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Anti-HIV Agents: Entry Inhibitors – Antiviral Drugs

by Pravin Shukle, MD

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    00:00 So let’s talk HIV agents now and let’s focus on the entry inhibitors.

    00:05 So you can see why me talking about the molecules is important because we classify our drugs based on the molecules that they attached to.

    00:14 So let’s talk first about the Gp41 inhibitors.

    00:17 Now the Gp41 inhibitors are a very effective drugs.

    00:21 The prototypical one in this drug class is Enfuvirtide.

    00:25 Now, the downside and I’ll say it right up front incredibly expensive.

    00:30 So very few of patients in the United States can afford to get this medication.

    00:35 Fortunately, if you’re in Canada or in Europe and you have a socialized health care system, you can actually get this medication for your illness.

    00:43 Now it is little used in the United States due to its prize.

    00:48 The other downside of this particular medication is that it’s injectable.

    00:52 However, this is a favorite topic for exam questions and I want you to know this drug particularly well.

    00:58 This is one of the reasons why I put it at the top of your list.

    01:02 The mechanism of action is that it binds to the Gp41 molecule and it interferes with the ability to create an entry pore for that virus or for the capsid.

    01:14 Now, I want to point out that this is going to be an exam question.

    01:19 It’s active against HIV-1 only.

    01:23 Now one of the adverse events that you have to be particularly aware of are injection site reactions.

    01:29 From a clinical point of view almost all of these drugs that are injectable have some kind of element of injection site reactions to them.

    01:37 Now, that’s not going to be on the exam question, what will be on the exam questions is cough, dyspnea, and arthralgia.

    01:43 So think about that triumvirate when you’re talking about Enfuvirtide.

    01:48 This is something that’s a common, common question.

    01:51 The next category of drugs are the CCR5 inhibitors.

    01:55 Remember what CCR5 is, I just spoke about it in the last section.

    02:01 CCR5 is a transmembrane receptor that’s involved in the fusion or binding of the HIV envelope to the mammalian cell membrane.

    02:12 Now these drugs like maraviroc, vicriviroc, cenicriviroc, bind to CCR5, it targets that particular molecule.

    02:22 Now if you have a cell that binds with Gp120 and is unable to bind with CCR5, you can’t get entry of the virus into the cell.

    02:32 Now one of these drugs, Cenicriviroc also targets another receptor complex called the CCR2 complex.

    02:41 That’s a little complicated but if you just remember that C comes before M and V so CCR2 comes before CCR5 alphabetically, that’s how I remember which one does what.

    02:54 Now, if the HIV particle uses the CXCR4 receptor, remember the CXCR4 receptor looks just like the CCR5 receptor, these agents don’t work.

    03:05 So the CCR5 antagonists, like their names, are only active against CCR5.

    03:11 If a virus has CXCR4, this drug won’t work so we have to do a Trofile assay on particles on the patient’s blood to see if these particular agents will work.

    03:25 Now in terms of resistance, the nice thing about these agents is that there’s not really a lot of cross-resistance between these agents and others.

    03:34 We will sometime see resistance of the virus through a mutation in the env gene in the virus itself.

    03:42 Now in terms of Maraviroc, there are side effects.

    03:45 It can cause some serious life-threatening side effects which include hepatitis and can include allergic reactions.

    03:53 Now I just want to give you a little clue or a little help on your exams.

    03:59 Generally speaking, almost all drugs can cause a hepatitis or an allergic reaction.

    04:06 So if you’re not sure how to pick the answer in a question, sometimes you can actually put these down and play the odds and still get it right.

    04:16 Let’s move on to the Gp120 binders.

    04:19 Remember that Gp120 is a molecule or a protein that’s on the surface of the HIV particle.

    04:26 Now, one of the most commonly known of these drugs is fostemsavir. It targets a highly conserved protein and the resistance it should be low. Initial studies indicate that that is the case.

    04:41 Now this is a prodrug of another drug that is commonly being used in practice today. So remember that this drug does have to be converted from the original to the active component. Finally, we have the CD4 binders. This is the last category in our Entry Inhibitors on my list, but I do want to point out that as many molecules there are on the surface of the HIV particle, there are probably going to be drug categories coming up in the future.

    05:09 So, even though this is being made in the early 21st century, this lecture, it still may be relevant, you know, 50 years from now because every single particle is probably going to have a drug attached to it. So just keep that in mind. Now moving back to the CD4 antagonists, this is an exciting area because as I've told you probably 100 times in these lectures, the new era of pharmacology is upon us and it's not really pharmacology, it's immunology. And we're using these monoclonal antibodies to target very specific receptors either on the HIV particle or on the million cell. Now, this drug is called ibalizumab. Mab refers to monoclonal antibody so you know that it's a) going to be very expensive and b) probably pretty effective. This was approved in 2019 for multidrug-resistant HIV. It is a monoclonal antibody and it's a fully humanized monoclonal antibody. How do you know that just by looking at the drug name? If you look at the name, it ends with umab. The mab stands for monoclonal antibody. The u or said u stands for fully humanized. So we know right away just looking at this drug that it's a fully humanized monoclonal antibody. This monoclonal antibody binds to the CD4 receptor on the surface of the CD4 cell. Now, there is a study that had come out in 2019 which showed that at 48 weeks, 59% of patients achieved viral suppression which was shocking. You know none of us expected these kinds of numbers.

    06:55 So it's a very exciting time to see that high level of viral suppression in our patients. This drug has to be administered by healthcare professionals every 14 days. So in our HIV clinics in Ottawa, we have patients getting it through nurse-administered injections.


    About the Lecture

    The lecture Anti-HIV Agents: Entry Inhibitors – Antiviral Drugs by Pravin Shukle, MD is from the course Antimicrobial Pharmacology.


    Included Quiz Questions

    1. HIV-1 infection
    2. HIV-2 infection
    3. HIV-1 and hepatitis C virus infection
    4. HIV-1 and hepatitis B virus infection
    5. HIV-1 and HIV-2
    1. Trofile assay
    2. Western blot
    3. Enzyme-linked immunosorbent assay
    4. Fluorescence in situ hybridization
    5. G6PD assay
    1. Temsavir
    2. Maraviroc
    3. Vicriviroc
    4. Cenicriviroc
    5. Tenofovir
    1. Ibalizumab
    2. Rituximab
    3. Galcanezumab
    4. Infliximab
    5. Ustekinumab

    Author of lecture Anti-HIV Agents: Entry Inhibitors – Antiviral Drugs

     Pravin Shukle, MD

    Pravin Shukle, MD


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