Anti-retrovirals are the cornerstone to treat patients with human immunodeficiency virus or HIV. Anti-retrovirals work on different parts of the viral life cycle. All patients with a HIV infection should begin anti-retroviral therapy as soon as they are ready, regardless of CD4 T cell count.
So let's recap the HIV life cycle to understand the pharmacotherapy, the drugs used, to treat HIV. HIV targets the CD4 T cells such as this cell here. The CD4 T cell are the human immune cells.
The glycoproteins on the envelope of the HIV, GP120, binds to CD4 receptors, together with the co-receptors CCR5 and CXCR4 on the surface of T cells. This allows fusion of the viral envelope with the cell membrane, which is facilitated by the glycoprotein GP41. Fusion releases the capsid with the viral content, including the enzymes necessary for viral survival.
The third step, reverse transcription, involves the virus reading its own genetic RNA material. and then making a DNA copy of it with its enzyme reverse transcriptase. From a single-stranded viral RNA, the virus produces double-stranded viral DNA, which will be transported to the nucleus of the host cell via integrase. This allows integration of the viral DNA with the host DNA, which is the fourth step in the HIV.
life cycle. The HIV virus is now part of the cell, essentially the CD4 T cell, and can use the cell's own machinery to create more of its genetic material and more of its structures in order to make more HIV viruses. Transcription is where the host's own RNA polymerase reads the viral DNA, and with that information, it creates viral RNA, which is the genetic material, as well as mRNA, which will be used to create important proteins for the virus. Translation is where the mRNA that was just made is read by the host's ribosomes to create proteins that will essentially create the enzymes and other proteins required to make a new HIV virus.
All these enzymes proteins and the viral RNA that is created gets assembled, packaged up and released by the CD4 T cell. Once released, there is a final process of maturation where the HIV virus uses its enzyme again to form its final infective form. While the virus replicates within the CD4 T cell, it actually injures the cell itself. and thus causes a slow reduction in the CD4 T cell count. Antiretrovirals are the cornerstone to treat patients with HIV.
These antiretrovirals work on different parts of the viral life cycle we just learned. All patients should be started on antiretroviral therapy. Let's learn about these antiretrovirals by looking at each step of the HIV life cycle. Now there are several antiretrovirals which block different stages of the process of attachment and entry.
The CD4 binding inhibitors such as ibalizumab, the monoclonal antibody, it binds to CD4 T cells inhibiting the HIV virus from entering the cell. You also have CCR5 inhibitors Maraviroc, which mechanism of action is as the name suggests it blocks the CCR5 co-receptor that is essential to cell infection for some HIV genotypes. Common adverse effects of this drug include hepatotoxicity and rash.
There are also antiretrovirals which inhibit fusion. such as enfovirtide, which mechanism of action is it competitively binds to the viral protein GP41 and thereby prevents fusion of the virus envelope with the cell. This is an injection and so common adverse effects include localized skin reaction.
Then you have the antiretrovirals that target reverse transcription. Most of these drugs end in I-N-E, INE, except two very important reverse transcriptase inhibitors, abacavir and tenofovir, which you have to know. Now, the two main types of reverse transcriptase inhibitors are the nucleoside reverse transcriptase inhibitors and the nucleotide reverse transcriptase inhibitors.
And both work to essentially stop the enzyme reverse transcriptase and so stop the creation of DNA, the viral DNA. Nucleoside reverse transcriptase inhibitors include abacavir, lamivudine, and Zidovudine. Essentially these drugs work as a thymine analog. They incorporate into the viral DNA via reverse transcriptase, essentially disrupting the creation of the viral DNA and thus terminates the DNA chain. Here you have the single viral RNA.
The reverse transcriptase helps create the viral DNA. Nucleoside reverse transcriptase inhibitors such as abacavir act as a thiamine analog, disrupting this whole process, terminating the strand early. Abacavir specifically is important to know because it is commonly used.
Side effects of abacavir include hypersensitivity reaction, and so patients with abacavir normally undergo genetic testing to exclude HLA-B5701. Abacavir also increases the risk of cardiovascular disease, and so patients with pre-existing heart conditions, you must be careful. Now, the nucleotide reverse transcriptase inhibitors, the most important to know is tenofovir.
Now, the mechanism of action is that it is an adenosine nucleotide analog and acts again as a chain terminator when incorporated into the viral DNA. Tenofovir comes in two forms, tenofovir disoproxil fumarate, TDF, and tenofovir alafenamide, TAF. TDF and TAF are oral tablets. They differ in half-life and effects on the kidneys and the bones.
Both TDF and TAF are taken up from the gut when you swallow the tablet. and act inside the cells to inhibit reverse transcriptase as mentioned. However, TDF has a shorter half-life and is taken up by the kidneys more readily. TDF is more present in plasma and because of this, it's taken up by the kidneys and increases the risk of nephrotoxicity as well as bone toxicity leading to osteoporosis.
Those are the two main types of reverse transcriptase inhibitors. The nucleotide and nucleoside reverse transcriptase inhibitors. However, there is another version, the non-nucleoside reverse transcriptase inhibitors. And an example of this is efevirenz.
The mechanism of action of efevirenz is that it binds directly to reverse transcriptase inhibiting its function, rather than being an analog of some nucleotide, nucleoside. The adverse effects of this drug include neuropsychiatric effects, having a hungover feeling, bizarre and vivid dreams. The reverse transcriptase inhibitors, all of them, block this step here, thus preventing viral DNA creation and therefore disrupts the viral life cycle.
Another class of... antiretrovirals are the integrase inhibitors which block the enzyme here. HIV integrase inhibitors usually end with gravir and have been developed to inhibit the HIV enzyme integrase, preventing the transfer and insertion of viral DNA to the host cell DNA. Examples of integrase inhibitors include raltegravir and doltegravir.
The main side effect of raltegravir is myopathy as well as an elevation in creatinine. and daltegravir causes elevation in creatinine. The next antiretroviral class are the HIV protease inhibitors. The protease inhibitors usually end with navir and are designed to block the activity of the protease enzyme. Inhibition of the viral protease here causes the inability of the virus to cleave certain proteins to activate certain proteins and thus results in the generation of an immature non-infectious HIV virus.
The protease inhibitors usually require a booster, another agent such as ritonavir or cobicistat. Examples of protease inhibitors include atazanavir and darunavir. All protease inhibitors have the side effects of nausea, diarrhea, hyperlipidemia, and insulin resistance.
You can think of metabolic syndrome for protease inhibitors. However, specifically, atazanavir causes hyperlipidemia and also requires gastric juices for its absorption. So patients that use PPI should not. Darunavir causes GI upset.
lipodystrophy, hyperlipidemia, and increases myocardial infarction risk. So those are some major classes of antiretroviral drugs. Other treatments that patients with HIV require include possibly prophylaxis for opportunistic infections.
So vaccination is very important. HIV patients can have live vaccines usually only if the CD4 cell count is greater than 200 cells per millimeter cubed. If the CD4 cell count is less than 200 really they're at risk of a lot of opportunistic infections and so Bactrim is usually used as prophylaxis against PJP and toxoplasmosis infections.
Previously if the CD4 cell count was less than 50 Azithromycin was used for myobacterium avium complex. However, my understanding is this is not used anymore. Finally, patients with latent TB who also have HIV require TB treatment.
When starting patients with HIV treatment, the antiretrovirals, it is important to look out for immune reconstitution syndrome, or IRIS for short. This occurs within a few months of starting antiretroviral therapy. Because what happens is when you treat patients with antiretroviral therapy, the CD4 cell count returns. It gets replenished, basically.
And so as a result, you get this inflammatory state. As the immune system begins to regain its function, it attacks any infection it has in the body. And so with iris, you develop...
bad infective symptoms as a result. To conclude, the antiretrovirals used for HIV are used in combination. So for example, a reverse transcriptase inhibitor with an integrase inhibitor.
And that concludes the video on HIV pharmacology. In this video, we looked at the HIV life cycle and we looked at how the antiretrovirals target different parts of the HIV life cycle. The important ones to remember include the reverse transcriptase inhibitors, integrase inhibitors, and the protease inhibitors.
Thank you for watching.