Could valproic acid eradicate HIV from the body?

Christopher Gadd
Published: 12 August 2005

A small proof-of-concept study has shown that the drug valproic acid (Depakote) may be able to reduce the pool of dormant HIV-infected cells in the body. According to the authors of the study, which was published in the 13th August edition of The Lancet, this may eventually point the way towards a cure for HIV infection.

However, this study is only the first small step towards larger investigations into eliminating HIV from the body. While it shows that the investigators’ hypothesis is feasible, many years of further research are required before experts will be able to understand if this drug will be effective in flushing out HIV from hidden stores.

Eradication of HIV?

As part of its life-cycle, HIV needs to insert its genetic material into the DNA of the human CD4 T-cells it infects. The virus’s incorporated genes are then used as a template for the production of new virus particles in active cells. This process leads to the cells being over-activated, eventually causing most of them to commit suicide or ‘apoptosis’ and CD4 cell counts to fall.

A small proportion of the HIV-infected cells do not die, but become dormant within the lymph nodes or other areas of the body. Since they are not actively producing new HIV particles, the virus’s genes remain hidden within the nuclei of these cells. These cellular stores are highly stable and long-lasting, but remain poised to start pumping out new HIV particles if they become activated by stimulation of the immune system.

Currently available antiretroviral drug combinations can reduce HIV to undetectable levels in the blood, but they can only do so by preventing HIV from making copies of itself, or 'replicating' in the body. They cannot remove HIV's genes that are integrated in the human cells' DNA, leaving the reservoir of HIV in latent infected cells untouched.

A new role for valproic acid?

Researchers are keen to find out ways in which resting, HIV-infected cells can be depleted in the body, to prevent the reactivation of HIV production from viral reservoirs when antiretroviral therapy is stopped.

Valproic acid, which is already licensed for the treatment of bipolar disorder and epilepsy, is an inhibitor of a cellular enzyme called histone deacetylase 1 (HDAC1). This enzyme is crucial for keeping HIV’s genes hidden within the host cell’s DNA.

In the test tube, studies have shown that valproic acid can stimulate the release of HIV from resting, infected T-cells. Consequently, researchers wished to find out whether giving the drug to HIV-positive patients could stimulate the resting cells to start producing HIV particles and eliminate the hidden store of HIV from the body.

The investigators tested the drug in four patients, all of whom had had undetectable viral loads on antiretroviral therapy for over two years. After intensifying their drug regimens with the fusion inhibitor T-20 (enfuvirtide, Fuzeon) for four to six weeks, the patients began to take valproic acid at a dose of 500 to 750mg twice daily alongside their anti-HIV drugs. T-20 was used to protect the patients from any increase in HIV production caused by the addition of valproic acid.

The number of resting, infected cells was stable in the patients before T-20 and valproic acid were added to their antiretroviral drug regimens. However, after 16 to 18 weeks of valproic acid treatment, the investigators saw a decline in resting, infected cell numbers of between 68 and over 84% in three of the patients. The fourth patient had a smaller reduction of 29%.

This, the investigators claim, indicates that valproic acid may be useful in driving the eradication of resting, infected cells in the body. “Our findings show that 16 to 18 weeks’ treatment with a standard clinical dose of valproic acid, in the setting of intensified highly active antiretroviral therapy, produces a substantial decline in the frequency of replication-competent HIV in circulating resting CD4 T-cells,” they conclude.

None of the patients experienced severe adverse effects during the trial, although all had mild irritation at the sites of T-20 injection, a well-known side-effect of this drug. In addition, one patient taking AZT (zidovudine, Retrovir) experienced anaemia, possibly due to increased AZT levels caused by addition of valproic acid.

In an accompanying commentary, Dr Jean-Pierre Routy from McGill University, Canada writes, “these results, although preliminary, merit further urgent study. In particular they argue for a randomised trial to assess changes in the blood and tissue of the number of latently infected cells.”

Proof-of-concept, not proof of efficacy

Despite their encouraging results, the authors acknowledge that their study is preliminary, and will require a bank of larger, longer studies before they can be certain about a role for valproic acid in reducing hidden HIV stores. “Our pilot study is limited and leaves many questions unanswered,” they write.

Notably, the use of only four volunteers makes it difficult to be confident of the robustness of the study's findings and to share their optimism that “new approaches will allow the cure of HIV in the future.”

Further questions surround the absence of any signs of immune activation during the study, despite the addition of a drug that was expected to stimulate release of HIV particles from resting infected cells. Similarly, a highly sensitive viral load test failed to show an increase of HIV levels in any of the patients during the study, with viral loads remaining below 1 copy/ml throughout most of the study.

Caution was also urged by experts in the field. Speaking to Associated Press, Dr Robert Siliciano from Johns Hopkins University said, "it's extremely unlikely that this approach would work.” Siliciano was one of the scientists who discovered dormant infection of HIV in the mid-1990s.

"It assumes something about the mechanism which we don't know is true. The mechanism may involve other issues that are not affected by this drug.

"It didn't get all the cells. That's probably because it's not really targeting the right mechanism for latency," Siliciano said. "It's got to be a 99.9999% reduction to be useful. When you stop the drugs the virus explodes back so quickly, even if you had one latently infected cell left, in a matter of days you would be back to where you started from."

"It's a little bit premature to be talking about a cure for HIV," he said

References

Lehrman G et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366: 549-555, 2005.

Routy JP. Valproic acid: a potential role in treating latent HIV infection. Lancet 366: 523-524, 2005.

Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

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We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

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