MDR HIV Treatment Approaches and Considerations for Therapeutic Adjustments

Therapy adjustments in MDR HIV are explored by Dr Sension.

Ryan Haumschild, PharmD, MS, MBA: You talked a lot about optimizing the medication regimen, and I’ve learned and known that’s essential to treatment success. We talked about promoting adherence in terms of making sure that we provide our patients with therapies they can take, and be consistent with, and maintain therapeutic drug levels. We know that several other factors are also important in reducing the spread of HIV [human immunodeficiency virus]. Some of these include immunological monitoring, such as the viral load and the CD4 count, and looking at resistance, and prompting intervention when treatment failure is identified, making sure we do that in a timely way. Dr Sension, could you discuss the optimal timeframe for performing this monitoring? What is your approach in deciding when a therapeutic adjustment may be necessary for a patient?

Michael Sension, MD: If I have somebody who’s viremic and I’m going to start them on a new regimen, I would bring them back at different time intervals for different reasons. For example, I might bring somebody back in a week or two just to see how they’re doing. Are they taking the medication? Are they tolerating it? Are they having any problems, do they have any questions? I may be more interested in assessing a virologic response perhaps in 2 to 4 weeks after they’ve been on the medication. If they’ve adhered to it well, if they’re tolerating the medication OK, then about a month later I might look to see, do I have a virologic response? I’ll continue to follow them closely, maybe a month after, until I get to where I’m hoping I’ll get, complete virologic suppression. Then I’ll follow them even more closely to make sure they maintain virologic suppression. Again, I might bring them in 1 or 2 weeks after making the change, then check laboratory test results a month later, then maybe a month later again, and then perhaps follow them closer in the next 6 to 9 to 12 months. As they demonstrate virologic suppression that’s durable and they’re doing well, then I might space those visits out further.

Ryan Haumschild, PharmD, MS, MBA: I think it’s helpful to hear the way you care for patients because it is important to make sure you identify early detection, but it doesn’t become all-consuming, where they can still have a good quality of life, even outside of this monitoring and dose adjustment. Dr Sension, you mentioned some exciting new therapies that have come out recently, and I think we’re all excited because anytime we can add new therapies that improve the lives of our patients, improve their clinical efficacy and outcomes, that’s something we want to rally around. My question is up until now, there were 2 available commercial options for heavily treatment-experienced adults with multidrug resistant HIV. The ones I typically think about are ibalizumab, which is the IgG4 monoclonal antibody, and the fostemsavir extended-release tablet, which is an HIV attachment inhibitor. If you could, review for our viewing audience the mechanism of action for each of those agents, and how do those mechanisms of action differ from what we think of as conventional HIV therapy?

Michael Sension, MD: Over the entire lifespan of our knowledge of HIV, we’ve attempted to understand how it works. By understanding the biology of HIV, we’ve been able to identify critical steps that are essential in HIV making a copy of itself, the HIV lifecycle. By understanding how it works, we then can develop medications to block these critical steps. The traditional or the more historic medications we’ve had have been blocking reverse transcriptase, whether they are nucleoside or non-nucleoside reverse transcriptase inhibitors. Then we were able to develop medications to block protease, and we called them protease inhibitors. Then we were able to develop medications to inhibit the integration of the HIV genome, to put it simply, into the host cell. We call those integrase inhibitors. More recently we’ve had drugs that we refer to as attachment inhibitors, which inhibit attachment. You just described a couple of them.

Ibalizumab is a monoclonal antibody. Again, we have to understand how HIV attaches. HIV attaches to a host cell through glycoprotein-120, as it is referred to, on the virus, and it attaches to the CD4 receptor of a host cell. When it attaches, it then induces a confirmational change of this CD4-GP120 attachment to allow for coreceptor binding, which is critical for the HIV to then fuse to the cell membrane and enter the cell. When GP120 attaches to the CD4 receptor, one can infuse a monoclonal antibody, which also can attach to this complex, and it inhibits through steric hindrance. It inhibits this confirmational change and does not allow for coreceptor attachment. It blocks the ability to attach and for the virus then to fuse and enter the cell, so it is an entry inhibitor in that mechanism.

Fostemsavir on the other hand attaches directly to the GP120 molecule on the viral surface, or there’s soluble GP120 that fostemsavir can bind to as well. Whereas ibalizumab attaches directly to the cell, fostemsavir attaches to the virus. Either way, it blocks the attachment then of GP120 to the CD4 receptor. Either you’re attaching to the cell in the way of ibalizumab and then inhibiting a confirmational change, which then would lead to coreceptor attachment and then fusion and cell entry, or you coat, if you will, the virus with a molecule, fostemsavir, which then inhibits the attachment. They operate in 2 very different ways, but the result is very similar. That is it inhibits the attachment and ultimate fusion and entry of the virus into the cell.

Ryan Haumschild, PharmD, MS, MBA: You did a great job giving that overview. I can tell you know your pharmacology, from a pharmacist, I want to give you a gold star on that one. I really appreciate you taking the time to discuss it because I think it’s great for our viewing audience to understand the unique mechanism of action and how it does a great job breaking through multidrug resistant HIV and providing great therapeutic impact.

Transcript edited for clarity.

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