Discovery, Development and Delivery for an Increasingly Interconnected HIV Landscape 

By Carl Dieffenbach, Ph.D., director, Division of AIDS, NIAID

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

The NIAID HIV clinical research enterprise has celebrated important scientific advances since awards were made to the current networks in 2020. These achievements include the culminating steps in decades of research that led to approval of the first generation of long-acting medications for HIV prevention—a milestone that raises the standard for any future antiretroviral drug development to levels unimaginable even a decade ago. Our research has highlighted opportunities to maintain the overall health of people with HIV throughout their lifespans. We continue to expand the boundaries of scientific innovation in pursuit of durable technologies that could hasten an end to the HIV pandemic, especially preventive vaccines and curative therapy. During the COVID-19 public health emergency, our networks stepped forward to deliver swift results that advanced vaccines and therapeutics within a year of the World Health Organization declaring the global pandemic, while maintaining progress on our HIV research agenda. The impact of this collective scientific progress is evident worldwide.

Together with my NIH colleagues, I express sincere gratitude to the leaders and staff of current clinical trials networks, our research and civil society partners, and most importantly, clinical study participants and their loved ones, for their enduring commitment to supporting science that changes lives.

As we do every seven years, we are at a point in the funding cycle when our 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 and priorities. Subsequent NIAID HIV research investments will build on the conclusions of these discussions.

Looking to the future, we envision an HIV research enterprise that follows a logical evolution in addressing new scientific priorities informed by previous research progress. We will fund our next networks to align with updated research goals to take us through the end of 2034. The HIV research community’s outstanding infrastructure is the model for biomedical research. Now, our capacity must reflect an increasing interdependence across clinical practice areas and public health contexts. Our goals for the next networks are to:

• Maintain our support for core discovery and translational research to address gaps in biomedical HIV prevention and treatment, including a vaccine and therapeutic remission or cure. Our objective is to identify effective interventions that expand user choice and access, as well as improve quality of life across the lifespan;
• Provide the multidisciplinary leadership required to address the intersections between HIV and other diseases and conditions throughout the lifespan, including noncommunicable diseases, such as diabetes mellitus and substance use disorder, and infectious diseases that share health determinants with HIV, such tuberculosis and hepatitis;
• Compress protocol development and approval timelines for small and early-stage trials to enable more timely translation of research concepts to active studies; 
• Respond to discrete implementation science research questions as defined by our implementation counterparts, including federal partners at the Centers for Disease Control and Prevention, Health Resources and Services Administration, U.S. Agency for International Development, agencies implementing the U.S. President’s Emergency Plan for AIDS Relief, and other nongovernmental funders and implementing organizations worldwide;  
• Draw from nimble and effective partnerships at all levels to leverage the necessary combination of financial resources, scientific expertise, and community leadership and operational capacity to perform clinical research that is accessible to and representative of the populations most affected by HIV, especially people and communities that have been underserved in the HIV response; 
• Leverage our partners’ platforms if called on to close critical evidence gaps for pandemic response; and,
• Plan for impact by mapping clear pathways to rapid regulatory decisions, scalable production, and fair pricing before the start of any efficacy study.

Our shared goal is to produce tools and evidence to facilitate meaningful reductions in HIV incidence, morbidity and mortality globally. I invite you to continue sharing your thoughts with us to help shape the future of HIV clinical research, and to review the blogs on specialized topics that we will continue to post on the HIV Clinical Research Enterprise page in the coming weeks. Please share your feedback, comments, and questions at NextNIAIDHIVNetworks@mail.nih.gov. Submissions will be accepted through December 2024. 

Fourteen vaginal bacterial species and the presence of a protein that promotes inflammation were associated with increased odds of HIV acquisition in a study of more than 500 cisgender women in African countries with high HIV incidence. The study was the largest to date to prospectively analyze the relationship between both the vaginal microbiome and vaginal tissue inflammation and the likelihood of acquiring HIV among cisgender women in this population. The NIAID-sponsored research was published in The Journal of Infectious Diseases.

Research is limited regarding the potential impacts of vaginal bacteria and inflammatory markers on HIV acquisition. Only one previous study has characterized both factors in women before they had HIV to investigate their odds of acquiring the virus, but the number of HIV acquisition events in that study was low, potentially limiting their ability to detect associations.

To increase understanding of these issues, researchers analyzed vaginal swab samples from 586 cisgender women participating a large biomedical HIV prevention clinical trial in South Africa, Uganda and Zimbabwe, and compared the bacterial and inflammatory profiles of samples from 150 participants who acquired HIV during the study with the samples of 436 participants who did not. The team identified 14 bacterial species associated with HIV acquisition and noted that participants whose samples contained most or all of those bacteria had the highest odds of acquiring HIV, while the presence of none or few of the identified bacteria was associated with the lowest odds of HIV acquisition. They similarly identified six inflammatory cytokines and chemokines—proteins that communicate with other cells to prompt the body to fight infections through inflammatory processes—associated with HIV acquisition, and identified the highest odds of HIV acquisition in participants whose samples contained all six of those proteins. Furthermore, they identified a single chemokine called interferon gamma-induced protein 10 associated with the highest odds of HIV acquisition out of the six.

These results suggest that strategies to reduce concentrations of the 14 identified bacterial species and inflammatory proteins could help prevent HIV acquisition, according to the authors. They also recommended that additional studies be conducted to understand the mechanisms by which these factors contribute to biological susceptibility to HIV.

Reference: Srinivasan, S et al. Vaginal Bacteria and Proinflammatory Host Immune Mediators as Biomarkers of HIV Acquisition 3 Risk among African Women. Journal of Infectious Diseases. DOI 10.1093/infdis/jiae406 (2024).

This blog is the second in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the HIV Clinical 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 NextNIAIDHIVNetworks@mail.nih.gov.

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 NextNIAIDHIVNetworks@mail.nih.gov.

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.