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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, mainly used as a treatment for alcohol dependence (and well-known under the brand nameAnti-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 the cell reservoir, whose HIV infection is invisible to the immune system while they are quiescent, compel them to unfold. The hope is that they may be caught by the immune system or, more likely, the effect of a therapeutic vaccine to pre-synthesize the immune system against them, or an antibody-toxin was specifically based on searching 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 an average age of 57 years (range: 26 the 67) and almost all were men (the other two were transgender women). They had an average score of CD4 of 562 cells / mm3 (range: 390 the 1180). All had undetectable viral load in a variety of therapeutic regimens. Everyone was on a backbone of two nucleoside analogue drugs (NRTIs), but a person with lamivudine in the scheme; twenty-two were using tenofovir / emtricitabine. The third drug in their schemes were in fifteen of them a non-analog-nucleoside (NNRTI) Ten used to protease inhibitors, integrase inhibitors into two, one was using an ART with a third regimen class (NRTI + raltegravir + darunavir) and it was 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 tests," Sharon Lewin told aidsmap.com. "One assay that detects 20 copies and also a test capable of detecting a single copy of viral RNA to identify any low-level 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 adverse effects of 1 degree (mild) related to drug use in 1000mg dosing study arm and 2000mg (none in 500mg arm). Side effects were mild nausea, headache or delusions. There were no side effects of class 2, 3 4 or drug-related.

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, perhaps, the most intriguing findings of the study, however, is that while the levels of the drug in the body decayed to undetectable within one or two weeks (from the dose 2000mg) RNA levels do not cut 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 than in 500mg and 2000mg and 150% (2,5 times) higher in the 100mg Researchers are apparently lost when it comes to explaining the continued viral RNA accumulation;. 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 beneficiaries who receive 2000mg, there was also a doubling in the amount of HIV RNA in blood plasma. This is an indication that the dose has been forcing the cells to go further in the viral replication cycle and, in fact, produce viral particles (which may or may not be infectious). However, duplication (0,3 log) HIV RNA in the blood do not represent a significant increase in viral load sufficient to indicate standard loss of detectability in viral load tests, and certainly would not lead to the 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, once all the pre-dose blood samples were collected approximately 9h morning, the natural diurnal variation of the immune system would be the cause. The second hypothesis is supported by evidence showing that proteins that regulate the daily cycle sleep / wake also have immune activation effects; you're 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 effect observed was a strong magnitude less than the HDAC inhibitor drugsRomidepsinBut greater than that observed with the drugvorinostat, Which was the first HDAC inhibitor studied.

HDAC inhibitory drugs, although stimulate the production of HIV, they do not lead to any reduction in the number of carriers of the virus reservoir cells. This is so, it seems, because they have other effects on the immune system, suppressing the production of CD8 cells whose task is the choice of cells infected with virus that showed up. Lewin and his colleagues hope that disulfiram not have the same effect on the containment 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 might be disulfiram, the biggest selling factor is its low toxicity. Professor Steven Deeks, a world leader in curing HIV research and other researchers from the same template, commented: "most of the groups are seeking a powerful stun gun virus out of hiding." 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."

Published in aidsmap by Gus Cairns in November 20 2015.

Translated by Claudio Souza in November 27 2015 in the originalWidely-used anti-alcoholism drug wakes up dormant HIV-infected cells

Reviewed by Mara Macedo

Reference

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

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