Recently, the UN General Assembly held a High-Level Meeting to discuss an urgent, global public health problem: Antimicrobial resistance (AMR), which occurs when bacteria, viruses, fungi and parasites evolve to evade antibiotics and other medicines that are meant to kill them. Currently, antimicrobial resistance results in approximately 1.3 million deaths worldwide, including 35,000 in the United States each year, according to the Centers for Disease Control and Prevention. Antibiotic resistance can make infections more difficult to treat—and, unfortunately, due in part to overuse and misuse of antibiotics, antimicrobial-resistant infections are becoming more common.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has prioritized AMR research for many years. For instance, through the Antibacterial Resistance Leadership Group (ARLG), the Institute has supported more than 60 AMR clinical research projects, involving more than 20,000 participants at sites around the world. The results of this work, combined with 10 years of coordinated efforts from across the U.S. government, have led to significant improvements in how public health officials consider antibiotics and how physicians can tackle difficult infections. As a global, evolving problem, AMR continues to demand new research and innovations from the public health sector.

One ongoing clinical trial is examining a particularly thorny facet of treating antimicrobial resistant (AMR) infections: when dealing with antibiotic-resistant infections, healthcare providers may need to try several different treatments before they identify an effective one, and tests to verify whether treatments will work can take days to complete. This delay can slow the patient’s recovery or lead to death. For example, ineffective therapy due to treatment delay is associated with high mortality among patients with bloodstream infections caused by Gram-negative bacteria. 

A new clinical trial sponsored by NIAID is currently evaluating whether the use of a rapid test of antibiotic susceptibility for bacteria growing in blood cultures improves clinical outcomes for patients with sepsis in settings that have high rates of antibiotic-resistant bacterial infections. The trial is being conducted by ARLG and will ultimately enroll roughly 900 hospitalized participants at seven locations around the world. 

The Fast Antibiotic Susceptibility Testing for Gram-Negative Bacteremia Trial (FAST) will test whether use of the VITEK^® REVEAL™ AST System, a direct-from-positive-blood-culture fast phenotypic susceptibility test (manufactured by Specific Diagnostics, San Jose, CA, a wholly owned subsidiary of bioMérieux, Inc., Salt Lake City, UT), can speed up the identification of effective antibiotics to treat bloodstream infections and lead to better patient outcomes. The VITEK^® REVEAL™ system is already available for clinical use in the European Union (and recently received FDA 510(k) Clearance (K230675) on June 20, 2024, and can identify phenotypic susceptibility of 10 different bacteria to 23 different antibiotics. Unlike standard of care susceptibility testing, which typically takes several days to provide results, the VITEK^® REVEAL™ test results are available in an average of 5.5 hours.

A recent clinical trial supported by NIAID through the ARLG showed that using a similar rapid test for antimicrobial susceptibility helped healthcare providers identify and use effective antibiotics faster than standard-of-care testing. However, that trial was unable to show whether using a rapid test led to better patient outcomes—possibly because the trial was carried out in areas with relatively low rates of antimicrobial-resistant infections. The researchers hope that data from the FAST trial will show whether the test improves outcomes in regions where many patients have antimicrobial-resistant infections.

The FAST trial has enrolled hospitalized participants with Gram-negative bacteria identified in their blood. Such bacteria include Klebsiella species and Escherichia coli. They have been randomized to one of two groups: half the participants are having their blood cultures tested with VITEK^® REVEAL™ as well as standard bacterial culture and antibiotic susceptibility testing. The other participants are serving as a control group and their blood cultures will undergo standard bacterial culture and susceptibility testing. The participants’ progress is being monitored for 30 days, as clinical staff record how quickly participants recover and whether they experience any negative effects, such as worsening or relapsing while still in the hospital, requiring readmission to the hospital later for the same problem, acquiring a new infection while in the hospital, or death.

Improved testing alone will not eliminate the threat of AMR infections. For that, healthcare providers will need better therapeutics, better means of keeping the infections from spreading, and other tools. However, when patients present to the hospital with severe infections, the initial hours of waiting for test results can make all the difference. Confirming that rapid tests actually improve patient outcomes is an important step on the road to fighting back against ever-changing pathogens.

To read more about this trial, search ClinicalTrials.gov using the identifier NCT06174649.

A drug that blocks danger signals that can lead to harmful inflammation could help reduce COVID-19 lung damage, a new study from NIAID scientists and colleagues has found. Scientists from NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, and the University of Utah completed the project, published online in JCI Insights.

Though they completed the study in laboratory mice modified to model COVID-19 in people, the scientists think their findings are important enough to pursue further studies of the drug, FPS-ZM1, to determine dosing and timing strategies for possible human clinical trials. FPS-ZM1 is an immune modulatory therapeutic – the drug is designed to prevent a specific immune system response from occurring. The investigational therapy has been evaluated in preclinical studies to treat conditions such as diabetes, lung injury and stroke. In their study, the scientists used FPS-ZM1 to block the “receptor for advanced glycation end products” (RAGE), which senses danger signals and can generate inflammation and coagulation known to damage the lungs of COVID-19 patients.

Therapeutic treatment with FPS-ZM1 during the study improved survival in mice infected with SARS-CoV-2, the virus that causes COVID-19. Further, FPS-ZM1 specifically reduced damage to the lung vasculature, an important system for circulating blood through the lungs that becomes damaged during SARS-CoV-2 infection. FPS-ZM1 also has shown in other rodent studies that it can protect against injury in disease models of brain injury, sepsis, asthma, diabetes, acute lung injury and ischemic/reperfusion (organ damage due to blood flow).

The study also identified two distinct phases of COVID-19 disease development in the mice. The scientists want to further explore those phases as potential guides for treatment strategies. For example, FPS-ZM1 limited specific types of inflammation and tissue damage, so it would likely be most effective if administered during the intermediate to later stages of SARS-CoV-2 infection, whereas antiviral treatment may be most effective when given early following infection.

Reference: F Jessop, et al. Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection. JCI Insights DOI: https://doi.org/10.1172/jci.insight.155896. (2022).

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. 

The world of fungi includes a wide range of organisms, such as mushrooms, molds, and yeast, that are common outdoors in water, soil, and air; indoors on surfaces; and on our skin and inside our bodies. Although many fungi are helpful—or even delicious, like some mushrooms—there are many others which can cause disease. Some fungal infections are more common in people with weakened immune systems or hospitalized individuals, while other fungal infections can infect anyone, including otherwise healthy people. According to the Centers for Disease Control and Prevention (CDC), more than one billion people worldwide get a fungal infection each year. There are four main classes of antifungal drugs, and the rising rate of antimicrobial resistance is limiting and complicating existing treatment options. Currently, there are no approved vaccines to prevent fungal infections.

NIAID conducts and supports basic, translational, and clinical research to understand how fungal pathogens cause disease and how the immune system responds to infection. NIAID researchers are exploring how fungal susceptibility and infection impact the function of immune cells. The following are examples of ongoing clinical trials supported by NIAID through the investigator-initiated clinical trial funding mechanism investigating various aspects of fungal disease.

Stewardship in AMR – Examining a shorter treatment course for children

Immunocompromised patients are at risk for the development of fungal infections. Hospitalized patients can get severe, often deadly, fungal diseases like candidemia, a bloodstream infection caused by the Candida fungus. According to the CDC, candidemia is one of the most common bloodstream infections in the U.S. with an estimated 25,000 cases each year. The current treatment guidelines for invasive candidemia recommend 14 days of antifungal therapy. This guideline is based on expert opinion rather than comparative data and the optimal treatment duration remains unknown. NIAID-funded researchers Drs. William J. Steinbach and Brian T. Fisher are conducting a clinical trial (NCT05763251) to examine whether a shorter 7-day treatment strategy is just as safe and effective as current practice. This trial is only enrolling pediatric patients at the study-site hospitals with uncomplicated cases of candidemia. A shorter treatment would significantly reduce the burden of care on sick and recovering pediatric patients, allowing families to come home earlier from the hospital, and could help combat the rising rates of antimicrobial resistance. This is the first randomized control trial to explore the efficacy of a shorter course treatment for any invasive fungal disease. The trial is supported through NIAID grant funding R01 AI 170385.

Cryptococcus neoformans contributing to HIV/AIDS-related mortality

Cryptococcus neoformans is a fungal pathogen that can cause cryptococcal meningitis. Those most at risk are immunocompromised, such as people/persons living with HIV/AIDS. Although Antiretroviral therapy (ART) has significantly reduced the incidence of HIV/AIDS in the United States, regions of the world with limited access to ART are still seeing tens of thousands of cases. According to the CDC, each year an estimated 152,000 people living with HIV experience cases of cryptococcal meningitis, of which an estimated 112,000 deaths occur, most in sub-Saharan Africa. In the weeks prior to the onset of meningitis, the cryptococcal antigen (CrAg) is detectable in the blood and is a good predictor of meningitis and death. NIAID-funded researcher Dr. Radha Rajasingham is leading a clinical trial (NCT03002012) to examine whether the treatment combination of liposomal amphotericin (AmBisome) and fluconazole for those who receive a positive CrAg antigen test effectively prevents cryptococcal meningitis and death. Dr. Rajasingham’s lab at the University of Minnesota is dedicated to improving cryptococcal meningitis treatment strategies and outcomes for people/persons living with HIV/AIDS and is supported through NIAID grant funding U01 AI 174978 and R01 AI162181.

Though these conditions can be severe, they are not the only fungal diseases of concern for NIAID. From aspergillosis to Valley Fever, NIAID is committed to researching new treatments, diagnostics, and preventative measures for a wide array of fungal diseases, especially in the face of rising antifungal resistance.