Pharmacology · Antiviral Pharmacology

PIs, INSTIs, and Entry Inhibitors

Mechanisms, resistance profiles, key interactions, and preferred regimens

Protease inhibitors block the HIV-1 aspartyl protease that cleaves Gag and Gag-Pol polyproteins after virion budding — without this cleavage, released particles are structurally immature and non-infectious; all clinically used PIs require pharmacokinetic boosting with ritonavir or cobicistat to reach therapeutic plasma concentrations via CYP3A4 and P-glycoprotein inhibition.
Darunavir has an exceptional resistance barrier because it forms extensive hydrogen bond contacts with the protease backbone atoms rather than just the active-site amino acid residues — this means at least three simultaneous major mutations are required to confer significant resistance, making darunavir the preferred PI for both treatment-naive and most treatment-experienced patients.
Second-generation INSTIs dolutegravir and bictegravir have a fundamentally different resistance profile than first-generation raltegravir — single mutations that confer significant resistance to raltegravir (Y143, Q148, N155) produce only minimal fold-changes in dolutegravir susceptibility, explaining the clinical observation of zero treatment-emergent resistance in phase 3 trials of second-generation agents in naive patients.
Maraviroc targets a host protein (CCR5 co-receptor) rather than a viral protein — this means conventional drug-target mutations cannot confer resistance; instead, the virus escapes by shifting tropism from CCR5-using (R5) to CXCR4-using (X4) virus, which requires that a validated co-receptor tropism assay confirm exclusively R5 virus before maraviroc is prescribed.
Long-acting cabotegravir plus rilpivirine administered monthly or every 2 months creates a pharmacokinetic tail risk after discontinuation — cabotegravir remains detectable for up to 12 months and rilpivirine for up to 4 years, producing a functional drug-level window where both drugs are present but below therapeutic concentrations, selecting for resistance; patients must transition immediately to oral ART the day after the last injection.

Abbreviations: PI = protease inhibitor · INSTI = integrase strand transfer inhibitor · ART = antiretroviral therapy · CYP = cytochrome P450 · UGT1A1 = uridine diphosphate glucuronosyltransferase 1A1 · MDR = multi-drug resistant · GFR = glomerular filtration rate · CAB = cabotegravir · RPV = rilpivirine

Protease Inhibitors — Mechanism and Boosting

Class Mechanism

Protease Inhibition

Block HIV-1 aspartyl protease, which cleaves Gag and Gag-Pol polyproteins into mature structural proteins after virion budding
Uninhibited protease → non-infectious immature particles released — virion assembly is blocked, not replication entry
All PIs require pharmacokinetic boosting (ritonavir or cobicistat) to achieve therapeutic plasma concentrations
Boosting works via CYP3A4 and P-glycoprotein inhibition → dramatically extends PI half-life

Pharmacokinetic Boosters

Ritonavir vs. Cobicistat

Ritonavir (100–200 mg)Inhibits CYP3A4, CYP2D6, CYP2C9 — broader interaction profile; more drug interactions
Cobicistat (150 mg)Inhibits CYP3A4 only — cleaner profile; but blocks MATE1 → serum creatinine rises 0.1–0.2 mg/dL without true nephrotoxicity
Neither booster has antiviral activity at boosting doses — pharmacokinetic effect only
Both contraindicated with rifampin — rifampin induction overwhelms CYP3A4 inhibition

Preferred PI

Darunavir

Very high resistance barrier — requires ≥3 simultaneous major mutations for significant resistance
Extensive hydrogen bond contacts with protease backbone atoms — not just active-site residues
Rash — sulfonamide moiety; cross-reactivity possible in sulfa-allergic patients
Rifampin contraindicated; reduce statin doses significantly (CYP3A4 inhibition)

Alternative PI

Atazanavir

UGT1A1 inhibition → unconjugated hyperbilirubinemia, scleral icterus — benign and reversible
Nephrolithiasis in ~1–3% — atazanavir crystallizes in renal tubules; adequate hydration required
Unboosted atazanavir: PPIs absolutely contraindicated — requires gastric acid for absorption
Moderate resistance barrier compared to darunavir

Statins + Boosted PIs — Absolute Contraindication

Simvastatin and lovastatin are absolutely contraindicated with boosted PIs — CYP3A4 inhibition raises statin plasma levels up to 50-fold, causing severe myopathy and rhabdomyolysis. Use rosuvastatin or pravastatin instead (minimal CYP3A4 metabolism). Atorvastatin may be used at the lowest effective dose with careful monitoring. This rule applies to all ritonavir- and cobicistat-boosted regimens.

Integrase Strand Transfer Inhibitors

First Generation

Raltegravir

Twice-daily dosing; eliminated entirely by UGT1A1 — no CYP involvement, fewer drug interactions
Low resistance barrier — single mutation (Y143, Q148, or N155) can confer significant resistance
Preferred in pregnancy — most long-term safety data of any INSTI
Preferred in severe hepatic impairment — UGT1A1 metabolism less affected than CYP in liver disease

Second Generation

Dolutegravir

Once-daily; metabolized by UGT1A1 and CYP3A4; high resistance barrier — single mutations produce minimal fold-change
Creatinine artifact: OCT2 inhibition raises serum creatinine without affecting true GFR
Dofetilide contraindicated — OCT2 inhibition dramatically raises dofetilide levels
Neural tube defect signal largely resolved; acceptable in pregnancy with counseling
Associated with weight gain — monitor body weight during treatment

Second Generation

Bictegravir

Available only as Biktarvy (BIC/TAF/FTC) — single-tablet regimen, once daily
Equivalent resistance barrier to dolutegravir; no treatment-emergent resistance in phase 3 trials
Creatinine artifact: OCT2 and MATE1 inhibition — same mechanism as dolutegravir
Rifampin contraindicated — AUC reduced ~75%; no dose doubling possible in fixed-dose combo

Polyvalent Cation Chelation — Most Missed INSTI Interaction

Calcium, magnesium, aluminum, and iron ions in supplements and antacids chelate the diketo acid pharmacophore of all INSTIs in the GI tract, dramatically reducing absorption. For dolutegravir and raltegravir: separate from polyvalent cations by at least 2 hours before or 6 hours after. Bictegravir may be taken with calcium or iron supplements if the entire dose is taken with food. Counsel every patient on calcium supplements, multivitamins, and antacids before starting any INSTI.

Resistance

INSTI Resistance Pathways

First generation (RAL/EVG)Y143C/R, Q148H/R/K, N155H — single mutations confer resistance
Q148 pathway + G140S: reduces dolutegravir susceptibility 8–25-fold — most clinically significant cross-resistance
Second generation (DTG/BIC)No consistent single-mutation pathway in treatment-naive patients — high barrier
Never use a second-generation INSTI after first-generation INSTI failure without resistance testing

Drug Interaction

Rifampin + INSTIs

Rifampin induces UGT1A1 and CYP3A4 — affects all INSTIs to varying degrees
Dolutegravir: AUC reduced ~54% → dose-double to 50 mg twice daily; takes rifampin schedule into account
Bictegravir: AUC reduced ~75% → contraindicated; no dose adjustment possible in fixed-dose combo
Rifabutin: weaker inducer — standard INSTI doses can be used; preferred over rifampin with INSTIs

Entry and Fusion Inhibitors

CCR5 Antagonist

Maraviroc

Blocks conformational change of CCR5 co-receptor required for gp41-mediated viral fusion — targets host protein, not viral protein
Resistance = tropism shift (R5 to X4), not drug-binding site mutation — unique mechanism of escape
Requires validated co-receptor tropism assay confirming exclusively R5 virus before prescribing
CYP3A4 substrate: dose 150 mg BID with boosted PIs; 600 mg BID with CYP3A4 inducers

Salvage Agents

Other Entry and Attachment Inhibitors

Enfuvirtide (T-20)HR2 peptide mimetic — prevents gp41 six-helix bundle formation; subcutaneous injection BID; universal injection site reactions; salvage only
IbalizumabAnti-CD4 domain 2 monoclonal antibody; IV every 2 weeks; MDR HIV only
FostemsavirOral gp120 attachment inhibitor; heavily treatment-experienced MDR HIV only

Preferred First-Line Regimens and Long-Acting ART

Current DHHS Preferred Regimens — Treatment-Naive Adults

Bictegravir/TAF/FTC (Biktarvy) — single tablet once daily; no food requirement; no significant CYP interactions; highest-barrier INSTI; ~90% virologic suppression by week 48 with no resistance documented at failure.

Dolutegravir + TAF/FTC — two pills once daily; component-level flexibility allows substitution when individual drug toxicity occurs. Both achieve equivalent virologic outcomes and share the same high-barrier INSTI resistance profile.

Long-Acting CAB+RPV — Pharmacokinetic Tail Warning

Cabotegravir + rilpivirine IM administered monthly or every 2 months. After stopping injections, cabotegravir remains detectable for up to 12 months and rilpivirine for up to 4 years — creating a prolonged window of subtherapeutic drug levels that select for INSTI and NNRTI resistance.

Patients must transition to oral ART the day after the last injection to bridge the pharmacokinetic tail. Absolute contraindications: prior NNRTI or INSTI resistance mutations, concurrent rifamycins, VL >100,000 copies/mL, CD4 <200 cells/μL, and pregnancy.

Suggested References

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Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter 49: Antiviral Agents	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. — Chapter 55: Antiretroviral Agents and Treatment of HIV Infection	McGraw-Hill; 2023
Kohl NE et al.	Active human immunodeficiency virus protease is required for viral infectivity	Proc Natl Acad Sci USA. 1988
Zeldin RK, Petruschke RA	Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients	J Antimicrob Chemother. 2004
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Dooley KE, Flexner C, Andrade AS	Drug interactions involving combination antiretroviral therapy and other anti-infective agents	J Infect Dis. 2008
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Sax PE et al.	Coformulated bictegravir, emtricitabine, and tenofovir alafenamide vs dolutegravir with emtricitabine and tenofovir alafenamide	Lancet. 2017
Gulick RM et al.	Maraviroc for previously treated patients with R5 HIV-1 infection	N Engl J Med. 2008
Orkin C et al.	Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection	N Engl J Med. 2020
Margolis DA et al.	Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2)	Lancet. 2017
Segal-Maurer S et al.	Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection	N Engl J Med. 2022