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.

This blog is the first in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the HIV Clinical Research Enterprise page.

NIAID supports four research networks as part of its HIV clinical research enterprise. Every seven years, the Institute 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.

Pregnancy, childbirth and the postnatal period are a key focus of NIAID HIV research and call for measures to support the health of people who could become pregnant as well as their infants. Biological changes and social dynamics such as gender inequality, intimate partner violence, and discrimination can increase the likelihood of HIV acquisition during all natal stages. Of note, breastfeeding/chestfeeding is emerging as the predominant mode of vertical HIV transmission. NIAID is committed to optimizing HIV treatment and prevention options for people who might become pregnant, people who are pregnant and lactating, newborns, and young children who are still nursing or are living with HIV. Our goals are to offer safe, effective, acceptable, and accessible tools that provide evidence-based HIV prevention choices throughout the period of reproductive potential; prevent vertical HIV transmission to infants; and enable infants born with HIV to experience long periods of HIV remission or complete HIV clearance. We think these goals can be reached with discovery and development studies to advance biomedical interventions, and implementation science to rapidly introduce state-of-the-art interventions where they are needed most urgently.

In the current evaluation of our clinical trials networks, NIAID and other stakeholders are assessing novel interventions to interrupt the unacceptably high rate of new pediatric HIV diagnoses that persist in high burden countries. Recent research is rapidly expanding the evidence base for treatment for children and pregnant people with HIV, as well as biomedical prevention tools for pregnant people and people of reproductive potential who stand to benefit from their use. Some key advances include: 

• Expanded evidence to support a cascade of multiple regulatory approvals making new therapeutic agents available to the youngest children with HIV;
• Demonstrated safety of prevention products and antiretroviral therapy (ART) throughout pregnancy, including long-acting cabotegravir for HIV pre-exposure prophylaxis (PrEP); the controlled-release vaginal ring for HIV PrEP; and integrase strand transfer inhibitor-based ART for viral suppression in people with HIV; and
• Rigorous examination of the potential of treatment initiation within hours of birth to enable ART-free HIV remission in children in a research setting.

Together, these advances open doors to improved tools for HIV prevention and treatment and help define remaining evidence gaps and research needs.

Biomedical research to accelerate evidence responsive to pediatric and perinatal needs 

As noted above, a NIAID-sponsored clinical trial led by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT), called IMPAACT P1115, found that four children surpassed a year of HIV remission after pausing ART. The protocol remains active with subsequent iterations of the trial in children receiving more advanced ART regimens and novel broadly neutralizing antibody-based therapy. Further research is planned to identify biomarkers to predict the likelihood of HIV remission or rebound following ART interruption. Additional studies also are needed to better understand the mechanisms by which neonatal immunity and very early ART initiation limited the formation of latent HIV reservoirs to drive the original P1115 results.

Additional research priorities include developing early infant HIV testing assays that can promptly detect vertical HIV acquisition through breastfeeding/chestfeeding; wider examination of the safety and efficacy of presumptive ART pending an HIV diagnosis; administration of very early neonatal and pediatric formulations of the latest and future generations of long-acting ARVs for prevention and treatment and antibody-based therapy; and optimization of long-acting HIV treatment regimens to support health through periods of reproductive potential, pregnancy, and lactation.    

Implementation science to strengthen delivery 

Improving HIV prevention and care through reproductive years and intense early-life HIV intervention for infants will require an unprecedented level of reproductive health, prenatal, postnatal and pediatric HIV service integration. Several key clinical and operational questions warrant investigation through implementation science. The first is assuring availability of acceptable HIV testing modalities pre-conception, as well as universal HIV testing as part of routine obstetric care, and then supporting access to a person’s preferred PrEP method or ART based on HIV status. For infants whose birthing parent has HIV, we need evidence-based models for offering very early point-of-care infant HIV diagnosis and treatment, including presumptive ART for infants exposed to HIV in utero pending confirmatory testing. We also need to understand how to better support continued engagement in care to maintain viral suppression for childbearing people with HIV through the end of the lactating period and life course. We will provide special consideration for the preferences of adolescent and young adult cisgender women who are disproportionately affected by HIV in high burden settings globally. Defining local and contextually appropriate adaptations of successful models will be paramount for successful uptake. 

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 Clinical Trials Networks and Pediatric HIV

The IMPAACT Network examines prevention and treatment interventions for HIV, HIV-associated complications, and related pathogens in infants, children, and adolescents, and during pregnancy and postpartum periods. The Network is supported through grants from NIAID, with co-funding and scientific partnership from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development and the NIH National Institute of Mental Health. Three other networks—the HIV Vaccine Trials Network, HIV Prevention Trials Network, and Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections—generate complementary evidence and provide research infrastructure where needed when rapidly evolving prevention and treatment science has implications for IMPAACT priority populations. 

Editorial note: NIAID encourages the use of inclusive language in all communications. The terms related to lactation and pregnancy in this blog reflect the diverse gender identities and experiences of all people who stand to benefit from HIV prevention and cure research. For more information on inclusive language related to pregnancy and family, please visit the NIAID HIV Language Guide.  

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. Below are recaps of four livestreamed conversations:

NIH Research Updates

Brian Minalga, M.S.W., deputy director of the NIH-supported Office of HIV/AIDS Network Coordination, spoke with Carl Dieffenbach, Ph.D., director of the Division of AIDS at NIH’s National Institute of Allergy and Infectious Diseases. They discussed the importance of including people who inject drugs in HIV research because the population is disproportionately affected by HIV and currently underrepresented in clinical studies. They highlighted the current HIV Prevention Trials Network 103 study of long-acting lenacapavir for HIV pre-exposure prophylaxis (PrEP) in people who inject drugs in the United States.

They also discussed the NIH-supported HIV clinical trials networks, and the process underway to plan for the next ten years of HIV clinical research through networks. They both emphasized that the networks not only continue to advance HIV research, but they also serve as a platform for responding to urgent health threats affecting people with and without HIV, such as mpox and COVID-19.

Learn more about their conversation below:

Following the presentation of promising results from the PURPOSE 1 study of twice-yearly lenacapavir for HIV PrEP in cisgender women in South Africa and Uganda, several HIV leaders gathered to discuss the implications of the findings for HIV prevention. Dr. Dieffenbach, Jonathan Mermin, M.D., M.P.H., director of CDC’s National Center for HIV, Viral Hepatitis, STD, and TB Prevention, and PACHA member Tori Cooper shared their thoughts.

The PURPOSE 1 presentation showed lenacapavir was 100% effective at preventing HIV in cisgender women when compared to the estimated HIV incidence in the general population in the study countries. The group discussed how a twice-yearly PrEP could overcome barriers to use for some people and reduce the number of healthcare visits needed for people using PrEP. They also reminded viewers that lenacapavir is not yet approved for use.

They also discussed another study, PURPOSE 2, which examined the efficacy and safety of lenacapavir for PrEP among gay and bisexual men, transgender women, and nonbinary people who have sex with people assigned male a birth. Finally, they discussed outstanding questions from the PURPOSE 1 study, including the need to better understand why two daily oral PrEP formulations that were also examined in the study did not show a preventive effect.

HIV Criminalization Laws

Earlier in the day, HIV.gov director Miguel Gomez asked Francisco Ruiz, White House Office of National AIDS Policy Director, Janet Butler-McPhee of the HIV Legal Network, and Robert Suttle of the Elizabeth Taylor AIDS Foundation to share their thoughts about the opening plenary on HIV criminalization laws. The panelists discussed how outdated and unscientific laws add to stigma and discrimination against people with HIV and drive new HIV transmissions. The conversation also focused on reasons to be hopeful about progress being made.

Learn more about their conversation below:

PEPFAR and Safe, Responsible Use of AI

Miguel also spoke with Mike Reid, M.D., chief science officer in the U.S. Department of State’s Bureau of Global Health Security and Diplomacy – PEPFAR, about the safe, responsible use of artificial intelligence (AI). Dr. Reid said PEPFAR is looking at the transparent and incremental ways to implement AI to advance the program’s strategic goals. PEPAR will participate in a workshop on Thursday at IAS highlighting several use cases of AI.

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