Antiretroviral Therapy
Antiretroviral therapy combines drugs targeting HIV reverse transcriptase, integrase, and protease to achieve viral suppression and immune reconstitution.
Overview
HIV antiretroviral therapy (ART) has transformed HIV from a fatal disease to a manageable chronic condition. Modern ART combinations suppress viral load to undetectable levels, restore immune function (CD4 T cells), prevent AIDS-defining illnesses, and prevent HIV transmission. Current guidelines recommend ART for all HIV-infected persons regardless of CD4 count.
HIV Life Cycle and Drug Targets
HIV replication involves: attachment → fusion → reverse transcription → integration → transcription → assembly → budding/maturation. Each step offers potential drug targets.
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs/NtRTIs)
NRTIs are prodrugs activated by intracellular phosphorylation to triphosphates that compete with natural dNTPs and terminate reverse transcription (chain terminators). They are the backbone of all ART regimens.
- Tenofovir (two forms: TDF = tenofovir disoproxil fumarate; TAF = tenofovir alafenamide): Adenosine analog. TAF has less renal and bone toxicity than TDF due to more efficient intracellular delivery.
- Emtricitabine (FTC): Cytidine analog; usually combined with tenofovir (Truvada, Descovy)
- Abacavir (ABC): Guanosine analog; associated with HLA-B*5701-mediated hypersensitivity reaction (test before prescribing — black box warning)
- Lamivudine (3TC): Widely used; dual activity against HBV
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTIs bind an allosteric site on HIV reverse transcriptase (non-competitive), causing conformational change that reduces polymerase activity. They do NOT require intracellular phosphorylation.
- Efavirenz: CNS side effects (vivid dreams, dizziness), CYP3A4/2B6 inducer
- Rilpivirine: Better-tolerated; requires food for absorption; must not be used with PPIs
- Doravirine: Newer, favorable drug interaction profile
Integrase Strand Transfer Inhibitors (INSTIs)
INSTIs block HIV integrase from inserting viral cDNA into the host chromosome. Preferred first-line agents due to high efficacy and excellent tolerability.
- Bictegravir (in Biktarvy = BIC/TAF/FTC): High barrier to resistance; once-daily
- Dolutegravir (in Triumeq, Dovato): Very high barrier to resistance; used in children and pregnancy
- Raltegravir: First approved INSTI; BID dosing; lower barrier to resistance
Protease Inhibitors (PIs)
PIs inhibit HIV protease, preventing cleavage of Gag-Pol polyprotein precursor and producing immature, non-infectious virions. All current PIs are co-formulated with ritonavir or cobicistat (pharmacokinetic boosters — CYP3A4 inhibitors) to increase PI plasma levels. Darunavir/ritonavir or /cobicistat: high genetic barrier, preferred PI component.
Current First-Line Regimen
Bictegravir/TAF/FTC (Biktarvy) or dolutegravir + TAF/FTC (Triumeq or Dovato) — single-tablet, once-daily, high efficacy, high barrier to resistance.
Key Takeaways
- ART combines drugs from different classes targeting reverse transcription, integration, and maturation
- INSTIs (bictegravir, dolutegravir) have the highest barrier to resistance and are preferred first-line agents
- HLA-B*5701 testing must be done before abacavir prescription to prevent fatal hypersensitivity
- Pharmacokinetic boosting (ritonavir, cobicistat) inhibits CYP3A4, elevating PI plasma concentrations