This blog is the second in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the /research/hiv-research-enterprise page.

The impact of clinical research is often measured by its outcomes. From trials that provide groundbreaking evidence of efficacy to those stopped early for futility, the end results of clinical trials shape practice and future research priorities. However, years of effort from scientists, study teams and study participants while a trial is underway are sometimes overshadowed by final study outcomes. In this regard, trial implementation requires clinical research sites’ operational excellence for the duration of a study. Access to relevant populations depends on the location of each clinical research site as well as investigators' and clinical care providers’ engagement with the local community and understanding of their needs and preferences. A high-functioning clinical research site anchored in the communities it works in and comprised of cohesive, well-integrated components is essential to producing high-quality outputs. 

Currently, NIAID supports four research networks as part of its HIV clinical research enterprise. The networks are made up of more than 100 clinical research sites, each with local experts, robust research infrastructure, and well-trained, cross-functional staff who maintain standardized procedures and quality controls aligned with their network.

Every seven years, NIAID engages research partners, community representatives, and other public health stakeholders in a multidisciplinary evaluation of network progress toward short- and long-term scientific goals. This process takes account of knowledge gained since the networks were last funded and identifies essential course corrections based on the latest scientific and public health evidence. Subsequent NIAID HIV research investments build on the conclusions of these discussions. This process includes examining the networks’ infrastructure model, which the Institute updates and refines to stay aligned with its scientific priorities. 

The HIV clinical trials network sites have made tremendous contributions to NIH’s scientific priorities by offering direct access to and consultation with populations most affected by HIV globally, and by delivering high-quality clinical research with strong connections to trusted community outreach platforms. Their approach to community engagement anchors clinical research sites beyond the scope of any individual study, and when possible, aligns scientific questions and study protocols based on local context. 

Since the start of the 2020 research network grant cycle, HIV clinical research sites have enrolled about 93,000 participants across 78 clinical trials in 25 countries. The networks were able to quickly pivot to support NIAID’s emerging infectious disease priority areas, including COVID-19 and mpox. Of the 93,000 participants since 2020, approximately 78,000 were enrolled into COVID-19 clinical trials sponsored by NIAID’s Division of AIDS. 

Clinical trials sites currently operate with a hub-and-spoke model, with each hub providing centralized support to their linked clinical research sites. This model leverages shared resources where possible and practical, and ensures robust oversight to promote high-quality clinical trial operations. Hubs provide infrastructure and services including laboratory, pharmacy, regulatory, data management, and training to support execution of NIAID-sponsored clinical research. 

Future networks will need to maintain core strengths of current models while expanding capacity in areas vital to further scientific progress. These include operations that inform pandemic responses and extending our reach within communities impacted by HIV, including populations historically underrepresented in clinical research. Additionally, there may be opportunities for clinical research sites and other partners to conduct implementation science research based on their capacity and access to relevant populations in the context of specific scientific questions. 

Make seamless progress on established and emerging scientific priorities

Our goals include maintaining the strength and flexibility of our current network model and infrastructure to support established scientific priorities that improve the practice of medicine, including high-impact registrational trials to identify new biomedical interventions and support changes to product labelling. The networks also must remain capable of directing operations to generate evidence on interventions for pandemic responses. 

Engage underserved populations for more representative studies 

Building on its current reach, NIAID and its partners have identified opportunities to expand or strengthen our connections to medically underserved populations affected by HIV, and to increase representation of geographic areas with limited access to current clinical trials sites. We also are seeking clinical research sites with longstanding community relationships and experience conducting randomized clinical trials that include Black gay, bisexual, and other men who have sex with men, transgender people, people who sell sex, people who use drugs, and adolescent girls and young women, as well as populations in African countries with a high HIV prevalence. 

Integrate implementation science within clinical research practice

Implementation science is the scientific study of methods and strategies that facilitate the uptake of evidence-based practice and research into regular use by practitioners and policymakers. As biomedical HIV prevention, treatment, and diagnostic options expand, our scientific questions must expand to address not only whether an intervention works, but how it can be delivered to offer health care choices that people need, want and are able to use. This expanded scientific scope calls for research sites to have a diverse reach and skill sets, including experience and capacity for conducting implementation science research and fostering and maintaining partnerships with organizations that conduct implementation science research on key topics and interventions on which implementers seek stronger evidence.

The research community plays an essential role in shaping NIAID’s scientific direction and research enterprise operations. We want to hear from you. Please share your questions and comments at Next NIAID HIV Networks.

About NIAID’s HIV Clinical Trials Networks

The clinical trials networks are supported through grants from NIAID, with co-funding from and scientific partnerships with NIH’s National Institute of Mental Health, National Institute on Drug Abuse, National Institute on Aging, and other NIH institutes and centers. There are four networks—Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, the HIV Vaccine Trials Network, the HIV Prevention Trials Network, and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network.

NIAID-supported Clinical Studies Assess Therapeutics for Clearance of HIV from the Reservoir

Antiretroviral therapy (ART) has been a game-changer for people with HIV. But HIV is skilled at “hiding” and can reappear in the blood stream shortly after ART is stopped. That’s why NIAID and partners are investigating strategies to completely clear HIV from a person’s body, effectively curing them, or to reduce it to levels that can be suppressed by their own immune systems. 

Many promising HIV cure strategies use broadly neutralizing antibodies, or bNAbs, which can neutralize a wide range of HIV variants, homing in on and binding to specific viral components, and then acting to destroy the virus by triggering an immune response. Several HIV bNAbs have been developed and tested to determine whether they can prevent or treat HIV. NIAID and partners are evaluating bNAb-based strategies alone and in combination with other immunity-enhancing strategies for HIV clearance in clinical trials in Africa, North and South America, and Southeast Asia.

Finding a cure for HIV is complex, largely due to the tenacity of the virus—it can persist in some tissues or cells without being attacked by the immune system. This is even the case for people whose viral load—the amount of virus in the blood—is suppressed below a level that can be detected by routine diagnostic tools. As a result, most people who experience an interruption in treatment will experience a viral rebound, in which the previously dormant virus begins to replicate and can attack the immune system. This problem is especially urgent for people with HIV who have limited access to treatment, including those in areas with limited resources. A treatment that can be given for a limited time to stop the virus from replicating long term, or one that removes it from the body entirely, could eliminate the need for lifelong treatment, improve quality of life for people with HIV, and reduce further HIV transmission.  

Two studies beginning this summer are assessing the use of bNAbs to enable HIV remission in people with HIV in African countries. Both studies will include closely monitored ART interruption to examine whether bNAbs can lead to long-term ART-free control of HIV. One trial, called Pausing Antiretroviral Treatment Under Structured Evaluation (PAUSE), enrolled its first participant in June 2024 and continues to enroll people with HIV in Botswana, Malawi, and South Africa. Participants on ART with no detectable virus in their blood stream will receive two long-acting bNAbs (3BNC117-LS-J and 10-1074-LS-J) and then pause ART to determine whether the bNAbs are sufficient to control HIV in the body when ART is stopped. 

A second study, called Antiretrovirals Combined With Antibodies for HIV-1 Cure In Africa (ACACIA), is starting soon and will examine the bNAbs 3BNC117-LS (also known as teropavimab) and 10-1074-LS (also known as zinlirvimab) in adults living with HIV in Botswana, Malawi, South Africa and Zimbabwe who are beginning ART. The bNAbs will be given while there is still virus in the blood stream to see if they can enhance the body’s immune response to HIV, which could reduce the amount of virus that hides in viral reservoirs in the body. Once the bNAbs are no longer present in the body, ART will be interrupted for each participant, and they will be evaluated to determine how long viral suppression is maintained without ART and whether the bNAbs affect the immune response to HIV.

Researchers are also evaluating bNAb-based HIV cure strategies in children through the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network. The IMPAACT P1115 study has examined very early HIV treatment strategies in infants who were exposed to or acquired HIV before birth. The study is assessing VRC01 and VRC07-523LS to see whether these bNAbs, when given with ART early in life, may enable ART-free remission in children. Another study, IMPAACT 2042, will evaluate the use of three bNAbs, VRC07-523LS, PGDM1400LS, and PGT121.414.LS, in children and young adults with HIV between the ages of 2 and 25 to determine whether the bNAbs can be part of a strategy to suppress HIV and clear the virus from the body.

Other clinical studies are combining bNAbs with therapeutic vaccines for HIV clearance. These vaccines are designed to improve the immune response to the virus in a person with HIV. ACTG A5374, which enrolled its first participant in early 2024, is evaluating the bNAbs teropavimab and zinlirvimab in combination with the therapeutic vaccines ChAdOx1.HIV cons1/62 and MVA.HIV cons3/4 and an immune booster called vesatolimod. The trial will assess the safety of the regimen in people with HIV in the U.S. and Brazil, and whether the combination can eliminate cells harboring HIV and prevent viral reservoirs from reactivating when ART is interrupted. 

The findings from these and related trials will provide researchers with new insights into how to effectively treat HIV or clear the virus from people’s bodies. This work is implemented by leveraging the strengths of all of the NIH-funded HIV clinical trials networks and collaborating institutions. The Bill & Melinda Gates Foundation is co-funding PAUSE and ACACIA. IMPAACT P1115 and 2042 are co-funded by the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

The bNAbs VRC01 and VRC07-523LS were developed by NIAID’s Vaccine Research Center and Division of Intramural Research. The bNAbs 3BNC117 and 10-1074 were discovered by researchers at the Rockefeller University, funded in part by NIAID. PGT121.414.LS and PGDM1400LS are being developed by NIAID and collaborators.

Additional information about the trials: 

• ACTG A5374: ClinicalTrials.gov ID NCT067071767.
• ACTG A5416 (also called PAUSE): ClinicalTrials.gov ID NCT06031272.
• ACTG A5417 (also called ACACIA): ClinicalTrials.gov ID NCT06205602.
• IMPAACT P1115: ClinicalTrials.gov ID NCT02140255. (Recent P1115 findings were presented at the 2024 Conference on Retroviruses and Opportunistic Infections.)
• IMPAACT 2042 (also called Tatelo Plus): ClinicalTrials.gov ID coming soon.

This blog is adapted and cross-posted from HIV.gov.

HIV.gov continued daily coverage of AIDS 2024. Tune in to four conversations livestreamed at the conference.

Research Highlights

Jeanne Marrazzo, M.D., M.P.H., director of the National Institute of Allergy and Infectious Diseases (NIAID) at NIH, shared research highlights with Kaye Hayes, M.P.A., deputy assistant secretary for Infectious Disease and the director of the Office of Infectious Disease and HIV/AIDS Policy. Dr. Marrazzo celebrated how much the field is learning about long-acting pre-exposure prophylaxis (PrEP), from the results of the PURPOSE 1 study of lenacapavir for twice-yearly PrEP, to new evidence on cabotegravir (CAB-LA) administered every two months for PrEP, including its safety in pregnancy.

Dr. Marrazzo reflected on the IAS conference theme, “Put People First,” and shared what she had been hearing from conference attendees. Among her observations was the importance of involving people living with and affected by HIV throughout the scientific process.

Learn more about their conversation below:

HIV Prevention

Carl Dieffenbach, Ph.D., director of the Division of AIDS at NIAID and Michele Andrasik, Ph.D., of the HIV Vaccine Trials Network & COVID-19 Prevention Network summarized today’s plenary on HIV prevention and noted that while more scientific advances are needed to get to an HIV vaccine, they explained that the field is on the right path. Dr. Dieffenbach described an HIV vaccine development strategy called germline targeting, which trains the immune system to generate several types of HIV broadly neutralizing antibodies (bNAbs)—a promising approach for a preventive vaccine.

They also reviewed findings Dr. Marrazzo mentioned, showing long-acting cabotegravir for HIV PrEP can safely be used during pregnancy, based on an analysis from a large multi-country study. Finally, they talked about the importance of learning from missed opportunities in HIV prevention service delivery, particularly within the context of PrEP, to ensure that services are person-centered and reach people in a way that is acceptable and convenient for their lifestyles.

Learn more about their conversation below: 

Bi-Directional Collaboration

HIV.gov director Miguel Gomez spoke with Tanchica West, M.A., M.P.H., of the Health Resources Services Administration and Dianne Rausch, Ph.D., of the National Institute of Mental Health to discuss the global-domestic bi-directional satellite session on global health reciprocal innovation that took place today. Kaye Hayes delivered opening remarks during the session, which featured case examples, research, and highlights of innovations. Please follow HIV.gov for more information on this bi-directional session.

Learn more about their conversation below:

PACHA Reflections

Caroline Talev, M.P.A., executive director of the Presidential Advisory Council on HIV/AIDS (PACHA), talked with PACHA Global Subcommittee Co-Chairs Jennifer Kates, Ph.D. and Patrick Sullivan D.V.M., Ph.D., D.I.P.L., A.C.V.P.M. (EPI), about what stood out to them at AIDS 2024. They said the conference theme—Put People First—resonated with them, as well as news about twice-yearly, long-acting injectable PrEP for women, and global-domestic bidirectional learning about HIV prevention and care.

Learn more about their conversation below:

Check out all of the AIDS 2024 blogs 

AIDS 2024: NIH Research Updates, Inequities, U=U, and Doxy PrEP (VIDEO), July 24, 2024

AIDS 2024: Research Updates, HIV Criminalization Laws, and AI (VIDEO), July 25, 2024

A Year of Hepatitis Advances to Mark World Hepatitis Day

Viral hepatitis affects the lives of about one in twenty people in the world, resulting in over a million deaths each year. NIAID is working on many ways to prevent and treat the different types of hepatitis, including the development of vaccines and improved therapeutics and diagnostics. July 28 is observed annually as World Hepatitis Day, providing an opportunity to reflect on the impact of hepatitis on global health and focus on strategies to reduce its burden. To observe World Hepatitis Day, NIAID highlights recent advancements researchers have made in these areas.

Hepatitis is an inflammation of the liver, which can cause liver damage that is fatal in some cases. Most hepatitis cases are caused by viruses, although other infections, heavy alcohol use, exposure to toxins or some medications, or autoimmune disease can also cause hepatitis. There are five main virus types that cause hepatitis, types A, B, C, D and E. The different hepatitis viruses are spread in different ways, and each has unique impacts on health. Hepatitis A and E are generally spread through contaminated food and water, while hepatitis B, C and D are spread through body fluids. People with HIV have an increased risk of severe disease when hepatitis A, B, or C is present in the body. Additionally, presence of hepatitis B and C can affect treatment for HIV. Because of these interactions, people with HIV are disproportionately impacted by viral hepatitis.

Progress Towards Effective Hepatitis B Vaccines for People with HIV

Conventional vaccines against hepatitis B are sometimes unable to provide adequate immunity to people with HIV. An ongoing clinical trial is evaluating the effects of a vaccine against hepatitis B called HepB-CPG (also known as Heplisav-B) in people with HIV. HepB-CPG was shown to provide people with HIV high levels of immunity against hepatitis B. Researchers specifically looked at the effects of HepB-CPG vaccine in people with HIV who had previously not responded to conventional hepatitis B vaccines. The HepB-CPG vaccine uses an adjuvant—or immune booster—called CPG-1018. In the study, they compared HepB-CPG to a hepatitis vaccine that uses alum, a more conventional adjuvant, instead of CPG-1018. The researchers found that the vaccine containing CPG-1018 was superior to the conventional hepatitis B vaccine. The vaccines were safe and well tolerated. This work provides important evidence supporting the further development of vaccines for prevention of hepatitis B in people with HIV. The study is being led by ACTG, an NIAID-led clinical trials network. 

Exploring New Pathways of Immunity Against Hepatitis C

Hepatitis C can be cured with antivirals, but there are currently no vaccines against this type of hepatitis, due in part to the large number of variants and rapid evolution of the virus. People cured from hepatitis C can also become reinfected. The number of people diagnosed with hepatitis C is increasing, and a vaccine would be an important tool in preventing the spread of this dangerous virus, which can cause liver failure and cancer. Some people naturally clear hepatitis C from their bodies and have protective immunity against developing the disease when re-exposed to the virus. NIAID-funded researchers are investigating the immune responses in these individuals compared to those who develop persistent infections. The researchers found that neutralizing antibodies contributed to the clearance of hepatitis C virus from people’s bodies, and that these antibodies were directed to specific sites on the surface of the virus. Investigating how these antibodies are produced and how they target the virus may help researchers develop vaccines against hepatitis C. 

Advancing the Development of Vaccines Against Hepatitis E

Hepatitis E is the leading cause of acute hepatitis worldwide, causing about 20 million infections and 70,000 deaths each year, with greater impacts in regions with limited access to resources. There are no treatments for acute hepatitis E or approved vaccines against the virus. A vaccine is in development, called HEV-239, which was recently found in a NIAID-supported trial to be safe and achieve a durable immune response in adults in the United States. These promising results support the evaluation of the vaccine in in further clinical trials.

Understanding Hepatitis B-Associated Liver Cancer

NIAID researchers are studying diseases resulting from viral hepatitis-related liver damage, including a type of liver cancer called hepatitis B-associated hepatocellular carcinoma (HCC), which causes malignant tumors in the liver. Although immunotherapy can be effective to treat various forms of solid tumors, HCC-related tumors often do not respond to this treatment. To understand why, researchers carefully studied the tumor microenvironment—the specific molecular and cellular conditions that exist inside tumors—in 12 people with HCC. They found that two distinct subtypes of tumors existed in people with HCC. In about half of the people, the microenvironments of the tumors had high levels of immune activity, while lower levels were observed in the tumors in the other half of the people. This finding may help scientists understand how people with these types of HCC respond to treatments and could allow for development of treatments tailored to individuals with different subtypes.

New Animal Models for Hepatitis B and C

NIAID is funding several new projects focused on developing small animal models to understand and combat hepatitis B and C. This work is important because research on these viruses has been hindered by the lack of available animal models to study promising preventive and therapeutic concepts. Recipients of the new awards include:

• Wake Forest University for a project titled “Novel mouse models of hepatitis B virus infection and replication.” Guangxian Luo is the principal investigator. (Grant number: R01 AI183855-01.)
• The Research Institute at Nationwide Children’s Hospital for a project titled “Animal Model to study heterogeneous outcomes of HCV Infection and Pathogenesis. Amit Kapoor is the principal investigator. (Grant number: R01 AI183877-01.)
• The Rockefeller University for a project titled “Breaching the species barrier: Towards an immunocompetent HBV-susceptible mouse model.” Charles Rice is the principal investigator. (Grant number: R01 AI183884-01.)
• Georgetown University for a project called “Developing woodchucks susceptible to hepatitis B virus infection by modifying the virus or host.” Stephan Menne and Jianming Hu (at Penn State College of Medicine) are the principal investigators. (Grant number: R01 AI183788-01.) 

These advances and active projects underscore the important work NIAID is doing to prevent and treat viral hepatitis, with the aim of reducing the global burden of this disease. 

For more information, please visit NIAID’s hepatitis research page.