Investigators presented advances in basic and clinical research on infectious diseases and HIV in the past year at ID Week.
Basic and clinical research on infectious disease and HIV continued at a brisk pace in the past year. As outlined by 4 speakers at a symposium at the annual ID Week conference in San Diego, California, real advances were made.
A hot clinical topic for a long time in infectious diseases has been multidrug resistance (MDR). Now, according to Stan Deresinski, MD, Stanford University, Palo Alto, California, “the great fear has come true.” A report last year from China described deaths due to hypervirulent and carbapenem-resistant Klebsiella pneumonia (ST11). The report once again highlights the need for an expedited pathway for antibiotic development and approval.
The US Food and Drug Administration (FDA) has several expedited pathways of approval. One option is the 505(b)(2) pathway, that grants approvals that involve changes to previously approved drugs. This pathway was exploited to gain FDA approval in 2015 of the combination of ceftazidime and avibactam based on prior data from ceftazidime alone and phase 2 clinical data on the combination. The latter data, noted Dr. Deresinski, came from only 160 patients and preliminary information from uncompleted clinical trials. Antibiotics that target MDR gram-negative bacteria that may or likely will be approved in the next year or two include eravacycline, plazomicin, fosfomycin, and cefiderocol.
Further efforts to accelerate development of antibiotics in the United States include CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator), a public-private partnership focusing on preclinical discovery, and ARLG (Antibacterial Resistance leadership group) that focuses on clinical research including fostering the formation of clinical research networks.
Another hot clinical topic in infectious disease is sexually transmitted diseases, which are now at record high levels in the United States. A recent report by the Centers for Disease and Control and Prevention chronicled increases of chlamydia, gonorrhea, and syphilis in the past 2 years of 4.7%, 18.5%, and 17.6%, respectively. Another recent ominous report from the United Kingdom described the failure of ceftriaxone and azithromycin in a patient with gonorrhea. On an optimistic note, the meningococcal serotype B vaccine was found to provide protection against gonorrhea, likely because of the presence of outer membrane vesicles that spawn a protective cross-reaction. A multivalent vaccine (Bexsero, GlaxoSmithKline) that has FDA approval for use against Meningitis B is soon to be evaluated for gonorrhea.
Switching microbial gears, azole resistance in Aspergillus has become a pressing concern. Although it’s a “problem on the horizon” in the United States, elsewhere fungal resistance to azole is a big deal. “In Germany, as many as 30% of Aspergillus fumigates isolates are resistant to azole,” said Dr. Deresinski. MDR Candida auris, which carries a high mortality rate, is already established in several US states nationwide.
Dealing with the clinical realities of these and other infections demands more discovery-driven data. Liise-Anne Pirofski, MD, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, discussed hot topics in the basic science of infectious diseases.
The microbiota—the total microorganism community in and on the body—is attracting attention as a regulator of conditions that can help thwart infections or, if the microbiota has gone awry, as can happen in antibiotic therapy, open the door for infections to become established. Examples in the literature during the past year included the protection against Enterobacteriaceae infection by colonic epithelial cells, the role of the gut microbiota in polypharmacy in elderly hospitalized patients, inhibition of host response to Candida by lactate, and the role of sodium in the kidney in protection from bacterial infection. “Environmental conditions matter,” said Dr. Pirofski.
So do antibodies. “Non-neutralizing antibodies open new possibilities for vaccine design and antibody engineering. A unique benefit of some antibodies, not afforded by antibiotics, is their ability to dampen inflammation. Antibodies that alter microbial gene expression suggest a new paradigm for antibody-mediated immunity. Platforms for producing and engineering monoclonal antibodies make it possible to design antibodies with different functions for specific roles in therapy,” said Dr. Pirofski.
Recent research concerning the differing efficacies of some vaccines has driven home the point that one size does not fit all when it comes to a vaccine. The basis of the variable success of some vaccines may be an individual’s immune response. A vaccine may need to boost the immune response in some people while dampening the response in others.
The past year has also been a busy one for clinical and basic research on HIV. A look at the hot clinical areas was provided by Wendy Armstrong, MD, Emory University, Atlanta, Georgia.
Pre-exposure prophylaxis (PrEP)—a regimen of drug therapy for someone who does not have HIV, but who is deemed at substantial risk of the infection— is a hot clinical area. “Like [antiretroviral therapy] for treatment of established infection, we need to develop a range of options that might have different acceptability in different populations. The need for implementation studies remains high and may help inform choices between agents and delivery methods to maximize use and adherence. The composition of the microbiome may influence the efficacy of [nucleoside reverse transcriptase inhibitors] topical drugs and adds a new level of complexity to these studies,” said Dr. Armstrong.
Improving antiretroviral therapy, with the mantra of “fewer pills, less often” has been a driver of recent studies. The goals include boosting treatment effectiveness, simplifying treatment including less frequent dosing, and limiting adverse effects and interactions with other drugs. Improved therapy will require policy initiatives, given the disparities in treatment success, especially among African Americans. According to Dr. Armstrong, the physician-as-activist can have a powerful influence on changing policy.
Joel Blankson, MD, PhD, Johns Hopkins Hospital, Baltimore, Maryland, discussed hot topics in basic HIV research, for example, how CD32a may be a biomarker for latently infected cells. The research findings of the past year still need confirmation; however, if they bear out “it would be very useful for understanding the biology of latently infected cells and viral persistence,” said Dr. Blankson.
Basic research on HIV-infected macrophages as a reservoir of HIV during combination antiretroviral therapy bore fruit. “A viral reservoir can exist in humanized mice without T cells. But, the study can’t really be confirmed in humans. So, it’s possible that macrophages can contribute to the viral reservoir,” said Dr. Blankson.
Another research avenue has focused on broadly neutralizing antibodies—monoclonals that can neutralize many different HIV-1 isolates. These workhorse antibodies are present in about 10% of patients. A manufactured antibody with activity against 3 domains was shown to be protective in monkeys infected with a hybrid simian immunodeficiency virus and HIV that expresses the HIV envelope glycoprotein. “This has major implications for vaccine and vectored immunoprophylaxis development,” said Dr. Blankson.
Stan Deresinski: None
Liise-Anne Pirofski: none
Wendy Armstrong: none
Joel Blankson none
Symposium: What’s Hot in HIV Science
Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at firstname.lastname@example.org.