part of their REPRIEVE participants lives for more than five years! For the FAM CRS site, a major milestone was enrolling nearly 100 participants onto the REPRIEVE study before enrollment closure and being able to celebrate yearly milestones with study participants.
“I am always told that they look forward to their visits as the site. They take care to follow our instructions and are always happy to receive the thank you cards, birthday cards, masks, and participant newsletters that we provide them , said Lynne Cornelissen, MBChB, sub-investigator. “As a clinician, I appreciate the opportunity to regularly provide our participants with the opportunity to have more continuity of care than in other local clinics.” In the time of COVID-19, the site’s participants are thankful to be involved in ACTG studies, as they have access to clinical care that was not as readily available at their local facilities at times.
The ACTG has been able to move swiftly into new study environments, such as COVID-19 treatment trials, using existing network study sites under difficult circumstance. The network’s dedication to perform important work on current urgent research gaps makes it a unique first responder. The FAM CRS staff considers REPRIEVE to be one of those gaps, being the largest HIV trial to date. The study is providing valuable information concerning cardiovascular disease in those over 40 years old and is already producing many manuscripts.
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