NIH grants support UCLA and Charles Drew University researchers' efforts to end HIV epidemic
NIH grants support UCLA and Charles Drew University researchers' efforts to end HIV epidemic
The National Institutes of Health (NIH) has granted $2.1 million to UCLA’s Center for HIV Identification, Prevention, and Treatment Services (CHIPTS) and the UCLA-CDU Center for AIDS Research (CFAR) to support four research projects and an implementation science consultation hub. These awards will fund projects to strengthen research-community collaborations and enhance implementation strategies needed for the Ending the HIV Epidemic in the U.S. (EHE) initiative.
“These awards will support our scientists and community partners to address the systemic factors impacting our most vulnerable populations and explore innovative implementation strategies to help end the HIV epidemic,” said Steve Shoptaw, CHIPTS director and professor of family medicine at the David Geffen School of Medicine at UCLA. “We also look forward to continuing to support the research priorities of the EHE initiative through our Implementation Science Hub.”
Funded projects include:
Advancing HIV Implementation Research (Implementation Science Consultation Hub)
Implementation science plays an important role in the advancement of HIV research. The field recognizes that healthcare systems, public health agencies and communities often struggle to provide high quality services with limited resources. Alison Hamilton, professor-in-residence of psychiatry and biobehavioral sciences at UCLA’s Semel Institute for Neuroscience and Human Behavior and chief officer of implementation and policy at the VA Center for the Study of Healthcare Innovation, Implementation & Policy at Greater Los Angeles Healthcare System, will lead the UCLA Rapid, Rigorous, Relevant Implementation Science Hub, which will offer tailored coaching, training, and technical assistance to NIH-supported implementation research projects across the U.S. in efforts to end the HIV epidemic .
Addressing HIV Risk Among Vulnerable Youth
Dallas Swendeman, associate professor in the Division of Health Promotion and Behavioral Science in the School of Public Health at San Diego State University and a licensed clinical psychologist, will lead a project that explores strategies to support the implementation of an intervention to reduce HIV risk among sexual and gender minority and racial/ethnic minority youth aged 12 to 24. These groups face disproportionate risk of acquiring HIV due to various factors, including low uptake of pre-exposure prophylaxis (PrEP), yet effective and scalable interventions for youth remain limited. This study will accelerate implementation of the Adolescent HIV Medicine Trials Network (ATN) Protocol 149 Optimizing the HIV Prevention Continuum for Youth. The researchers will collaborate with community partners to explore implementation strategies for this intervention and prepare for application in real-world settings.
Enhancing HIV Prevention for Transgender and Nonbinary Individuals
Erik Storholm, professor of psychiatry and biobehavioral sciences at the Semel Institute, will lead a project to address low PrEP uptake and persistence among transgender and nonbinary individuals (TGNB) at-risk of HIV in Los Angeles County. Multiple syndemic barriers have been found to contribute to low PrEP uptake and persistence among TGNB individuals, such as intimate partner violence (IPV) and mental health burdens. This project will assess implementation outcomes and preliminary effects of integrating IPV prevention and mental health services into an ongoing gender-affirming PrEP program at a Los Angeles-based trans community center.
Reducing Barriers to HIV Prevention and Treatment among Black Americans
Black Americans are disproportionately affected by HIV, particularly young Black sexual minority men. Laura Bogart, professor-in-residence of psychiatry and biobehavioral sciences at the Semel Institute and chief officer of implementation and policy at the VA Center for the Study of Healthcare Innovation, Implementation & Policy at Greater Los Angeles Healthcare System will lead a study to enhance the implementation strategies and create a sero-status neutral version of the Rise intervention, a culturally tailored program to address adherence and retention barriers among Black individuals with HIV. Rise intervention, built on a 17-year community-academic partnership, will be expanded and tailored to address PrEP and antiretroviral therapy (ART) uptake and adherence among Black Americans in Los Angeles County and in Jefferson County, Alabama.
Improving PrEP Access for Black, Latino Sexual Minority Men and People who Inject Drugs
Dr. Gabriel Edwards, associate project scientist at the Geffen School, aims to bridge disparities in PrEP uptake among Black and Latino sexual minority men and people who inject drugs. The study will partner with the Los Angeles Centers for Alcohol and Drug Abuse (L.A. CADA) to provide community outreach to expand HIV testing and linkage with PrEP navigators to help facilitate PrEP medication access. The study will identify factors affecting successful linkages to PrEP in order to develop recommendations for improvement.
“Taken together, these awards reflect UCLA’s and CDU’s commitment to ending the HIV epidemic through innovative and community-focused approaches by focusing on populations most impacted by HIV and addressing the systemic barriers that put these populations at risk,” said LaShonda Spencer, director of Drew CARES and professor of pediatrics and internal medicine at Charles R. Drew University of Medicine and Science.
Researchers launch first study of a vaginal film that dissolves in 30 days to assess its acceptability as a potential HIV prevention method for women
Study taking place in US and sub-Saharan Africa will also help inform final design of a monthly film containing dapivirine
PITTSBURGH – November 2, 2023 – A vaginal film designed to slowly dissolve over the course of 30 days is being put to the test for the first time in a study launched this week that aims to determine its feasibility and acceptability as a potential HIV prevention method for women.
The study, which is being conducted in the United States and Africa by MATRIX, a United States Agency for International Development (USAID)-funded project focused on the early research and development of innovative HIV prevention products for women, will help inform the final design of a monthly film containing the antiretroviral (ARV) drug dapivirine. The monthly dapivirine film is one of nine products being developed under MATRIX, which also includes a dual-purpose monthly film containing both dapivirine and a hormonal contraceptive to prevent pregnancy.
Similar to thin breath mint strips that dissolve in the mouth, vaginal films are products designed to dissolve after being inserted into the vagina. Previous studies exploring the use of vaginal films as a drug delivery method for HIV prevention have been of quick-dissolve films or films designed to dissolve within a week.
In the new study, known as MATRIX-002, researchers are assessing the acceptability, usability and safety of two prototype monthly vaginal films that contain no active drug. In this way, they will be able to learn what refinements may be needed in the film’s design, including to its shape, before conducting a first-in-human study of the monthly dapivirine film.
MATRIX-002 will enroll 100 women, as well as 30 sexual partners, at five sites in Kenya, South Africa, Zimbabwe and the United States. Enrollment of the first participants took place at the US site, based at the University of Pittsburgh and Magee-Womens Research Institute (MWRI), which is also where the monthly dapivirine vaginal film products are being developed.
“By conducting a study of placebo films with no active drug, we will be able to answer fundamentally important questions. For instance, are women, especially African women, comfortable with the idea of using a vaginal film that takes 30 days to dissolve? What kind of support and counseling will they need to use it properly?,” noted Nyaradzo Mgodi, MBChB, MMed, MATRIX-002 protocol co-chair and investigator of record at the Harare Health and Research Consortium (HHRC) Zengeza clinical research site (CRS) in Zimbabwe, one of the five sites conducting the study.
“We are fully aware of the urgent need for more HIV prevention methods for women, but we also don’t want to rush into study of a new product with design features that may not be to the liking of women and could therefore impact product use. Something as simple as the shape of the film, or how it feels to the touch, are important considerations that are best resolved as early in the process as possible,” added Alexandra Minnis, PhD, a behavioral scientist from RTI International, Berkeley, Calif., who is protocol co-chair.
A key focus of MATRIX is being responsive to end-user and stakeholder feedback during the earliest stages of product development to inform decisions about product design and improve the odds for success of the products in its portfolio, which is why a study like MATRIX-002 is being conducted and why it is designed the way it is – evaluating two prototype vaginal films, both of which are of similar size (2” x 2”) but differ in their shape, one having straight corners and the other rounded corners. If not for the feedback that came out of stakeholder consultations convened in Kenya, South Africa, and Zimbabwe in 2022, during which prototype films were passed around, the MATRIX-002 study would have instead concentrated on the original square design. But upon learning that advocates and young women, in particular, disliked the straight corners of the film, researchers modified its shape by rounding the corners, recognizing also that this modification would result in a slightly higher product cost. While cost is an important factor to consider, so too are the preferences of women who will actually use the film, insight into which the MATRIX-002 study will provide.
As such, women who enroll in the study will be randomly assigned to use one of the two placebo films – either a film with straight corners or one with rounded corners. Participants will use their assigned film twice, for one month each. During the first month of film use, women are to refrain from vaginal sex and vaginal product use. During the second month, when a new film will be used, there will be no such restrictions. Women will insert the films themselves in the clinic with study staff providing guidance and instructions. As part of the study, participants will be asked questions about their experiences, including likes and dislikes, with film use, and up to 35 participants will also be asked to participate in an in-depth interview so that the study can gain deeper insight into women’s experience with and views about the film. In-depth interviews will also be conducted with approximately 30 sexual partners.
The study is expected to be underway at all five clinical research sites (CRS) by early 2024, which in addition to the University of Pittsburgh/MWRI and the HHRC CRS in Zimbabwe, includes the Kenya Medical Research Institute (KEMRI) Centre for Clinical Research Thika CRS and two sites in South Africa: the Aurum Institute Klerksdorp CRS and the Wits Reproductive Health and HIV Institute (Wits RHI) CRS in Johannesburg.
Follow-up of all participants is anticipated to be completed in July or August 2024, with study results anticipated by the end of the year (2024). MATRIX would then expect to be conducting the first-in-human study of the monthly dapivirine film in 2025.
Dapivirine is already known to be safe and effective for preventing HIV when formulated as a monthly vaginal ring, and in fact, the dapivirine vaginal ring has been recommended by the World Health Organization as an additional HIV prevention option for women and approved for use in several African countries, including Kenya, South Africa and Zimbabwe. The monthly film containing dapivirine is designed so that when it is placed inside the vagina and comes in contact with vaginal fluid, it will slowly begin to dissolve, and in doing so, release dapivirine. The drug would continue to be slowly released over the course of a month until the film completely dissolves and all of the drug has been delivered in the vagina. This means that there would be nothing to remove or discard before inserting a new film for another month of protection.
Development of both the monthly dapivirine film and the monthly dual-purpose dapivirine and contraceptive film is being conducted by a team of researchers at the University of Pittsburgh and MWRI under the direction of Lisa Rohan, PhD, professor of pharmaceutical sciences, University of Pittsburgh School of Pharmacy, and professor of obstetrics, gynecology & reproductive sciences, University of Pittsburgh School of Medicine. Both products are being developed in collaboration with the Population Council, a global nonprofit research organization, which acquired the dapivirine product pipeline from the International Partnership for Microbicides.
According to UNAIDS, women and girls accounted for 63 percent of all new HIV infections in sub-Saharan Africa in 2022, versus 46 percent globally. In much of Africa, daily oral PrEP (pre-exposure prophylaxis), which requires taking an ARV tablet every day, is the only biomedical prevention method available. Daily pill-taking has been especially challenging for adolescent girls and young women. Despite the dapivirine ring and cabotegravir long-acting injectable (CAB-LA) both being recommended by WHO and approved in several African countries, neither method is yet widely available. Even so, women have different preferences and needs, and at different times in their lives, which is why additional options are needed.
MATRIX is a five-year program funded by USAID in 2021 that aims to expedite the research and development of HIV prevention products for women – including products designed to protect against both HIV and pregnancy – that in addition to being safe and effective, will be acceptable, affordable, scalable and deliverable in the settings where they are needed most. MATRIX activities are focused on the early research and development of products, which involves both pre-clinical research and the first clinical trials of products. Through its North-South partnerships, MATRIX also aims to strengthen the capacity of African investigators to facilitate full and sustainable ownership of this work into the future. MATRIX is being implemented by Magee-Womens Research Institute (MWRI) in collaboration with partner organizations based in Kenya, South Africa, the United States and Zimbabwe. Leading the project is Sharon Hillier, Ph.D., of MWRI and the University of Pittsburgh School of Medicine, with Thesla Palanee-Phillips, Ph.D., from the Wits RHI and University of Witwatersrand, South Africa, serving as deputy director.
# # #
To learn about MATRIX go to www.matrix4prevention.org. Click here to read a QA about the dapivirine film and MATRIX-002 study. Additional information about MATRIX-002 can also be found at www.matrix4prevention.org/activity-hubs/clinical-trials/matrix-002.
MATRIX was established through the generous support of the American people through the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) and the U.S. Agency for International Development (USAID).
(United States Agency for International Development (USAID) Cooperative Agreement Number 7200AA22CA00002)
The content and views in this document are those of MATRIX and its partners and do not necessarily reflect the views of PEPFAR, USAID or the U.S. Government.
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
Pinpointing HIV immune response
Refined understanding of T cells’ action in the body’s battle against the AIDS-causing virus will help improve treatments
Peer-Reviewed PublicationNew research combining computer modeling and experiments with macaques shows the body’s immune system helps control human immunodeficiency virus (HIV) infections largely by suppressing viral production in already infected cells while also killing viral infected cells, but only within a narrow time window at the start of a cell’s infection.
“To eliminate HIV, we have to understand how the immune system attempts to control the infection,” said Ruy M. Ribeiro, a theoretical biologist at Los Alamos National Laboratory who led the development of the model underpinning the research. Ribeiro is the corresponding author of the paper about the findings, published in Nature Communications.
The research team included Los Alamos Senior Fellow Alan S. Perelson and a former Los Alamos postdoctoral researcher now at the Fred Hutchinson Cancer Research Center. Their collaborators at the University of Pittsburg managed the experiments with macaques infected with simian immunodeficiency virus (SIV) to validate the model. SIV infections in monkeys behaves the same way as HIV in humans.
Helping the immune system attack HIV
“The immune system can’t eliminate an HIV infection,” Ribeiro notes, “but pinpointing the existing mechanism by which it is to some extent controlling HIV is very important for designing treatments to enhance that mechanism. If we can modulate the immune system to help control HIV better, we may be able to cure the disease at some point.”
Under the overall leadership of Perelson, Los Alamos has been a global leader in modeling viral infections, including HIV, since the mid-1990s. For the Nature Communications paper, the research team extended a mathematical model published in 2017 by Ribeiro and others at Los Alamos that simulates the interactions and lifecycle of cells that will be infected, already infected cells and the virus.
The new model also simulates the potential effects of the immune response, which include killing the cells, generating proteins that suppress the production of virus or helping mount a defense that prevents the virus entering cells.
Resolving an open question about HIV
Specifically focused on a kind of immune response mediated by CD8+ T cells, the research resolved an open question in HIV research: Do these T cells control HIV by killing HIV cells or by triggering human cells to deploy defenses against the infection?
“There’s been controversy about whether this type of T cell controls infection by killing infected cells or by somehow controlling the virus without killing infected cells, so we’re trying to distinguish these possibilities and mechanisms,” Ribeiro said.
The answer turned out to be “a little of both.”
To isolate the role of the T cells, the Los Alamos team ran the model to predict the effects of treating groups of infected macaques variously with antibodies and antiviral drugs.
Some macaques were treated with a drug designed to prevent infection by blocking the virus from integrating into the DNA of the macaques’ cells. This drug, called an integrase inhibitor, “revealed the dynamics of the early part of the virus lifecycle that we couldn’t easily see with other types of treatment,” Ribeiro said. “It’s as if we used a microscope.”
Other macaques were treated with an antibody that depletes the CD8+ T cells, eliminating their role in fighting the infection. A third cohort of macaques received both treatments.
The Los Alamos team then ran the model to analyze the macaque data to determine the effects of the different immune responses. From the model they inferred the most relevant immune mechanisms that more closely described the observed data.
JOURNAL
Nature Communications
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
People
ARTICLE TITLE
CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production
