Anti-Alcoholism Drug Widely Used Capable of Awakening Latent HIV

"Less aggressive" non-toxic anti-alcoholism drug is an alternative to other experimental drugs

A research team from an Australian company found that disulfiram, a widely used and safe drug, used primarily as a treatment for alcohol dependence (and well-known under the brand name Anti-Abuse effect) Can "wake up" quiescent tanks cells infected with HIV and therefore can be used as a first stage of a hypothetical cure for HIV.

The researchers found that the dose of disulfiram up to four times greater than the licensed dose has produced modest, but sustained HIV RNA increases within the container cells and the higher dose also produced a doubling of the quantity of HIV RNA outside the cells, in the bloodstream.

This produces a detectable viral load by standard tests for any participant in the study, but an indication that cells where the HIV hides are being pushed or placed in activity and therefore revealing the immune system.

Disulfiram by itself or with other drugs, could be the first phase of a call healing strategy "kick and kill. This implies that reservoir cells, whose HIV infection is invisible to the immune system while they are quiescent, forces them to reveal themselves. The hope is that they may be picked up by the immune system or, more likely, by the effect of a therapeutic vaccine that pre-synthesizes the immune system against them, or an antibody-toxin that would be based specifically on looking for them.

Lead investigator Professor Sharon Lewin of the University of Melbourne said that "the dose of disulfiram, used this more than just a 'tickling' or a kick to the virus, but it could be enough."

The study

In the study, the Lewin team gave 30 people living with HIV who had CD4 counts above 350 cells / mm3 and had an undetectable viral load for at least three years of antiretroviral therapy (ART), three different doses disulfiram for three days. Ten subjects received 500 milligrams (mg) of the drug, the dose that is licensed to treat alcohol dependency; ten received 1.000 mg; and ten received 2000mg.

The 30 participants with mean age of 57 years (range: 26 to 67) and almost all were men (the other two were transsexual women). They had an average CD4 count of 562 cells / mm3 (range: 390 to 1180). All had undetectable viral load in a variety of therapeutic regimens. All were on a backbone of two nucleoside analogues (NRTIs), except one person with lamivudine in the scheme; Twenty-two were using tenofovir / emtricitabine. The third drug in their schemes was in 15 of them a non-analogue-nucleoside (NNRTI), ten were used protease inhibitors, integrase inhibitors in two, one used an ART with a third class of therapeutic scheme (NRTI + raltegravir + darunavir) and one used four classes of drugs (lamivudine, nevirapine, darunavir and raltegravir).

Blood samples to determine levels of HIV RNA in the cells and blood plasma are represented in a screened a few days before the first dose of disulfiram and then a new scan immediately before the first dose. It was found that it would be significant (see below).

"RNA in blood plasma was measured by two assays," Sharon Lewin told aidsmap.com. "An assay that detects the 20 copies and also an assay capable of detecting a single copy of viral RNA to identify any low level of change."

The samples were taken twice, 24 eight hours after the first dose; 24 hours after the second (i.e., just before the third); Two eight hours after the third 24; and then, seven days after the third 30. The drug levels in blood were also measured.

There were ten cases of 1 (mild) adverse events related to drug use in the arm of the 1000mg and 2000mg dosing study (none in the 500mg arm). The side effects were mild nausea, headache or delusions. There were no 2, 3 or 4 drug-related side effects.

There was an average increase of 60-90% for the so-called Not cut RNA CD4 cells in HIV during treatment with disulfiram. The largest increase of not cut RNA (90%) was the group with 1000mg dosage.

This indicates activity at an early stage of viral transcription when new genetic material is generated in the cells but this must be "spliced" namely cut up into different phases with proper functionality in all cropped units, in order to proceed toward the replication.

Lewin said, "Do not cut RNA is detected in most people on ART. I did not understand what that means, but it is likely that some low-level viral transcription forms in some cells. In latency reversal studies we are looking primarily by an increase in transcription of HIV as a first step. "

What is possibly the most intriguing finding of the study, however, is that although drug levels in the body decay to undetectable within one or two weeks, (from the dose of 2000mg), levels of unclotted RNA continued to increase and were at their highest level in the last measurement 30 days after the first dose; they were 110% higher (more than double that in 500mg and 2000mg and 150% (2,5 times) higher in 100mg.) Researchers who are apparently lost in explaining the continuous accumulation of viral RNA could be very interesting if disulfiram had a long lasting effect.

"We have not measured the subjects again, since the study was ended 30 days," Lewin said. "We are currently doing this for our patients with vorinostat, which are now at a stage more than two years of post-study."

For recipients receiving 2000mg, there was also a doubling in the amount of HIV RNA in the blood plasma. This is an indication that the dose was forcing the cells to go further into the viral replication cycle and, in fact, producing viral particles (which may or may not be infectious). However, a duplication (0,3 log) of HIV RNA in the blood does not represent a significant increase in viral load, sufficient to indicate a loss of pattern of undetectability in viral load tests, and would certainly not lead to infectivity or disease progression.

There was another unexpected finding in the study. The researchers found that higher levels not cut RNA were found in blood samples collected immediately before the first dose of disulfiram. What obviously can not be caused by the drug under study, what was happening?

Researchers have two options .:

  1. Possibly the stress of going to a clinic, and make blood collection and take a dose of an experimental drug has been enough that hormonal slightly stimulate the immune cells of people infected with HIV.
  2. In another alternative, since all pre-doses of the blood samples were collected about 9h in the morning, the natural daytime variation of the immune system would be the cause. The second hypothesis is supported by evidence demonstrating that the proteins that regulate the sleep / wake cycle also have immune activation effects; you will be more likely to get viral RNA transcription in the morning.

Sharon Lewin aidsmap.com said studies were initiated to determine which of these hypotheses was correct.

The unexpected effect of pre-treatment increased RNA was that the increase in RNA not cut during the experimental therapy with disulfiram were only modest (20% -60% increase) in 30º day, if they are compared only with the immediate measurement on the pre-doses. However, researchers have made an analysis where they took patients who had the highest levels of disulfiram in their blood and found that in such patients an increase of 60% in not cut RNA count at all doses and 7º and 30º day after the first dose.

More research

The observed effect was of a less strong magnitude than that of the HDAC inhibitor of the drug Romidepsin, but higher than that observed with the drug vorinostat, Which was the first HDAC inhibitor studied.

HDAC inhibitor drugs, while stimulating the production of HIV, do not lead to any decrease in the number of reservoir cells carrying the virus. This is, it seems, because they have other effects on the immune system, suppressing the production of CD8 cells whose task is the choice of the cells infected with viruses that have been revealed. Lewin and colleagues hope that disulfiram does not have the same containment effect on CD8 cells.

Now they are preparing to match disulfiram with other drugs and therapeutic vaccines designed to reverse the latency (invisibility) in HIV-infected cells, especially as there is evidence of additive effects of disulfiram and HDAC inhibitors.

However, what may turn out to be disulfiram, the biggest selling factor is its low toxicity. Professor Steven Deeks, one of the world leaders in HIV cure research and other researchers of the same genre, commented: "Most groups are looking for a powerful weapon to shock the viruses out of their hiding place." These approaches may prove to be harmful or dangerous.

"I see disulfiram as a smooth way to reach this same purpose, particularly if we can show that operates for a long period of time when data."

Posted in AIDSMAP by Gus Cairns on 20 November 2015.

Translated by Cláudio Souza in 27 of November of 2015 of the original in Widely-used anti-alcoholism drug wakes up dormant HIV-infected cells

Reviewed by Mara Macedo

Reference

Elliott JH et al. Short-term administration of disulfiram for reversal of latent HIV infection: a dose-escalation phase 2 study. The Lancet, early online publication. IT HURTS: http://dx.doi.org/10.1016/S2352-3018(15)00226-X 2015. See here for abstract.

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