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Research Alert: Study Casts Doubt on "Shock and Kill" Cure Strategy

Two Studies of Vorinostat

March/April 2013

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.


The Second Study

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.

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The average profile of participants was as follows:

  • age -- 48 years
  • gender -- 19 men, 1 woman
  • CD4+ count -- 721 cells
  • duration of virologic suppression on ART -- between three and 14 years
  • 14 participants were using regimens based on nevirapine (Viramune) or efavirenz (Sustiva and in Atripla); the remaining were taking boosted protease-inhibitor-based regimens

Although participants only took vorinostat for 14 days, they were monitored for up to three months.


Results

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:

  • lopinavir-ritonavir (Kaletra) + AZT (Retrovir, zidovudine) + tenofovir (Viread)

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.


Results -- Side Effects

According to the researchers, most side effects experienced were of mild intensity. Common side effects included the following:

  • diarrhea
  • altered sense of taste
  • nausea
  • lethargy

Less common side effects included the following:

  • nausea and/or vomiting
  • headache
  • dry mouth

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.


Making Sense of the Findings

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?


For the Future

San Francisco-based researcher Steven Deeks, MD, raised the following questions about the first vorinostat study and they are applicable to other similar studies:

  • "How should the field balance the ethical concerns about administering potentially toxic drugs to HIV-infected people who are otherwise healthy? The ideal population for these studies are those who have been doing well on long-term therapy, but this just happens to be the group with the lowest apparent need for a cure."
  • "Will future studies of anti-latency drugs require a costly and inconvenient leukapheresis before and after drug exposure? In San Francisco the cost for such a procedure is over US $2,500. Therefore a sensitive assay that can be easily used when [assessing millions of cells for the presence of latent HIV] is clearly needed."
  • "How much of the viral reservoir might be eliminated by HDAC inhibition?" In the case of the Australian study, data about this point was not presented.
  • "Which assays will we use in the future to screen potential drug candidates for anti-latency activity? Vorinostat has demonstrated [anti-latency] activity in most tests, but not all."
  • "What is the fate of virus-producing cells after HDAC inhibition? Although many investigators have assumed that either the virus or host immune system would destroy such cells and therefore clear the virus, recent data suggests that this might not be true."


References

  1. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5.
  2. Deeks SG. HIV: Shock and kill. Nature. 2012 Jul 25;487(7408):439-40.
  3. Cillo A, Sobolewski M, Coffin J, et al. Only a small fraction of HIV-1 proviruses in resting CD4+ T cells can be induced to produce virions ex vivo with anti-CD3/CD28 or vorinostat. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March, 2013, Atlanta, U.S. Abstract 371.
  4. Elliott J, Solomon A, Wightman F, et al. The safety and effect of multiple doses of vorinostat on HIV transcription in HIV-positive patients receiving cART. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta, U.S. Abstract 50 LB.
  5. McIlroy D. Do HIV-specific CTL continue to have an antiviral function during antiretroviral therapy? If not, why not, and what can be done about it? Frontiers in Immunology. 2013;4:52.



This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.
 

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