Long-awaited data from a follow-up study of valproic acid (Depakote®) indicate that it is not likely to be a “cure” for HIV infection. The new report, published on the Journal of Infectious Diseases’ website ahead of its official printing, debunks a paper released two years ago suggesting that the widely available anti-seizure medication may help decrease the pool of “latent HIV” in the body and, in turn, potentially allow for the eradication of the virus.
Back in 1995, papers published by researchers at the Aaron Diamond AIDS Research Center in New York and the University of Alabama suggested that HIV could possibly be eradicated from the body within three years of starting a protease inhibitor-based drug regimen. This theory was based on the assumption that all HIV-infected cells in the body are short lived and that combination antiretroviral therapy likely had the potency to snuff out viral replication completely.
In 1997, the publication of three additional papers threw a wet towel on the hope stemming from the 1995 findings. The papers – representing a series of studies conducted at Johns Hopkins University in Baltimore, the University of California, San Diego, and the National Institutes of Health in Bethesda – confirmed the presence of long-lived CD4 cell populations capable of harboring HIV for many months. Because these cells are “resting,” and because HIV medications can only go to work in HIV-infected cells that are actively dividing, the research teams estimated that eradication of the virus would require anywhere from 10 to 60 years of continuous “maximally suppressive” antiretroviral therapy.
Based on these and other observations, researchers have looked into ways to activate these long-lived resting cells so that standard antiretroviral therapy can get to the virus and stop it from replicating. Unfortunately, using immune-based therapies (such as Proleukin® [interleukin-2]) in combination with antiretroviral therapy did not work in this regard. A likely explanation for this is the fact that activation not only induced viral replication, it also increased the number of susceptible uninfected cells beyond the threshold that can be protected by antiretroviral therapy.
What was needed, it seemed, was a drug capable of inducing the expression of HIV hiding within these cells, while simultaneously limiting any activation of immune system cells. One such approach that has gained a lot of attention in recent years is the inhibition of histone deacetylase (HDAC), an enzyme believed to play a key role in maintaining HIV inside long-lived resting cells.
In 2001, it was determined that valproic acid – a medication commonly used to manage seizures, migraines, and bipolar disorder – is an inhibitor of HDAC, a finding that has resulted in great interest among researchers on the HIV eradication trail.
This was followed by another paper in 2005, authored by David Margolis, MD, of the University of North Carolina, Chapel Hill, and his colleagues, reporting on study results involving four HIV-positive patients receiving three months of valproic acid in combination with their antiretroviral drug regimens. In short, the study found that levels of HIV inside the quiescent cell population decreased dramatically. While Dr. Margolis’ group remained cautious in its interpretation of the results, they were widely seen by others as a sign that eradication of the virus may be possible after all.
Two years later, a new paper published by Janet Siliciano, PhD, of Johns Hopkins University and her colleagues has, unfortunately, concluded that valproic acid may not be the panacea many hoped it would be. The study enrolled nine HIV-positive patients taking antiretroviral therapy, along with valproic acid for at least three months for the management of neurologic and psychiatric problems.
Using a well-established assay to evaluate the size of the HIV reservoir in resting CD4 cells, Dr. Siliciano’s group reported that “latently infected cells were readily detectable in all patients studied and did not in general decrease over time in a given patient. The estimated decay of the latent reservoir was extremely slow and was similar to that previously reported for patients receiving [antiretroviral therapy] alone.” In other words, valproic acid’s affect on this hard-to-reach HIV population was limited at best.
While Dr. Siliciano group looked for key discrepancies between its research and the 2005 data published by Dr. Margolis’ group, there was no obvious explanation for the different results.
“Regardless of whether [valproic acid] proves to be useful,” Dr. Siliciano’s group writes in its concluding remarks, “the size of the latent reservoir through studies of the kind reported by [Dr. Margolis’ group] are of great importance, because cure of HIV infection cannot be achieved without elimination of the latent reservoir in resting CD4 cells.”
An accompanying editorial, written by Robert Schooley, MD, of the University of California, San Diego, and John Mellors, MD, of the University of Pittsburgh, implies that data from Dr. Siliciano’s group should not be seen as a letdown, but rather an important stepping stone to other avenues of eradication research.
“These studies should not be seen as failures but rather as examples of hypothesis-driven clinical investigation that should lay the groundwork for future work focused on achieving a cure,” Drs. Schooley and Mellors write. “There are a multitude of tools to apply to this goal, including small interfering RNA, passive cellular immune augmentation, therapeutic vaccination, stem cell biology, cellular activation with combinations of more-selective ligands – as well as combinations of these approaches.”
Sources:
Lehrman C, Hogue IB, Palmer S, et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 336:549-55, 2005.
Schooley RT, and Mellors JW. No cure yet for HIV-1, but therapeutic research presses on. J Infect Dis. Published online: January 31, 2007.
Siliciano JD, Lai J, Callender M, et al. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J Infect Dis. Published online: January 31, 2007.
