The chemical compound EFdA is now thought to be the closest thing to a cure for HIV, after a study conducted by a team including Stefan Sarafianos, associate professor of molecular microbiology and immunology.
Japanese scientists in search of compounds to enhance the flavor of soy sauce stumbled upon EFdA in 2001. After testing by Hiroaki Mitsuya, who patented the first three forms of AIDS medication, Sarafianos and a team of researchers began more in-depth testing.
“We did work a lot on the molecular level,” Sarafianos said. “We tried to find what each part of the molecule contributes to the properties of the molecule itself, in terms of resistance, in terms of potency. We really characterized it exhaustedly.”
Patients with HIV commonly begin treatment with Tenofovir. However, over time, patients can develop a resistance to the drug, often by skipping doses because of side effects.
“(A higher potency) would suggest that if it were to be used in humans, then the dosage would be considerably lower than other compounds of this family,” Sarafianos said. “A lower dosage means most likely less side effects.”
Sarafianos worked with University of Pittsburgh professors Michael Parniak and Michael Murphey-Corb throughout the project. With Parniak, Sarafianos was able to observe the effects of EFdA on two monkeys, both of which had previously been used to test Tenofovir treatment.
“Eventually they failed therapy, and then we took them when they were scheduled to be euthanized, because they were in terrible shape,” Sarafianos said. “Dr. Murphy treated them (with EFdA) and in a week or so, they improved dramatically and their immune systems picked up. She said she hasn't seen something like that throughout her career.”
With such strong results, pharmaceutical company Merck licensed the compound in 2012 and is currently working through preclinical trials of the drug.
“We're an academic lab and our end goal is just basic science, to try and understand things and try to generalize how we can make it even better,” Sarafianos said. “At this point, when a company takes a compound, they really want to look very carefully.”
In the meantime, Sarafianos and his researchers will continue to look into activation mechanisms in EFdA and how its chemical processes can be applied to understanding other compounds, after having received a grant from the National Institutes of Health.
As Merck moves into further trials, there are still risks researchers must be weary of, Sarafianos said.
“Whenever you put a foreign chemical in a human, unfortunately the default is the assumption that these are safe, but no, they're not,” Sarafianos said. “These are chemicals that may have serious side effects, and sometimes they exhibit themselves much later.”
This will lead to researchers and pharmaceutical companies looking into Phase 4 trials, where long-term side effects and risk and optimization factors are monitored after a drug has gone on sale.
“It is a challenge, in particular for HIV therapy, because the patient has to take it for life,” Sarafianos said. “It's not like an antibiotic where you take it for one week and then you're done. You're going to have (to take the medication) day in and day out, so even small toxicity could have a cumulative effect.”
Sarafianos said he hopes learning more about EFdA could lead to a functional cure of HIV, suppressing the virus and ending the necessity of taking medications every day.
Currently, there are 31 antiretroviral drugs available that can suppress the HIV virus, so long as they are taken daily.
“The drugs are so good, and that's probably part of the problem,” Sarafianos said. “HIV has become a manageable disease, so to speak. That has resulted in a sense of security and taking risks that one should not be taking, especially in younger people.”
While it may not be as feared as it was in the 1980s, HIV remains a worldwide public health issue.
“The number of deaths has declined, but the spread of HIV has not really stopped,” Sarafianos said. “It's still a problem.”