This blog is the fifth 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 outcomes of HIV clinical trials are often determined by precisely and accurately measuring how specific interventions work biologically in people. Whether tracking immune responses to a preventive vaccine candidate, monitoring changes to the amount of virus in the body, or screening for certain adverse events after administering a novel therapeutic, study teams routinely interact with clinical trial participants to safely obtain, store, transport, and analyze tissue and bodily fluid samples to answer important scientific questions about the impact of an HIV intervention in a laboratory. High quality, reliable laboratory infrastructure is critical to the accuracy and validity of clinical trial results. 

More than 150 NIAID-supported laboratories in 20 countries are addressing the diverse scientific programs of the four clinical trials networks in the Institute’s HIV clinical research enterprise. Since the start of HIV clinical research, laboratory capacities have grown in scope to support an increasing number of global clinical trials, emerging complexities in study protocol design and laboratory testing demands and evolving regulatory requirements for research and licensure.

NIAID is engaging research partners, community representatives, and other public health stakeholders in a multidisciplinary evaluation of its HIV clinical trials networks’ progress toward short- and long-term scientific goals. This process assesses knowledge gained since the networks were last awarded in 2020 to identify an essential path forward based on the latest laboratory and clinical evidence. Future NIAID HIV clinical research investments build on the conclusions of these discussions. 

In the next iteration of HIV clinical trials networks, laboratory functions will continue to evolve to align with scientific priorities and research approaches. Networks will support small early-phase trials, large registrational trials and implementation science research to examine preventive vaccine candidates and non-vaccine prevention interventions, antiviral treatments, HIV curative strategies, and therapies to improve the clinical outcomes of people affected by and living with HIV. Selected studies also will rely on high quality laboratory resources to examine interventions for tuberculosis, hepatitis, mpox and other infectious diseases. Clinical trial networks will need to employ a variety of laboratory types to achieve these objectives.  To increase flexibility and ensure the timeliness and the high quality standards the HIV field relies on for evidence that informs science, licensure and equitable practice, NIAID will have the ultimate authority for laboratory selection and approval.

Efficiency and Versatility 

Laboratory assays for HIV clinical trials continue to expand in quantity and complexity and require proportionate technical expertise and management. Future clinical research needs will include immunologic, microbiologic, and molecular testing, as well as standard chemistries and hematologic assays, with fluctuating volumes across a global collection of research sites. Balancing capacity, efficiency, scalability, and cost will require a mixed methods approach. These may include centralized laboratory testing where feasible and advantageous for protocol-specified tests; standardized processes for rapid assessment and approval of new network laboratories; and validated third-party outsourcing of routine assays to ensure timely turnaround when demands surge. 

Quality and Standardization

Ensuring consistent laboratory operations and high quality laboratory data will require continued compliance with the NIAID Division of AIDS Good Clinical Laboratory Practices and other applicable regulatory guidelines, ongoing external quality assurance monitoring, strong inventory management, importation and exportation expertise, and data and specimen management.

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 fourth 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 development of HIV therapy is one of the great success stories in modern infectious disease research, marked by rapid advances that scientists in the field could only dream of in the 1980s and 1990s. Once a handful of daily pills that only partially suppressed the virus and caused systemic adverse events, today’s antiretroviral therapy (ART) consists of highly effective, well-tolerated medications that can be taken in a single daily dose or a long-acting injection. ART not only offers individual benefits, but also suppresses viral replication to prevent onward transmission. The understanding that undetectable = untransmittable, also known as “U=U,” is based on the foundational NIAID-funded discovery that an undetectable HIV viral load makes it impossible to transmit the virus to sexual partners.

Today’s high standard of HIV care is possible because of the enduring effort of advocates and policymakers who insist that HIV science be sufficiently funded to address key evidence gaps and public health needs, as well as the research teams that propel a constant stream of discovery and the clinical trial participants who allow their lived experience to become evidence for a population-level benefit. This progress is extraordinary, but more advances are still needed to assure the long-term health and quality of life of all people with HIV. Among many persisting challenges, we must address HIV-related complications and conditions that share health determinants with HIV, including tuberculosis (TB), viral hepatitis and mpox.

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 stock of knowledge gained since the networks were last awarded and identifies essential course corrections based on the latest laboratory and clinical evidence. Subsequent NIAID HIV research investments build on the conclusions of these discussions.

These investments are paying off. Recent scientific advances include:

• Basic and translational research that illuminated HIV’s structure, contributing to the development of the first drug in the capsid inhibitor class of antiretroviral drugs; 
• A U.S. clinical trial showing that long-acting injectable ART can support viral suppression in people who experience barriers to daily pill-taking;
• A global trial that found daily statin use reduces the risk of major adverse cardiovascular events in people with HIV;
• A large international clinical trial that found a one-month course of rifapentine and isoniazid was as safe and effective as a nine-month course of isoniazid for preventing active tuberculosis in people with HIV;
• Promising results from a hepatitis B virus (HBV) vaccine candidate for people with HIV who do not mount an immune response to current HBV vaccines;
• Evidence that sustained virological response to direct-acting antiviral therapy for hepatitis C virus (HCV) is possible with minimal clinical monitoring—a strategy that could be crucial to the global HCV elimination agenda; and
• Rapid engagement by the ACTG clinical trials network to examine antivirals for COVID-19 and mpox, demonstrating the essential role networks can—and should—play in pandemic preparedness and response.

We look forward to continuing to address the barriers that separate us from truly optimized HIV care. Our goals include fostering the next generation of discoveries that will open up possibilities for people with HIV—including people who have taken ART for decades—to experience a typical lifespan with high life quality, free from a chronic medication burden; reducing the incidence of concurrent TB and hepatitis; and ensuring scientific advances can feasibly be scaled to all who stand to benefit. 

Beyond Lifelong ART

Current therapeutic regimens are suppressive at best, meaning that if a person experiences an interruption in treatment, HIV replication will typically resume and continue to damage the immune system. Long-acting formulations are transforming quality of life for people who could not take daily ART, but their durability is measured in months, not years. While substantially extending the durability of ART is feasible, we will reach the limit of what long-acting molecules can do. Beyond the horizon of ART, we are exploring several strategies including gene therapy, administration of broadly neutralizing antibodies, and therapeutic vaccines that could either halt HIV replication for years or life or clear all HIV from the body—efforts collectively grouped under cure research. The design and development of cure strategies must advance technologies that could be implemented at scale, especially in resource-limited settings where HIV prevalence is high.

Non-HIV Pathogens 

Even when HIV replication is well-controlled with current therapy, the residual effects of infection can hamper a person’s immune responses and increase their likelihood of experiencing clinical disease from other pathogens. Several infectious diseases also share health determinants with HIV, and require researchers to consider the full constellation of biological, social, and structural factors that can threaten the health of people with HIV. Through collaboration with NIAID’s Division of Microbiology and Infectious Diseases and other NIH Institutes and Centers, we will ensure that we avoid resolving one health condition at the expense of another. We also need to ensure that interventions for non-HIV health conditions will work for people with HIV. Scientific priorities include developing shorter, safer, and more effective treatment regimens for all forms of TB, a preventive TB vaccine, and a hepatitis B cure. 

Quality of life

Conditions associated with aging can have greater impact on people with HIV, including (but not limited to) cardiovascular disease, diabetes, perimenopause, and dementia. HIV care models and tools are no longer sufficient if they only support viral suppression. Critical research is underway to define the ways that treated HIV exacerbates or accelerates other chronic conditions seen in older people. In partnership with other NIH Institutes and Centers, we will continue working to improve the quality of life for people with HIV by supporting research to prevent and treat HIV-related coinfections, complications and comorbidities through the lifespan. Furthermore, we will ensure that person-centered HIV care incorporates health-related quality of life metrics alongside standard HIV monitoring and management in our clinical trials. 

Equitable progress

Equity remains central to NIAID’s research and development decision-making. ART, once in short supply, is now globally available to most people living with HIV, and long-acting formulations herald a future of easier adherence schedules without the constant reminder of the burden of HIV. While our science has always focused on prioritizing concepts that could be rolled out to all populations who could benefit, we must provide an evidence base to support a faster translation of discovery to equitable health care service delivery. Implementation science and social science research including behavioral research, together with medical advances, can accelerate progress toward health equity. We seek to maintain a continuous feedback channel with implementers, so that our priorities are aligned with their most pressing challenges.

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

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections is a global clinical trials network that conducts research to improve the management of HIV and its comorbidities; develop a cure for HIV; and innovate treatments for tuberculosis, hepatitis B, and emerging infectious diseases. The Network is supported through grants from NIAID, with co-funding and scientific partnership from the NIH National Institute of Mental Health, the NIH National Institute on Drug Abuse, the NIH National Institute on Aging, and other NIH Institutes and centers. Three other networks—the HIV Vaccine Trials Network, the HIV Prevention Trials Network, and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network—generate complementary evidence on the scientific areas within their respective scopes.

New NIAID-supported science presented at the 2024 HIV Research for Prevention (HIVR4P) conference in Lima, Peru features a breadth of HIV discovery and translational findings and enriches the evidence base on HIV pre-exposure prophylaxis (PrEP) within the context of reproductive health. Select Institute-supported science highlights are summarized below. Full HIVR4P abstracts are posted on the official conference Web site.

Using PrEP Modalities Alongside Contraception and in the First Trimester of Pregnancy

The monthly dapivirine vaginal ring for HIV prevention was safe in cisgender women who used the ring during early pregnancy and then discontinued use as soon as they learned that they were pregnant. In a pre-licensure open-label study of the dapivirine vaginal ring, participants stopped using it if they became pregnant because ring use during pregnancy was beyond the scope of the study. Pregnant study participants remained enrolled after discontinuing the ring and were monitored for safety throughout their pregnancies. An analysis of data from 72 pregnancies found that there were no notable adverse effects among the participants or their infants when the ring was used in early pregnancy. These findings add to the growing evidence that the dapivirine vaginal ring is safe to use throughout pregnancy. Data presented from another study previously confirmed the safety of the ring when participants initiated use during the second trimester and continued to use it until delivery.

An analysis from the Phase 3 study of long-acting injectable cabotegravir (CAB-LA) PrEP in cisgender women found the drug did not interact with long-acting reversible contraceptive (LARC) drugs. A subset of study participants taking the LARCs etonogestrel, medroxyprogesterone acetate or norethindrone provided additional blood samples so that the study team could analyze how taking LARCs together with CAB-LA or oral PrEP with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) could affect the levels of the antiretroviral drugs and contraceptive agents in the body. There were no drug interactions between CAB-LA and any of the LARCs. Interaction between TDF/FTC and LARCs could not be determined because adherence to TDF/FTC was low in the participating cohort. CAB-LA and TDF/FTC were previously shown to be safe for use in pregnancy. 

Early-Stage Findings on HIV Vaccines to Produce HIV Broadly Neutralizing Antibodies

Several studies of germline targeting—a promising HIV vaccine strategy that stimulates the immune system to generate antibodies capable of neutralizing diverse HIV strains—reported results to inform the next stages of vaccine development. Findings in people and animal models showed that several immunogens—molecules used in a vaccine to elicit a specific immune system response—began to prompt immune responses that could generate HIV broadly neutralizing antibodies (bNAbs). In one study of 53 participants without HIV, a vaccine containing a nanoparticle immunogen called 426.mod.core-C4b was safe at multiple dosing levels and appeared to generate B cells capable of producing bNAbs if stimulated further. These findings are informing the development of more advanced HIV vaccine concepts involving the 426.mod.core-C4b immunogen. 

Understanding the HIV Reservoir and HIV Remission Off Antiretroviral Therapy

HIV is difficult to cure because the virus is skilled at “hiding” in the body and can reappear in the blood stream shortly after antiretroviral therapy (ART) is stopped. These hiding places, called reservoirs, are unaffected by ART. NIAID-supported scientists are exploring strategies to clear HIV and its reservoirs from the body or to reduce HIV to levels that can be suppressed by a person’s own immune system. A new small study found that monocytes—a type of white blood cell—expressing a gene called interleukin 1 beta (IL1B) are associated with smaller HIV reservoirs after a person acquires HIV. Further understanding of the influence of IL1B on HIV reservoir size could guide future novel HIV remission strategies.

Clinical trials and animal studies of HIV remission approaches reported outcomes of interventions designed to maintain HIV viral suppression or remission after ART was paused. When ART is paused in an HIV remission study it is called an analytical treatment interruption (ATI). In one study, researchers infected 16 infant monkeys with the simian version of HIV (SHIV), then placed them into three different treatment groups, each including ART with various combinations of the investigational HIV drug leronlimab and the HIV bNAbs called PGT121-LS and VRC07-523-LS. After 27 weeks of treatment, the research team conducted an ATI and observed outcomes by treatment group. Animals that received ART and both HIV bNAbs experienced rapid rebound of detectable SHIV. Two of 6 animals that received ART and leronlimab remained free of detectable virus through 20 weeks after ATI. All of the animals that received ART, leronlimab and the two HIV bNAbs remained free of detectable virus at the time of abstract submission, 15 weeks after ATI. Monitoring and assessment of monkeys’ SHIV reservoirs is ongoing, and further studies are warranted to understand the effects observed, according to the authors.

Novel PrEP Implant Technology 

Available PrEP methods currently include oral pill, long-acting injectable, and controlled release vaginal ring formulations. A novel refillable controlled-release antiretroviral drug (ARV) implant was found to be safe and capable of delivering one or more ARVs. The implant, placed subdermally—just under the skin—was examined in monkeys and demonstrated that it could provide sustained release of the investigational ARVs islatravir and MK-8527 as well as the lenacapavir, which is licensed for ART and being studied for PrEP, and bictegravir and dolutegravir, both licensed for ART. Implants containing islatravir were evaluated for efficacy as PrEP and found to completely protect the animals from SHIV challenge—direct administration of the virus vaginally and rectally—through 29 months. The implant is being studied for delivery of ARVs for PrEP and ART.

HIV clinical research builds upon basic science discoveries, preclinical studies, and consultations with communities affected by HIV. Further, clinical research relies on the dedication of study participants and the people who support them. NIAID is grateful to all who contribute to advancing HIV research.

References

P Ehrenberg et al. Single-cell analyses reveal that monocyte gene expression impacts HIV-1 reservoir size in acutely treated cohorts. HIV Research for Prevention Conference. Tuesday, October 8, 2024.

W Hahn et al. Vaccination with a novel fractional escalating dose strategy improves early humoral responses with a novel germline targeting HIV vaccine (426.mod.core-C4b): preliminary results from HVTN 301. HIV Research for Prevention Conference. Wednesday, October 9, 2024. 

N. Haigwood et al. Short-term combination immunotherapy with broadly neutralizing antibodies and CCR5 blockade mediates ART-free viral control in infant rhesus macaques. HIV Research for Prevention Conference. Wednesday, October 9, 2024.

M Marzinke et al. Evaluation of potential pharmacologic interactions between CAB-LA or TDF/FTC and hormonal contraceptive agents: a tertiary analysis of HPTN 084. HIV Research for Prevention Conference. Thursday, October 10, 2024.

A Mayo et al. Pregnancy and infant outcomes among individuals exposed to dapivirine ring during the first trimester of pregnancy in the MTN-025/HOPE open-label extension trial. HIV Research for Prevention Conference. Thursday, October 10, 2024.

F Pons-Faudoa et al. Drug-agnostic transcutaneously-refillable subdermal implant for ultra-long-acting delivery of antiretrovirals for HIV prevention. HIV Research for Prevention Conference. Wednesday, October 9, 2024.

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. 

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.  

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 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.

by Jeanne Marrazzo, M.D., M.P.H., NIAID Director

The HIV research community is led by scientists with deep personal commitments to improving the lives of people with and affected by HIV. Some researchers, like me, have pursued this cause since the start of the HIV pandemic, growing our careers studying HIV from basic to implementation science. Our collective decades of work have generated HIV testing, prevention and treatment options beyond what we could have imagined in the 1980s. Those advances enable NIAID to explore new frontiers: expanding HIV prevention and treatment modalities, increasing understanding of the interplay between HIV and other infectious and non-communicable diseases, optimizing choice and convenience, and building on the ever-growing knowledge base that we need to develop a preventive vaccine and cure. The next generation of leaders will bring these concepts to fruition, and we need to welcome and support them into the complex and competitive field of HIV science.

Click below for a video in which NIAID grantees and I discuss the value and experience of early-stage HIV investigators (the audio described version is here):

NIAID wants to fund more new HIV scientists and we have special programs and funding approaches to meet that goal. This week, the NIH Office of AIDS Research will host a virtual workshop on early-career HIV investigators tomorrow, April 24, and NIAID will host its next grant writing Webinars in May, June, and July.

For more information about programs and support for new and early-stage investigators as well as people starting to implement their first independent grant, visit these NIAID and NIH resources: 

Information for New Investigators (NIAID)

HIV/AIDS Information for Researchers (NIAID)

OAR Early Career Investigator Resources (NIH)

Resources of Interest to Early-Stage Investigators (NIH)

Early Career Reviewer Program (NIH)

Switching to an antiretroviral therapy (ART) regimen containing the drug dolutegravir was associated with a significant temporary increase in reservoirs of latent HIV, according to a new analysis from a study in Uganda. HIV reservoirs are cells where HIV lies dormant and cannot be reached by the immune system or ART. They are central to HIV’s persistence, preventing current treatments from clearing the virus from the body. The findings were published today in eBioMedicine.

When taken as prescribed, ART can stop HIV from replicating. The different classes of available antiretroviral drugs (ARVs) interrupt different stages of HIV replication. People are often prescribed drug regimens composed of multiple drug classes to increase the likelihood that ART will fully suppress HIV replication. In 2018, many countries began using dolutegravir-based ART regimens following studies that showed the drug had higher efficacy and fewer side effects than the drugs that had been in use previously. Uganda was among these countries and recommended dolutegravir together with the ARVs tenofovir and lamivudine for all people whose HIV was treatable with those drugs.

In 2015, NIH scientists and researchers from the Rakai Health Sciences Program in Uganda began a longitudinal study of reservoirs among people with HIV in the Rakai and Kyotera Districts in Uganda. Study participants were people whose HIV was suppressed by ART and had agreed to provide blood samples and receive a routine physical examination annually. People meeting study entry criteria continued to enroll each year. As part of this study, the team examined whether the introduction of dolutegravir-based regimens in 2018 had any effect on the makeup of HIV reservoirs in study participants. At the time of the published analysis, 63% of participants were female. The study observed that HIV reservoir size was generally decreasing as participants remained virally suppressed for longer periods. In the analysis of samples provided post-dolutegravir introduction, they observed a surprising 1.7-fold average increase in HIV reservoir size above pre-dolutegravir levels, which lasted for approximately a year, then returned to normal. This effect was consistent across the majority of study participants regardless of how long they had been living with HIV. 

According to the study authors, no other study has found significant differences in HIV reservoir characteristics due to ART regimen changes, but previous research has identified changes in immune characteristics and cardiovascular disease risk, as well as other effects in the period after dolutegravir initiation, suggesting the body goes through a period of adjustment when switching to use the new drug. The authors state that it is important to explore whether other populations experience the same temporary reservoir increase post-dolutegravir initiation, and that more research is needed to understand the mechanism causing the increase, especially if it is starting dolutegravir or stopping the previous ARV. They further suggest that these findings may inform HIV cure research, including approaches referred to as “Shock and Kill” that attempt to stimulate HIV reservoirs to resume activity, then promptly remove them. The authors did not observe any negative clinical ramifications, such as loss of viral control, associated with this finding.  

Most HIV reservoir research has been conducted among predominantly male study populations in Europe and North America, unlike the primarily female participants in this study. The authors highlight the importance of exploring sex-based differences in HIV reservoir characteristics and the inclusion of representative populations in HIV studies.

This research was conducted by NIAID, Western University, and the Rakai Health Sciences Program and with co-funding from other NIH institutes, the Gilead HIV Cure Grants Program, the Canadian Institutes of Health Research, and the Ontario Genomics-Canadian Statistical Sciences Institute.

Reference:

RC Ferreira, et al., Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen. eBioMedicine DOI: 10.1016/j.ebiom.2024.105040 (2024)