0:00 Anti-retrovirals are the cornerstone to treat patients with human immunodef 0:09 iciency virus 0:10 or HIV. 0:12 Anti-retrovirals work on different parts of the viral life cycle. 0:17 All patients with a HIV infection should begin anti-retroviral therapy as soon 0:23 as they are 0:23 ready, regardless of CD4 T cell count. 0:28 So let's recap their HIV life cycle to understand the pharmacotherapy the drugs 0:34 used to treat 0:34 HIV. 0:37 HIV targets the CD4 T cells, such as this cell here. 0:43 The CD4 T cell are the human immune cells. 0:48 The glycoproteins on the envelope of the HIV, GP120, binds to CD4 receptors, 0:55 together 0:56 with the co-receptors CCR5 and CXCR4 on the surface of T cells. 1:04 This allows fusion of the viral envelope with the cell membrane, which is 1:09 facilitated by 1:11 the glycoprotein GP41. 1:14 Fusion releases the capsid with the viral content, including the enzymes 1:19 necessary 1:20 for viral survival. 1:23 The third step reverse transcription involves the virus reading its own genetic 1:31 RNA material 1:33 and then making a DNA copy of it with its enzyme reverse transcriptase. 1:40 From a single-stranded viral RNA, the virus produces double-stranded viral DNA, 1:46 which 1:47 will be transported to the nucleus of the host cell via integrase. 1:53 This allows integration of the viral DNA with the host DNA, which is the fourth 2:00 step 2:01 in the HIV life cycle. 2:05 The HIV virus is now part of the cell, essentially, the CD4 T cell, and can use 2:11 the cell's own 2:12 machinery to create more of its genetic material and more of its structures in 2:18 order to make 2:19 more HIV viruses. 2:23 Transcription is where the host's own RNA polymerase reads the viral DNA, and 2:29 with that 2:30 information, it creates viral RNA, which is the genetic material, as well as 2:37 mRNA, which 2:38 will be used to create important proteins for the virus. 2:44 Translation is where the mRNA, that was just made, is read by the host's ribos 2:50 omes to create 2:51 proteins that will essentially create the enzymes and other proteins required 2:55 to make 2:56 a new HIV virus. 3:00 All these enzymes, proteins, and the viral RNA that is created gets assembled, 3:07 packaged 3:08 up, and released by the CD4 T cell. 3:13 Once released, there is a final process of maturation, where the HIV virus uses 3:17 its 3:17 enzyme again to form its final infective form. 3:24 While the virus replicates within the CD4 T cell, it actually injures the cell 3:30 itself, 3:31 and thus causes a slow reduction in the CD4 T cell count. 3:39 Antiretrovirals are the cornerstone to treat patients with HIV. 3:44 These antiretrovirals work on different parts of the viral life cycle we just 3:49 learned. 3:50 All patients should be started on antiretroviral therapy. 3:54 Let's learn about these antiretrovirals by looking at each step of the HIV life 4:00 cycle. 4:01 Now there are several antiretrovirals which block different stages of the 4:06 process of attachment 4:07 and entry. 4:09 The CD4 binding inhibitors, such as Ibar-Lizumab, monoclonal antibody, binds to 4:18 CD4 T cells, 4:20 inhibiting the HIV virus from entering the cell. 4:25 You also have CCR5 inhibitors, Maraviroc, which mechanism of action is, as the 4:34 name 4:35 suggests, it blocks the CCR5 co-receptor that is essential to cell infection 4:43 for some HIV 4:45 genotypes. 4:47 Common adverse effects of this drug include hepatotoxicity and rash. 4:54 There are also antiretrovirals which inhibit fusion, such as enfuviritide, 4:59 which mechanism 5:02 of action is it competitively binds to the viral protein GP41 and thereby 5:10 prevents fusion 5:12 of the virus enveloped with the cell. 5:17 This is an injection and so common adverse effects include localized skin 5:28 reaction. 5:30 Then you have the antiretrovirals that target reverse transcription. 5:35 Most of these drugs end in I and E, I, except two very important reverse 5:43 transcriptase inhibitors, 5:46 abacavir and tenofovir, which you have to know. 5:51 Now the two main types of reverse transcriptase inhibitors are the nucleoside 5:58 reverse transcriptase 6:01 inhibitors and the nucleotide reverse transcriptase inhibitors, and both work 6:08 to essentially 6:09 stop the enzyme reverse transcriptase and so stop the creation of DNA, the 6:19 viral DNA. 6:21 Other side reverse transcriptase inhibitors include abacavir, lambivudine and z 6:30 idovudine. 6:32 Essentially these drugs work as a thymine analog. 6:36 They incorporate into the viral DNA via reverse transcriptase, essentially 6:41 disrupting the 6:42 creation of the viral DNA and thus terminates the DNA chain. 6:49 Here you have the single viral RNA. 6:53 The reverse transcriptase helps create the viral DNA. 7:01 Nucleoside reverse transcriptase inhibitors such as abacavir acts as a thymine 7:06 analog, 7:06 disrupting this whole process, terminating the strand early. 7:12 Abacavir specifically is important to know because it is commonly used. 7:17 Other effects of abacavir include hypersensitivity reactions and so patients 7:22 with abacavir are 7:22 normally undergo genetic testing to exclude HLAB5701. 7:27 Abacavir also increases the risk of cardiovascular disease and so patients with 7:32 pre-existing 7:33 heart conditions, you must be careful. 7:37 Now the nucleotide reverse transcriptase inhibitors, the most important to know 7:43 is tenofovir. 7:44 Now the mechanism of action is that it is an adenosine nucleotide analog and 7:50 acts again 7:51 as a chain terminator when incorporated into the viral DNA. 8:00 Tenofovir comes into forms, tenofovir disoproxylfumarate, TDF and tenofovir all 8:09 ofinamide, TAF. 8:12 TAF and TAF are oral tablets. 8:16 They differ in half-life and effects on the kidneys and the bones. 8:23 Both TDF and TAF are taken up from the gut when you swallow the tablet and act 8:31 inside 8:32 the cells to inhibit reverse transcriptase as mentioned. 8:38 However, TDF has a shorter half-life and is taken up by the kidneys more 8:44 readily. 8:45 TDF is more present in plasma and because of this it is taken up by the kidneys 8:50 and increases 8:51 the risk of nephrotoxicity as well as bone toxicity leading to osteoporosis. 8:58 Those are the two main types of reverse transcriptase inhibitors, the nucle 9:01 otide and nucleoside 9:02 reverse transcriptase inhibitors. 9:05 However, there is another version that non-nucleoside reverse transcriptase 9:10 inhibitors and an example 9:12 of this is e-feverines. 9:16 The mechanism of action of e-feverines is that it binds directly to reverse 9:20 transcriptase 9:20 inhibiting its function rather than being an analog of some nucleotide nucleos 9:26 ide. 9:27 The adverse effects of this drug include neuropsychiatric effects, having a 9:33 hungover feeling, bizarre 9:35 and vivid dreams. 9:38 The reverse transcriptase inhibitors, all of them block this step here thus 9:43 preventing 9:43 viral DNA creation and therefore disrupts the viral life cycle. 9:52 Another class of antiretrovirals are the integrase inhibitors which block the 9:57 enzyme here. 9:58 HIV integrase inhibitors usually end with grovere and have been developed to 10:05 inhibit 10:05 the HIV enzyme integrase preventing the transfer and insertion of viral DNA to 10:12 the host cell 10:13 DNA. 10:15 Examples of integrase inhibitors include raltegravir and doltegravir. 10:22 The main side effect of raltegravir is myopathy as well as elevation in creatin 10:28 ine and doltegravir 10:29 it causes elevation in creatinine. 10:37 The next antiretroviral class are the HIV protease inhibitors. 10:42 The protease inhibitors usually end with novere and are designed to block the 10:47 activity of 10:49 the protease enzyme. 10:51 The inhibition of the viral protease here causes the inability of the virus to 10:58 cleave certain 10:59 proteins, to activate certain proteins and thus results in the generation of an 11:05 immature 11:06 non-infectious HIV virus. 11:10 The protease inhibitors usually require a booster, another agent such as ralteg 11:15 ravir 11:15 or cabissistat. 11:25 All protease inhibitors have the side effects of nausea, diarrhea, hyperlipid 11:30 emia, and insulin 11:31 resistance. 11:32 You can think of metabolic syndrome for protease inhibitors. 11:36 However, specifically, atazinovir causes hyperlipidemia and also requires gast 11:42 ric juices for its 11:44 absorption, so patients that use PPI should not. 11:51 Darunavir causes GI upset, lipodistrophe, hyperlipidemia, and increases myocard 11:56 ial infarction risk. 12:02 So those are some major classes of antiretroviral drugs. 12:07 Other treatments that patients with HIV require include possibly prophylaxis 12:11 for opportunistic 12:13 infections. 12:15 Vaccination is very important. 12:18 HIV patients can have live vaccines, usually only if the CD4 cell count is 12:21 greater than 12:22 200 cells per millimeter cubed. 12:27 If the CD4 cell count is less than 200, really, they are at risk of a lot of 12:32 opportunistic 12:32 infections, and so bactrim is usually used as prophylaxis against PJP and tox 12:39 oplasmosis 12:40 infections. 12:42 Firstly, if the CD4 cell count was less than 50, azithromycin was used for myob 12:50 acterium 12:50 complex. 12:51 However, my understanding is this is not used anymore. 12:56 Finally, patients with latent TB who also have HIV require TB treatment. 13:04 When starting patients with HIV treatment, the antiretrovirals, it is important 13:10 to look 13:10 out for immune reconstitution syndrome, or IRIS for short. 13:15 This occurs within a few months of starting antiretroviral therapy, because 13:20 what happens 13:20 is when you treat patients with antiretroviral therapy, the CD4 cell count 13:27 returns. 13:28 It gets replenished, basically, and so as a result, you get this inflammatory 13:33 state as 13:33 the immune system begins to regain its function and attacks any infection it 13:39 has in the body. 13:40 And so, IRIS, with IRIS, you develop bad infective symptoms as a result. 13:49 To conclude, the antiretrovirals used for HIV are used in combination, so for 13:55 example, 13:56 a reverse transcriptase inhibitor with an integrase inhibitor. 14:03 And that concludes the video on HIV pharmacology. 14:06 In this video, we looked at the HIV lifecycle, and we looked at how the antiret 14:11 rovirals target 14:12 different parts of the HIV lifecycle. 14:16 The important ones to remember include the reverse transcriptase inhibitors, 14:21 integrase 14:21 inhibitors, and the protease inhibitors. 14:24 Thank you for watching. 14:36 [MUSIC]
