In this session, I ask Dr. Riddell to tell us about the drugs used to keep HIV infections in check, and thus, to keep patients healthy. He talks about the various categories of drugs, their side effects and the problems facing patients who must take them every day for the rest of their lives. He gives us a great deal of information and uses the technical terms of his medical specialty. For most of us, it is not terribly important that we know the details or that we remember the terms. At the conclusion of this part of my conversation with Dr. Riddell, I will post the list of the different categories of antiretroviral drugs for those of you who wish to do further research into them. It is important for all of us however, to understand the general idea behind anti-HIV drug therapy and that is not difficult at all. Let me give you a bit of information before we hear Dr. Riddell's account. We know how HIV reproduces and the goal of controlling an HIV infection is to interfere with that process of reproduction. Here is one of those schematic diagrams of the HIV life cycle. Let's go through it, as preparation for Dr. Riddell's description of the drugs. This large circular form at the bottom of the diagram represents part of the white blood cell that is the host for an HIV infection. The inner circle at the very bottom represents the cell's nucleus which contains its genetic material, the genes, made up of DNA. The smallest circle at the top left represents an HIV particle, a virus. It has an outer shell and an inner core which contains its genetic material, a small member of genes. HIV is called aretrovirus because its genes are made up of RNA. The RNA is represented by these red lines. The green circles in the spinal core represent the chemical and enzyme called reverse transcriptase, which is very important to the story. Here the virus attaches to the outer membrane of the cell and its genetic contents enter the cell. If a patient with HIV was given a drug that prevented the virus from attaching to the cell, that would be one way of protecting the infected person from an explosive growth of his or her infection. Once the virus attaches, it empties its contents into the cell. Here we see the RNA and the reverse transcriptase entering the cell. Now the reverse transcriptase does its work. Its work is to fashion a piece of DNA that copies the code of the RNA. Since the cell's genetic materials are DNA, this copy of the viral genetic code in its DNA form will enter the cell's nucleus and reproduce using the reproductive machinery of the nucleus. Here is the Viral RNA being transcribed into DNA with the help of the reverse transcriptase. And here is a representation of the Viral DNA already in the nucleus of the cell, ready to be reproduced. A drug that prevented the reverse transcriptase from doing this work accurately would protect the patient. Or if there were a drug that prevented the new DNA from integrating itself into the host cell's DNA, that too would be protective. If the viral DNA does in fact reproduce itself in the nucleus and become active, it begins to produce the building blocks, the proteins and new strings of RNA that will form new HIV. This is represented here by this group of blue circles and red lines, the viral proteins and RNA that will eventually be assembled to form the new HIV. The assembling process requires another chemical, an enzyme called protease. Again, if a drug were to block this part of the process, the patient would be protected from the expansion of his or her infection. If the process is not interrupted the virus reforms and leaves the cell. The process is called budding. If this is interrupted that too would protect the patient. Now let's listen in to the part of my conversation with Dr. Riddell in which he fills in the details of all of this. Here it is. Could you bring us up to speed on the various drugs that are available, the various drug categories that are available to treat HIV infection? And, with some simple explanation of how they work. >> Sure. So, we can kind of go through each category. I'd, I'll start with sort of the oldest drugs, that we've had to use are the nucleoside reverse transcriptase inhibitors or NRTIs. The first one of those drugs was AZT, or zidovudine, which was developed right here in Michigan. It was a chemotherapy drug that was on the shelf at the Detroit Medical Center that was discovered it had antiviral activity, so it was the very first drug we had. And the way these drugs work is they basically act as false nucleosides or nucleotides in the elongating DNA chain. So, as reverse transcriptase is making HIV DNA these drugs are inserted instead of a nucleotide like an A, C, T, or G, and then it causes premature chain termination, and that prevents replication from occurring. >> So the HIV is trying to make a copy of its, of its RNA to translate into, to, to translate into DNA, and the rever, the drug goes in there and messes up the copy. >> That's correct. Gums up the works. >> And so it doesn't work. >> That's right. that's right. So that's sort of the first and oldest group that we had. And after AZT, there were other drugs that categories such as upper view, CTC, zeretor D4T and the very first, when these drugs were first developed, we discovered that if you just use one drug it would lower the bit but after the purely time the viral load would rebound again because of resistance. So, one drug was not good enough. Two drugs were also not good enough. Same problem. So it wasn't until the next category called non-nucleoside reverse transcriptase inhibitors were developed and protease inhibitors where we were able to combine three drugs together to create a cocktail that suppressed the virus more completely. >> Did you just talk about the two additional kind of therapies or one additional category? >> So, two so far. >> Ok. >> So the non nucleoside reverse transcriptase inhibitors, they're drugs that bind the reverse transcriptase enzyme itself to inhibit its activity. The other category, the protease inhibitors, which interfere with the protease enzyme's activity, which is involved in post-translational modification of HIV proteins. >> Am I right in saying that, that that the DNA of the successfully formed. But the pieces of the final virus are not put together correctly? >> With the, for, for the protease inhibitor. >> These protease inhibitors, yeah. >> That's right. Yeah, that's that's where, that's the mechanism of action. That's where they're acting. >> Mm-hm. >> So those are sort of the first three categories that were developed. But since that time, there have been several other categories. And I may not have the exact chronology [LAUGH] correct, but- >> You're a doctor, not a historian. [LAUGH] That's right? >> [LAUGH] That's right. The next one I remember that was developed was a drug that was called a fusion inhibitor, or T-20, or Fuzion. And it was a synthetic peptide that bound to GP41, which a structure on the HIV capsid of, protein so by binding to GP 41 when HIV would come to bind to the CD4 cell to enter it. This drug would interfere with that process and so we would call that an attachment inhibitor. Fusion inhibitor is the other term for it. The problem with this drug is that it is injectable and patients frequently side effects at the injection site. Also very expensive drug to manufacture and so it's one that's hardly ever used. >> Is there only one fusion inhibitor? >> Only one, there was another fusion inhibitor that was in development but because there were so many issues with the first one, [LAUGH] and the, the second generation fusion inhibitors were, were never fully developed. >> Mm-hm. >> And marketed. The next category would be the CCR5 inhibitor, which is maraviroc and it was developed as, to exploit the CCR5 mutation that we described earlier. >> Right, we talked about that as being the mutation that the donor, the bone marrow donor had. >> Exactly. And the people who had this mutation are resistant to, to acquiring HIV infection. So, with that knowledge, we developed a, a drug that binds to CCR5 and inhibits HIV's attachment to the CCR5 co-receptor, by blocking that interaction it prevents HIV from entering the cell. The issues there are that HIV can use another co-receptor CXCR4 and get around that. Or it can actually mutate and get around the drug itself. Although that requires multiple steps and probably doesn't happen very often. But that's another, drug that can help prevent HIV entering the cell in the first place. So, that, that, that's another drug that's in our armamentarium. And I think that the newest drugs which have come around which are probably the most exciting are the integrase inhibitors or what they call a single strand transfer inhibitors. And they're drugs that inhibit HIV integration into the host cell genome. And, it turns out these drugs are very potent. They reduce the viral load very quickly and have relatively few side effects and drug interactions compared to some of the other, medications that are available. >> So, the new DNA is actually formed but somehow prevented from getting into the DNA of the nucleus. >> Exactly. There's another enzyme that's responsible for that transfer to occur. >> I see. >> And these [CROSSTALK]. >> Like clothing to grace? >> Exactly. These drugs are inhibiting, that enzyme from performing, it's function. All these drugs have their own sort of set of side of side effects and drawbacks. With the integrase inhibitors, it's a low genetic barrier to resistance that can be seen there. So in patients who are poorly adherent, resistance can develop. >> Very quick. >> More quickly. >> Are there new drug categories coming along? Yeah, there are a few that are in the pipeline,. There are drugs called maturation inhibitors which are able to inter, sort of intertercolate with the developing HIV capsid that's becoming ready to bud off the host cell. Those are in development. I think, you know, rather than new drug categories I think the really exciting research is coformulation of different drugs to make it easier for patients to take. Or reformulation of older drugs to make them less toxic. >> I see. >> So, for instance, tanofovir can be hard on the kidneys. It can cause kidney toxicity. they're, they're developing a new version of this drug, to be less nephrotoxic and actually penetrate into other cells better and so that's an exciting development. And then there's also ways of combing multiple drugs together now to make more single drug fixed dose condemnation pills. To make it much more easier for patients to take their regimens. >> From a patient's point of view, those are great, those are great developments. >> That's right. >> When they have them. >> Yeah, that's right. >> Thank you so much for joining us today, it's always very productive to listen to you. >> Oh, it's my pleasure.
