Image Courtesy of NIAID.
While the world faces the novel SARS-CoV-2 virus, another pandemic continues to afflict nearly forty million people worldwide: human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Though incurable, HIV is treatable, and many successful antiretroviral (ARV) therapeutic options exist. However, due to the chronic nature of the illness, treatments must be lifelong, and as a result, many struggle with nonadherence. Long-acting HIV medications have the potential to alleviate the burden of daily dosing, but most approved ARVs are not well-suited for conversion into extended-release formulations due to issues with solubility and toxicity. An interdisciplinary team of Yale researchers, including Professor of Pharmacology and of Molecular Biophysics and Biochemistry Karen Anderson, Sterling Professor of Chemistry William Jorgensen, Associate Professor of Infectious Diseases and of Microbial Pathogenesis Priti Kumar, and Goizueta Foundation Professor of Biomedical Engineering, Chemical and Environmental Engineering and Physiology W. Mark Saltzman, have developed two forms of a synergistic HIV two-drug combination to combat the aforementioned concerns: a biodegradable removable implant and an injection.
Both the implant and the injection contain two investigational drugs: a Merck-made nucleoside inhibitor called EFdA and a non-nucleoside inhibitor called Compound I that was previously developed by the Yale team. Both target HIV’s reverse transcriptase enzyme – an essential protein responsible for replicating the virus’ genome. Thus, inhibiting its activity allows for the suppression of disease manifestation. “[EFdA and Compound I] have different mechanisms, and … in a structural sense, they’re binding to two different parts of the HIV reverse transcriptase protein,” Anderson said. Kumar also explained that HIV is highly mutable when allowed to replicate. Thus, two inhibitors binding a protein at different positions provide compounded activity resulting in better inhibition of the virus. As a result, viral load is suppressed, and the virus cannot mutate as easily.
The injection and the implant demonstrated successful extended-release activity for the duration of the study. Each method offers numerous benefits. Injection provides direct delivery to allow the particles to form deposits in the deep, innermost tissues such as lymph nodes and bone marrow. Here, the drug is delivered in large quantities and can be released for long periods without toxicity. Injections, however, have one key flaw: permanence. For drugs with well-established safety profiles, this factor is a non-issue. For novel compounds, however, or those with a propensity for viral resistance, the implant provides the benefit of removability should toxicity or adverse reactions arise. In addition, the implant itself is both safe and biodegradable.
Regarding future directions for this research, scientists are increasingly interested in developing long-acting modes of drug delivery. “Eventually, you want this kind of research going to high-risk areas like in Africa, where it’s difficult to get oral tablets out to the public for daily doses of antiretroviral therapy,” Kumar said. These extended-release therapies have significant implications for conditions other than HIV as well. In the short term, however, further research aims to optimize multiple antiretroviral drug combinations to allow for maximal loading and at least a year-long extended release.