[procaare] Anticonvulsant May Help Keep Lid on HIV

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Resource: Anticonvulsant May Help Keep Lid on HIV
By Michael Smith 
MedPage Today
11 August 2005
**************

MedPage Today Action Points

Advise patients that this study is a proof of concept and has no
clinical application yet.

Note that highly active anti-retroviral therapy reduces the amount of
circulating HIV and allows the immune system to continue to function,
but does not affect resting T-cells.

Review
 
DALLAS, Aug. 11-A 22-year old anticonvulsant -- or another agent like it
-- may take its place alongside modern antiretroviral drugs as the final
piece in the puzzle to eradicate the HIV virus, according to a pilot
study reported by researchers here.

In a small study, researchers at the University of Texas Southwestern
Medical Center here, led by David Margolis, M.D., have shown that the
anticonvulsant Depakene (valproic acid) can sharply reduce the number of
resting immune cells that are infected with HIV. 

We've shown a new approach by which -- with further advances someday --
we might be able to clear an infection, said Dr. Margolis. 

Depakene, which is used for epilepsy, migraines, and bipolar disorder,
reduced the number of infected resting cells by an average of 75% in
three of four HIV-infected patients, Dr. Margolis and colleagues
reported in the Aug. 13 issue of The Lancet.

Infected but resting CD4-positive T-cells constitute a reservoir of HIV
that is not affected by highly active antiretroviral therapy (HAART). If
therapy is stopped, the disease can return from the reservoir within
weeks.

Even as recently as two weeks ago -- at an international AIDS meeting in
Rio de Janeiro -- "people felt there was no mechanism through which we
could attack these latently infected cells," Dr. Margolis said.

But he cautioned that the study itself is a "pilot proof-of-concept"
that doesn't translate yet into any clinical benefit for HIV-infected
patients. Like the long-sought HIV vaccine, he said, a way to clear HIV
infection will depend on extensive further research.

Scientifically, it's amazing, said Jean-Pierre Routy, M.D., of McGill
University in Montreal. "For patients it doesn't mean anything yet."

But "at least we can work on something that was unthinkable two weeks
ago," said Dr. Routy, who is starting a 50-person randomized crossover
study that will test the effects of Depakene on a larger scale.

Current HIV therapy works by preventing the virus from replicating, but
doesn't stop the initial infection of CD4-positive T-cells. Most T-cells
die as a result of HIV infection, but some survive and go into a resting
state.

This pool of infected cells is highly stable and doesn't appear to
change much over the years, even in the face of successful HAART, said
Dr. Margolis, now at the University of North Carolina.

In the study, researchers enrolled four HIV-infected men whose virus had
been well suppressed for more than two years (fewer than 50 copies of
the virus per milliliter of blood). An additional anti-HIV drug was
added to intensify the HAART therapy.

After four to six weeks of the intensified treatment, they got oral
Depakene twice a day for three months; the dose was adjusted to maintain
plasma concentrations of between 50 and 100 mg/L.

With one exception, all the patients had sharp declines in the number of
infected T-cells, ranging from 68% to greater than 84%. In the other
man, persistent low levels of HIV in the blood, despite the addition of
the extra HAART drug, may explain the lack of response, the researchers
suggested.

Exactly what's happening in the cells is hard to say, Dr. Margolis said.
"You give the combination therapy to patients and you have a drop in
infected cells. There's a black box in between."

One possibility is that the Depakene causes the virus to be expressed
and the cells to leave their resting state. Then they commit suicide,
die because of infection, fall prey to an immune response, or simply die
because they're no longer resting.

The bottom line is "they can't be detected in the blood any more," he
said.

In another setting -- B-cell lymphoma cells associated with infection by
human herpes virus 8 -- it has been shown that the combination of
Depakene and the anti-herpes drug ganciclovir causes infected cells to
commit suicide, said Dr. Routy.

The depletion of the infected T-cell wasn't accompanied by any increase
in HIV in the blood of the participants, Dr. Margolis said, implying
that the approach is safe as well as at least partly effective.

All participants had minor reactions at the injection site. The only
side effect attributable to Depakene was zidovudine-related anemia that
occurred in one patient, probably explained by the increased
bioavailability of zidovudine in the presence of Depakene.

Related articles:

HAART Cuts Risk of HIV Progression to AIDS or Death by 86%
http://www.medpagetoday.com/InfectiousDisease/HIVAIDS/tb1/1448?pfc=101&s
pc=235

IAS: Needle-Less Injection System Makes Fuzeon Patient-Friendly
http://www.medpagetoday.com/InfectiousDisease/HIVAIDS/tb1/1440?pfc=101&s
pc=235

Primary source: The Lancet
Source reference: 
Lehrman G et al. Depletion of latent HIV-1 infection in vivo: a
proof-of-concept study. Lancet 2005; 366: 549-55
View this abstract. 

Additional source: The Lancet
Source reference: 
Routy J-P. Valproic acid: a potential role in treating latent HIV
infection. Lancet 2005; 366: 523-4 

Online at: http://www.medpagetoday.com/InfectiousDisease/HIVAIDS/tb/1526