PHAR2210 Foundations of Pharmacology Lecture 20 Anti-HIV Drugs PDF

PHAR2210 Foundations of Pharmacology Lecture 20 Anti-HIV drugs Dr Ricky Chen Chapter 53, Rang & Dale's Pharmacology (Tenth Edition, 2023)  Learning outcomes After completing this lecture, you should be able to describe the origin, structure, and life cycle...

PHAR2210 Foundations of Pharmacology Lecture 20 Anti-HIV drugs Dr Ricky Chen Chapter 53, Rang & Dale's Pharmacology (Tenth Edition, 2023)  Learning outcomes After completing this lecture, you should be able to describe the origin, structure, and life cycle of HIV and list important proteins involved in HIV-host cell interaction describe three anti-HIV drug classes in terms of pharmacokinetics, mechanism of action, and adverse effects and explain the use of pharmacokinetic enhancer in anti-HIV treatment explain the difference in toxicity between tenofovir alafenamide and tenofovir disoproxil in the context of pharmacokinetics describe anti-HIV drug development and treatment regimens list the modes of HIV transmission and relevant prevention strategies describe the differences between PrEP and PEP as HIV prevention strategies Core concepts of pharmacology pharmacodynamics pharmacokinetics Drug-target Drug target Steady-state Drug absorption Drug bioavailability interaction concentration Mechanism of Structure-activity Drug distribution Volume of distribution drug action relationship Zero- and first- order kinetics Drug metabolism Drug clearance Affinity Drug selectivity Drug elimination Drug elimination half-life Potency Efficacy DRUG Dose/concentration- Drug tolerance response relationship Therapeutic index Adverse drug reaction Individual variation Adapted from Guilding et al. (2023) Defining and Drug interaction in drug response unpacking the core concepts of pharmacology: A global initiative. British Journal of Pharmacology, 1-18. Patient outcomes https://doi.org/10.1111/bph.16222  First official reporting of AIDS 1981 a cluster of cases of pneumocystis carinii pneumonia in five young, previously healthy gay men in LA fungal infection caused by Pneumocystis jirovecii a cluster of cases of Kaposi’s Sarcoma among gay men in New York and California cancer affecting the skin and mucous membranes - viral infection caused by human herpesvirus 8 epidemiological investigations → low CD4+ T cell counts and acquired immune deficiency A Timeline of HIV and AIDS - https://www.hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline/  The origin of HIV originated from simian immunodeficiency virus (SIV) from primates to humans - preparation and consumption of bushmeat? earliest known case of HIV-1 infection a 1959 plasma sample (Democratic Republic of Congo) international movement sexual practices intravenous drug use blood products has spread globally Sharp and Hahn (2011)  HIV1 and HIV2 HIV-1: first isolated in 1983 (Barré-Sinoussi et al., 1983) Françoise Barré-Sinoussi (shared the 2008 Nobel Prize in Physiology or Medicine) HIV-2: first isolated in 1986 (Clavel et al., 1986) and is mostly limited to West Africa Peruski et al. (2020)  The structure of a HIV virion The HIV-1 genome is ~ 9 kb (human genome ~ 3 billion bp) Rossi et al. (2021) gag gag polyprotein matrix (MA), capsid (CA), nucleocapsid (NC), P6 pol pol polyprotein protease, reverse transcriptase, integrase env env polyprotein gp120, gp41 other six genes accessory and regulatory proteins  The HIV life cycle and anti-HIV drug classes 5 binding 1 maturation 5 2 fusion 2 budding & release 1 uncoating assembly reverse 3 3 translation transcription 4 4 integration transcription Barré-Sinoussi et al. (2013)  HIV-host cell interaction A. HIV: the env complex (a trimer of gp120-gp41) host cell: CD4 and CCR5 (C-C chemokine receptor 5; initial infection) / CXCR4 (C-X-C chemokine receptor 4; advanced disease) B. gp120-CD4 interaction → expose bind site for coreceptor (CCR5 or CXCR4) C. coreceptor binding → further conformational changes → expose gp41 D. - F. the fusion process slow T cell depletion leads to 'immune deficiency’ → unable to fight against otherwise rare infections (opportunistic infections) persistent viral replication impair tumour immunosurveillance Lobritz et al. (2010) HIV reverse transcriptase heterodimer the p66 subunit - catalytic role (polymerase and ribonuclease) the p51 subunit - structural role 2. ribonuclease (RNase H) - degrades RNA only if in the form of an RNA-DNA duplex 1. RNA-dependent DNA polymerase: ssRNA → ssDNA 3. DNA-dependent DNA polymerase: ssDNA → dsDNA Sarafianos et al. (2009)  HIV reverse transcriptase inhibitors nucleoside reverse transcriptase inhibitors (NRTIs) analogues of adenosine, cytidine, guanosine, or thymidine phosphorylated to form a triphosphate - incorporated into ssDNA to terminate elongation first drug (zidovudine or azidothymidine; FDA, 1987) Truvada emtricitabine/tenofovir disoproxil fumarate* Descovy emtricitabine/tenofovir alafenamide* GI disturbance, e.g., nausea, vomiting CNS effects, e.g., dizziness Goodman & Gilman's The Pharmacological Basis of Therapeutics (13th edition, 2018)  HIV reverse transcriptase inhibitors tenofovir disoproxil* phosphorylation deoxyadenosine deoxyadenosine triphosphate tenofovir alafenamide* phosphorylation phosphorylation tenofovir tenofovir monophosphate tenofovir diphosphate  TDF and TAF Truvada - emtricitabine 200 mg/tenofovir disoproxil fumarate (TDF)* 300 mg, daily Descovy - emtricitabine 200 mg/tenofovir alafenamide (TAF)* 25 mg, daily TDF and TAF are prodrugs of tenofovir - ↑ oral absorption converted to tenofovir at different locations (plasma vs. intracellular) renal toxicity and ↓ bone mineral density GI tract plasma lymphocytes tenofovir tenofovir tenofovir TDF tenofovir monophosphate diphosphate TDF TAF TAF TAF inhibit HIV reverse transcriptase  HIV reverse transcriptase inhibitors non-nucleoside reverse transcriptase inhibitors (NNRTIs) distinct binding site – a hydrophobic pocket in the p66 subunit o conformational change → inhibit enzyme activity six FDA approved drugs - first drug approved in 1996 rilpivirine Goodman & Gilman's The Pharmacological Basis of Therapeutics (13th edition, 2018)  HIV protease inhibitors HIV protease homodimer of two 99-amino acid monomers cleaves the Gag-Pol fusion polyprotein → into individual proteins HIV protease inhibitors (PIs; -navir) ten PIs approved by the FDA - most are peptidomimetics o first PI (saquinavir) approved by the FDA in 1995 combination antiretroviral therapy - NRTI + PI CYP3A4-mediated metabolism o boosted PI - a PI + low dose ritonavir* (a potent CYP3A4 inhibitor) insulin resistance hyperlipidemia cardiovascular disease A: protease only; B: inhibitor-bound [Hornak et al. (2006)]  HIV integrase inhibitors HIV integrase a 288-amino acid protein - integrate the proviral DNA into the host cell genome HIV integrase strand transfer inhibitors (INSTIs; -tegravir) bind to integrase and prevent DNA strand transfer elvitegravir* (FDA, 2012; fixed-dose combination only) o elvitegravir*/cobicistat*/emtricitabine/tenofovir disoproxil fumarate* cabotegravir (FDA, 2021; with rilpivirine [a NNRTI]) o extended-release injectable formulation GI disturbance, e.g., nausea, vomiting CNS effects, e.g., dizziness Craigie (2018) What is the clinical use of cobicistat here? Anti-HIV drug development treat complications from opportunistic infections before 1987 single drug - NRTI toxicity and resistance dual drugs - NRTIs multidrug resistance multiple pills and varying dosing frequency triple drugs - NRTIs + PI NRTIs + (NNRTI or boosted PI) HAART (highly active retroviral therapy) NRTIs + INSTI single-pill fixed-dose combination  HIV treatment HIV/AIDS is now a manageable chronic disease - life-long ART viral suppression (< 200 copies/ml) undetectable levels of viral load (< 20 copies/ml) = untransmittable (U=U) Initiation of treatment role of CD4+ cell count (< 350) in decision-making has changed immediately following HIV diagnosis Antiretroviral regimens INSTI-based (e.g., Stribild®) NNRTI-based (e.g., Atripla®) PI-based Mutations and (multi)drug resistance  From HIV treatment to HIV prevention mode of transmission unprotected sexual contact Use condoms - highly effective in preventing HIV transmission and certain STIs Treatment as prevention (TasP) - initiation of ART in seropositive individuals PrEP (pre-exposure prophylaxis) PEP (post-exposure prophylaxis) blood-borne exposure needle and syringe programs perinatal transmission PrEP HIV screening and initiation of ART CDC - avoid breastfeeding completely Ghosn et al. (2018)  HIV prevention - PrEP and PEP PrEP (pre-exposure prophylaxis) PEP (post-exposure prophylaxis) individuals at high risk of infection and tested occupational and non-occupational settings HIV-negative prior to initiation known or potential HIV exposure - initiate within 72 hours taken daily; follow-up, HIV test, and 2 or 3-drug regimen - daily for 28 days prescription every three months Truvada® HIV-1 treatment (FDA, 2004; combined with a NNRTI or a PI) HIV prevention (FDA, 2012) o ~ $1000 → ~ $40 per month following PBS listing (2018) delisted in 2020; generic brands on the PBS Descovy® FDA, 2019