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 with Next NIAID HIV Networks.

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.