Re: HIV can be Curable: bright light at the end of the tunnel ?

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Dear Forum members,

Here's the abstract of the original article in the Lancet (I have the full

article in pdf form)

My comment. It's a proof-of-concept study, the testing of an idea

and a preliminary study involving only four patients. They need clinical trials

on a large scale to confirm the success of this approach

Scientifically, it's amazing, said Jean-Pierre Routy, M.D., of McGill University

in Montreal. " For patients it doesn't mean

anything yet. "

Phi Huynhdo

E-mail " <huynhdophi@...>

____________________

Depletion of latent HIV-1 infection in vivo: a

proof-of-concept study

Ginger Lehrman BSa, Ian B Hogue BSa, Palmer

PhDb, Cheryl Jennings BSc, Celsa A Spina PhDd, Ann

Wiegand MSb, ProfAlan L Landay PhDc, W Coombs

MDe, Prof D Richman MDd, Prof W Mellors

MDf, Prof M Coffin PhDb, J Bosch PhDg and

Prof M Margolis MDa, h, ,

a)University of Texas Southwestern Medical Center at

Dallas, Department of Medicine, Division of Infectious

Diseases, 5323 Harry Hines Boulevard, Dallas, TX

753901, USA

b)HIV Drug Resistance Program, National Cancer

Institute, National Institutes of Health, Frederick,

MA, USA

c)Department of Immunology/Microbiology,

Rush-Presbyterian-St Luke's Medical Center, Chicago,

IL, USA

d)University of California San Diego and Veterans

Affairs Medical Center, San Diego, CA, USA

e)Departments of Laboratory Medicine and Medicine,

University of Washington, Seattle, WA, USA

f)University of Pittsburgh School of Medicine,

Pittsburgh, PA, USA

g)Harvard School of Public Health, Boston, MA, USA

h)North Texas Veterans Health Care Systems, Dallas, TX,

USA

Refers to: Valproic acid: a potential role in

treating latent HIV infection, The Lancet, Volume 366,

Issue 9485, 13 August 2005-19 August 2005, Pages

523-524

Summary

Background

Persistent infection in resting CD4+ T cells prevents

eradication of HIV-1. Since the chromatin remodeling

enzyme histone deacetylase 1 (HDAC1) maintains latency

of integrated HIV, we tested the ability of the HDAC

inhibitor valproic acid to deplete persistent, latent

infection in resting CD4+ T cells.

Procedures

We did a proof-of-concept study in four volunteers

infected with HIV and on highly-active antiretroviral

therapy (HAART). After intensifying the effect of

HAART with subcutaneous enfuvirtide 90 £gg twice daily

for 4¡V6 weeks to prevent the spread of HIV, we added

oral valproic acid 500¡V750 mg twice daily to their

treatment regimen for 3 months. We quantified latent

infection of resting CD4+ T cells before and after

augmented treatment by limiting-dilution culture of

resting CD4+ T cells after ex-vivo activation.

Findings

The frequency of resting cell infection was stable

before addition of enfuvirtide and valproic acid, but

declined thereafter. This decline was significant in

three of four patients (mean reduction 75%, range 68%

to >84%). Patients had slight reactions to enfuvirtide

at the injection site, but otherwise tolerated

treatment well.

Interpretation

Combination therapy with an HDAC inhibitor and

intensified HAART safely accelerates clearance of HIV

from resting CD4+ T cells in vivo, suggesting a new

and practical approach to eliminate HIV infection in

this persistent reservoir. This finding, though not

definitive, suggests that new approaches will allow

the cure of HIV in the future.

and here's a comment that makes sense

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 pilotstudy reported by researchers here.

In a small study, researchers at the University of

Texas Southwestern Medical Center here, led by 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 diebecause 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:

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

_________________

Greetings

Phi Huynhdo

E-mail " <huynhdophi@...>