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. Author manuscript; available in PMC: 2017 Feb 1.
Published in final edited form as: Semin Oncol. 2015 Sep 8;43(1):173–188. doi: 10.1053/j.seminoncol.2015.09.011

Table 2.

United States Food and Drug Administration approved targeted antiretroviral agents for the control of HIV

Class Mechanism of action Mechanism of resistance* Specific agents
Fusion/Entry Inhibitors Synthetic peptide corresponding to a region of the HIV envelope protein, gp41. Inhibits gp41-mediated virus entry. HIV mutations leading to amino acid substitutions in positions 36–38 in HIV gp41. Enfuvirtide (T20)
Imidazopyridine CCR5 ligand that alters conformation of extracellular loops (host targeted antiviral). Inhibits HIV binding and fusion to CCR5; active against CCR5-tropic HIV-1. HIV cell entry through CXCR4 co-receptors. HIV gp120 V3 loop mutations leading to HIV binding to CCR5. Maraviroc
Nucloside Reverse Transcriptase inhibitors (NRTIs) Deoxynucleoside analogue, active metabolites are competitive substrate inhibitors, incorporation by HIV reverse transcriptase leads to chain termination. HIV reverse transcriptase (RT) inhibitors’ mutations that lead to discrimination against select triphosphate derivatives of NRTIs (i.e. M184V interferes with binding to lamivudine or emtricitibine triphosphate).
Acquisition of thymidine analogue resistance mutations in RT that allow for excision of 3′ chain terminators (mechanism for zidovudine, stavudine, and tenofovir resistance).		 dTTP competitors:

  • Stavudine

  • Zidovudine

dCTP competitors:

  • Emtricitabine

  • Lamivudine

dATP competitor:

  • Didanosine

    dGTP competitor:

  • Abacavir

  • Tenofovir
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Direct inhibitors of HIV reverse transcriptase through interaction with p66 subunit of HIV-1 reverse transcriptase. Mutations in the NNRTI binding pocket (i.e. K103N) of HIV-1 reverse transcriptase that inhibit or modify interactions with NNRTIs.

  • Efavirenz

  • Etravirine

  • Nevirapine

  • Rilpivirine
Integrase Strand Transfer Inhibitors (INSTIs) Interfaces with HIV- Integrase catalytic core domain as well as divalent cationic co- factors (Mg2+ or Mn2+), inhibiting the catalytic activity required for transfer of HIV cDNA. Mutations in HIV-1 Integrase catalytic core domain (especially Q148H and N155H) that affect INSTI interactions. Q148H plus secondary HIV integrase mutations increase INSTI resistance.

  • Dolutegravir

  • Elvitegravir

  • Raltegravir
Protease Inhibitors (PI) Bind to Asp residues in the protease binding site, inhibiting the proteolytic cleavage of HIV polypeptides required for viral maturation and assembly. Darunavir also inhibits protease dimerization. Mutations in the HIV protease that lead to a conformational change and lower affinity for PI in relation to other HIV polyprotein substrates. Most major mutations occur at the HIV protease catalytic site (i.e. V82F/I84V double mutation), although distal site mutations may also lead to resistance, notably L90M occurs at the PI dimerization interface. Peptomimetics:

  • Atazanavir

  • Indinavir

  • Lopinavir

  • Ritonavir

  • Saquinavir

Non-peptidic:

  • Darunavir

  • Fosamprenavir

  • Nelfinavir

  • Tipranavir

Specific mutations do not necessarily lead to cross-resistance for an entire class of antiretroviral agents, and are sometimes agent specific. Some anti-retroviral agents have been designed to address common mechanisms of resistance noted in the same class. Selection of effective antiviral therapy in patients with resistant HIV generally requires expert input from infectious disease physicians and pharmacologists.