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How Can "JAK Inhibitors" Help Salvage Patients and the Search for an HIV Cure?


An Interview With Raymond Schinazi, Ph.D., D.Sc.

January 15, 2013

Nelson Vergel, B.S.Ch.E., M.B.A.

Nelson Vergel, B.S.Ch.E., M.B.A., is a leading HIV treatment advocate, author and founder of the Body Positive Wellness Center in Houston, Texas.

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It's amazing what you've done. Could you please tell us about the abstract that you presented at the International Workshop on HIV and Hepatitis in Sitges about JAK inhibitors?

There's this pathway called the JAK-STAT pathway, which is very important for HIV, because it is activated upon HIV infection. So, anything you can do to suppress it is a good thing, very simply. Basically, inhibition of the JAK-STAT pathway in addition could provide a mechanism to do several things. One, something we didn't expect, it could inhibit HIV replication in HIV-infected cells. And actually that was something we discovered for the first time: demonstrating this JAK inhibitor had intrinsic anti-HIV activity.

In addition, the JAK inhibitor renders bystander cells less susceptible to HIV infections by regulating the activation stage. In activation stage, basically the normal cells that are surrounding the infected cells become less susceptible to HIV, which is a good thing because it prevents the virus from spreading to these cells. It also prevents the recruitment of uninfected cells to the site of infection.

A really major mechanism of the JAK inhibitors is they reduce inflammation also. There are a whole bunch of pro-inflammatory cytokines that thrive when HIV infects the cells and JAK inhibitors can ablate these effects. This is not something new; we have known for some time the mechanism of these JAK inhibitors. They are used primarily for rheumatoid arthritis and autoimmune psoriasis. They are used for various cancers and one of them is actually approved for myelofibrosis. All these facts put together make these compounds amenable for testing to help suppress HIV and also reduce inflammation.

I think inflammation is a very important factor in HIV infection, not only at the site of infection, wherever active virus is, but also for cardiology; and as you know, there has been a strong relationship between the heart and HIV -- people even have sudden death. In a recently published paper that came out, people die from heart attacks or cardio disturbances because they're HIV infected. So, it is a good thing that these compounds could reduce the inflammation in addition to preventing the virus from replicating, preventing the virus from spreading and also suppressing virus replication at the cellular level unlike normal antiviral agents, which basically interfere with the virus machinery and ability to replicate themselves. Basically, after working on the virus, these JAK inhibitors also act on cellular mechanisms associated with inflammation.

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There are a lot of people involved in trying to cure HIV. They are actually activating the latently infected cells and trying to destroy them since they now become visible to the immune system -- trying to destroy the cells and the virus contained in these cells. Despite activating the virus from these cells, the cells are not totally destroyed; so all these approaches, in my personal opinion, will probably not work. So, I am concerned about this and I'm sure you've written about this before or you've spoken to other people. So, I'm thinking differently and during the Sitges meeting I was the only person talking about suppressing HIV rather than activating this virus.

We have in our body maybe 50 to 100 viruses right now and most of them are suppressed. They don't bother us and that's why we can live a normal life. When our immune system is debilitated, the viruses come out. For example, chicken pox infection is common when you're a kid, but the same virus becomes varicella-zoster when you're older. We have viruses all over our body, like we have bacteria too all over our body; so nothing's new there. My philosophy is to suppress, and end up with a "functional cure." That's what I'm interested in: a functional cure, rather than an eradication cure. This is going to be very hard to do. Even with the Berlin patient [Timothy Brown], as you well know, it's been extremely hard to prove a negative, i.e., that the patient is really cured and that there is no trace of virus in his body.

There is residual RNA or DNA present in the body of the Berlin patient that we don't quite understand. I'll call his cure a "functional cure," not actually a complete cure, despite what people may say. However, there is hope that you can actually do it and we would like to try to use the best JAK inhibitors. As I said, one of them is approved: Jakafi is approved by the FDA, which is used for myelofibrosis. Eventually, this drug will also be approved for rheumatoid arthritis, autoimmune psoriasis and also various other kinds of conditions. There are other drugs that are being developed in the same class for rheumatoid arthritis that will basically replace injectable anti-TNF-alpha therapy, which as you know can reduce inflammation, but with a number of side effects. So again, these are new modern drugs which are coming out that have this utility that we're trying to apply for HIV.

I was reading about a JAK inhibitor called tofacitinib, a drug made by Pfizer that got reviewed [in May] for a rheumatoid arthritis indication. I guess this drug will probably be approved by the FDA soon. It looks pretty good -- low side effect profile and BID [twice daily] dosing. I was looking at the in-vitro data you presented at the conference. The dose you used ranged from 0.02 to 0.3 µM. How does that dose translate if used in humans? Also, are you proceeding with studies in humans?

[Editor's note: Xeljanz (tofacitinib) was approved by the FDA to treat adults with moderately to severely active rheumatoid arthritis, in November 2012.]

These drugs are given as a dose of 20 mg per day -- very small pills, because at a higher dose they'd probably have some side effects. We will plan on using initially the smallest doses and they come in different sizes. I foresee using different inhibitors of different JAK pathways for patients who are infected with HIV. What we do now is that the JAK inhibitors could be dosed to provide blood levels in the nM range. As mentioned, one is already approved for chronic long term use in humans, which is important. Interestingly, some of these compounds, but not all of them, are CYP3A4 inhibitors, meaning they can actually boost protease inhibitors, for example. It's like ritonavir [Norvir] boosting. That's actually very interesting as well.

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