New research finds possible treatment for latent HIV
Valproic acid used to deplete HIV
Researchers have discovered a possible combination therapy that will help clear HIV from resting CD4 T-cells, which may open the doors to a new approach to eliminating HIV infection.
The recent study shows that highly-active antiretroviral therapy (HAART) with subcutaneous enfuvirtide, the fusion inhibitor, plus oral valproic acid accelerated the clearance of HIV from resting T-cells in vivo.1
Investigators first found they could recover HIV in the lab from resting T-cells of patients if they were treated with valproic acid, says David Margolis, MD, professor of epidemiology, microbiology, and medicine at the University of North Carolina at Chapel Hill.
"So then we thought if you are maintaining viral suppression with HAART and gave valproic acid over time, by whatever mechanism, we thought the virus would be expressed and, hopefully, that would lead to the disappearance of those latently-infected cells," Margolis explains. "Whether it leads to cell death or virus production in immune-mediated killing, we don’t know."
The approach raised a few concerns, including the possibility that if viruses were expressed, they could infect new cells and spread infection, Margolis says.
To prevent this from happening, the treatment was intensified with enfuvirtide (Fuzeon/T-20), he says.
"So, it wasn’t a perfect study," Margolis says. "All I can say is from beginning to end with intensified therapy, we had significantly less latently-infected cells than otherwise."
Plus there were only four patients, he notes.
"There was much argument on how many declines and how fast the declines and whether HAART would accelerate the decline, so we turned it into a plus or minus experiment," Margolis explains. "Subjectively, we decided that if we observed more than 50 percent depletion of latent infection and resting cells during the protocol period of 3.5 to four months, then we would call that a significant decline, a plus result."
Three of the four patients had a plus result, and one of the four patients had a 29 percent decline, Margolis says.
"The results were in the right direction for the fourth patient, but not significant by our arbitrary set point," he says. "If you’re willing to accept the limited accuracy of our measurements, the very small number of patients and infected cells—it’s an unexpectedly large depletion."
The average depletion was 75 percent, he says.
"I’m not giving much credence to the number of 75 percent because it means 25 percent was still there, so it’s clearly not a therapeutic success," Margolis says. "But the point of the paper is a conceptual point that we suggest that we can target the latent reservoir for depletion."
This strategy could lead to treatment that provides a reasonable approach to eradicating HIV in the future, Margolis says.
Although it’s a preliminary study, its findings are exciting and point to a new direction for HIV treatment, he adds.
One of the drawbacks to using valproic acid is that it slows the clearance of AZT, essentially increasing levels of AZT triphosphate. One patient who received AZT treatment developed grade one anemia toward the end of the study, Margolis says.
The patient’s condition was reversed when the study was stopped, Margolis says.
"We’re not enrolling patients on AZT in future studies," Margolis says.
Valproic acid, which is used to treat seizure disorders, also is inadvisable for people who have liver disease and for women who are pregnant and nursing.
Its advantages are that it’s inexpensive and provides a new therapeutic target, Margolis says.
Since the study never showed a complete eradication of latent HIV, the treatment obviously is not a cure, although it is an encouraging possible treatment for people in late stage HIV disease, which was the population in which it was studied, Margolis says.
"The problem with talking about eradicating HIV or using the C [cure] word is people want there to be a cure, and so do I," Margolis says. "But it’s not going to be easy or soon, and we want everybody to be responsible and take care of their own health."
Scientists need to make progress toward that goal of curing HIV without raising expectations too much, and without taking away from the focus on all of the important things people can and should do today to fight the epidemic, Margolis suggests.
"We need to develop a vaccine and treat people who have infection and identify people who have infection," Margolis says. "These are huge challenges at least as big as developing an eradication therapy, but it doesn’t mean that we should not try to make steps toward that goal just because it’s difficult."
The next step is a study that will look at how effective valproic acid and HAART are without the addition of enfuvirtide, Margolis says.
Reference
- Lehrman G, et al. Depletion of Latent HIV-1 Infection In Vivo: A Proof-of-Concept Study. Lancet. 2005;366:549-555.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content