In an attempt to bring HIV out of latency in ART users, researchers first conducted a limited study of vorinostat. Initially the drug was given in a single oral dose of 200 mg. Four weeks later participants received a dose of 400 mg, followed four weeks later by another single dose of 400 mg. Participants had their blood drawn before and after each dose of vorinostat for analysis. Specifically, participants underwent a procedure called leukapheresis after they received vorinostat. For this procedure, each participant's blood was removed, filtered of white blood cells and then reinfused into them. The white blood cells were intensely studied in the lab.
Tests revealed that a dose of 400 mg of vorinostat significantly increased production of HIV in resting CD4+ cells that were infected with this virus.
Spurred by these positive results and the need to give a longer duration of vorinostat, researchers in Australia conducted a two-week study with this anti-cancer drug given at a dose of 400 mg once daily.
Researchers recruited 20 HIV-positive participants who had been using ART for at least the past three years and whose CD4+ counts were greater than 500 cells and viral load less than 50 copies/ml.
The average profile of participants was as follows:
Although participants only took vorinostat for 14 days, they were monitored for up to three months.
Ninety percent of participants had a significant increase in HIV production from formerly latently infected cells.
There were no significant changes in the proportion of HIV-infected cells in the blood or in the rectal tissue (where there are many lymph tissues rich in CD4+ cells).
In most cases (17 out of 20 participants), viral load in the blood remained below the 20 copies/ml mark.
Two participants developed detectable viral loads (around 40 copies/ml) -- in one case on the first day of vorinostat exposure and the other on the 20th day of the study when vorinostat was no longer being used.
The third participant was taking the following regimen:
On the 7th day of the study, his viral load rose to above 150 copies/ml and then fell. Two months later, it was less than 20 copies/ml.
No participants developed significant levels of T-cell activation because of exposure to vorinostat.
According to the researchers, most side effects experienced were of mild intensity. Common side effects included the following:
Less common side effects included the following:
Laboratory analyses of blood revealed that some participants developed reduced levels of platelets and elevated levels of some liver enzymes (GGT and ALP).
Generally the side effects quickly appeared once participants initiated therapy with vorinostat and quickly resolved once they stopped taking it.
The two vorinostat studies prove that this drug can bring HIV out of hiding in resting T cells. Furthermore, exposure to the drug seemed generally safe. However, longer studies are needed to assess its impact on the reservoir of latently infected cells. Moreover, further safety studies are needed. This is because in tests with bacteria, vorinostat has the potential to cause mutations. Supposedly healthy human cells can repair damage caused by vorinostat but this needs to be investigated in HIV-positive people.
Limited exposure to vorinostat did not cure HIV; so much more work is needed. Will future clinical trials use higher doses of the drug or the same 400-mg dose for longer periods?
San Francisco-based researcher Steven Deeks, MD, raised the following questions about the first vorinostat study and they are applicable to other similar studies:
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