HIV Pharmacology Quiz

HIV Drug Classes

• Nucleoside Reverse Transcriptase Inhibitors (NRTIs) are purine or pyrimidine derivatives. They either remove the 3'-hydroxyl group entirely or replace it with an azido group. These drugs are incorporated into DNA, causing chain termination due to the lack of the 3' hydroxyl group.
• All NRTIs are prodrugs that are converted to triphosphates.
• Resistance to NRTIs is common due to mutations in reverse transcriptase.
• Examples of NRTIs include Zidovudine (AZT), Didanosine (ddl), Lamivudine (3TC), Stavudine (d4T), Abacavir (ABC), Tenofovir disoproxil.

Tenofovir Disoproxil

• Tenofovir disoproxil is a prodrug designed to improve bioavailability.
• It's converted to tenofovir by an esterase, then further processed by cellular kinase to tenofovir diphosphate, the active form.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• First-generation NNRTIs (nevirapine, delavirdine, efavirenz) bind to RT at an allosteric site, disrupting the catalytic site.
• Second-generation NNRTIs (etravirine, rilpivirine) are more flexible and bind to the non-nucleoside inhibitory binding pocket (NNIBP).
• Delavirdine inhibits CYP3A4, while etravirine induces CYP3A4.
• Hypersensitivity reactions, such as skin rashes, are possible side effects of NNRTIs.

HIV Integrase Inhibitors

• These inhibitors likely bind via chelation to divalent cations (like Mn2+ and Mg2+) in the catalytic core domain of integrase.
• They shouldn't be taken with di- or trivalent cations.
• Elvitegravir metabolism is primarily through CYP3A4.
• It's often given in combination with emtricitabine, tenofovir disoproxil fumarate, and cobicistat (a CYP3A4 inhibitor).
• Cobicistat also inhibits p-gp, increasing tenofovir absorption.
• Examples of integrase inhibitors include raltegravir, elvitegravir, and dolutegravir.

HIV Protease Inhibitors

• HIV protease is a dimer, with each monomer containing two aspartate residues in its active site.
• Protease prefers cleaving amino acids on the proline and phenylalanine side.
• Protease inhibitors mimic transition states (TS) to inhibit the enzymatic action.
• Examples of protease inhibitors include Saquinavir, Ritonavir, Indinavir, Nelfinavir, Fosamprenavir, Tipranavir, Darunavir, Atazanavir, Lopinavir.
• Some protease inhibitors, such as Ritonavir, are substrates for or inhibitors of CYP3A4, especially ritonavir (irreversible). This can affect the metabolism of other drugs.

Fusion Inhibitors

• Enfuvirtide is a 36 amino acid peptide that mimics a portion of the HIV surface protein gp41.
• The inhibitor binds to a tryptophan-rich region of gp41, preventing conformational changes necessary for gp120 binding to CD4 receptors.
• Resistance to enfuvirtide can arise due to mutations in gp41.
• Maraviroc is a CCR5 inhibitor that blocks the CCR5 coreceptor. Viral tropism must be evaluated using a tropism assay.

Summary of HIV Drug Classes

• NRTIs, NNRTIs, HIV Integrase Inhibitors, HIV Protease Inhibitors, and Fusion Inhibitors are the most common classes of HIV drugs.