Antiretrovirals

Background

Antiretrovirals (ARVs) are medications used for treatment and prevention of HIV infection. Emergency physicians most commonly encounter ARVs in the context of post-exposure prophylaxis (PEP), managing patients on chronic antiretroviral therapy (ART), and recognizing drug interactions or adverse effects. ART should never be discontinued in the ED — interrupting therapy risks viral rebound, immune reconstitution failure, and development of drug resistance.

Drug Classes

Class	Abbreviation	Mechanism	Common Examples
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors	NRTIs	Inhibit HIV reverse transcriptase (chain terminators)	Tenofovir (TDF/TAF), emtricitabine (FTC), lamivudine (3TC), abacavir (ABC), zidovudine (AZT)
Non-Nucleoside Reverse Transcriptase Inhibitors	NNRTIs	Bind and inhibit reverse transcriptase allosterically	Efavirenz (EFV), rilpivirine (RPV), doravirine (DOR)
Protease Inhibitors	PIs	Block HIV protease, preventing viral maturation	Darunavir (DRV), atazanavir (ATV); always given with ritonavir or cobicistat boosting
Integrase Strand Transfer Inhibitors	INSTIs	Block integration of viral DNA into host genome	Bictegravir (BIC), dolutegravir (DTG), raltegravir (RAL), cabotegravir (CAB)
Entry/Fusion Inhibitors	—	Block HIV entry into host cells	Maraviroc (CCR5 antagonist), enfuvirtide (fusion inhibitor), lenacapavir (capsid inhibitor)

Current Preferred Regimens (2024-2025)

Most patients on ART will be taking an INSTI-based regimen, typically as a single-tablet regimen (STR):

• Bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) — most commonly prescribed STR
• Dolutegravir/lamivudine (Dovato) — 2-drug regimen for select patients
• Dolutegravir/abacavir/lamivudine (Triumeq) — requires HLA-B*5701 testing prior to initiation
• Cabotegravir/rilpivirine (Cabenuva) — long-acting injectable given monthly or every 2 months

Administration

• Type: Antiviral (multiple drug classes; see table above)
• Dosage Forms: Oral tablets/capsules (most common as fixed-dose single-tablet regimens), oral solutions, long-acting injectables (cabotegravir/rilpivirine, lenacapavir)
• Routes of Administration: PO (most), IM/SC (long-acting formulations), IV (enfuvirtide, zidovudine)
• Common Trade Names: Biktarvy (BIC/FTC/TAF), Dovato (DTG/3TC), Triumeq (DTG/ABC/3TC), Genvoya (EVG/COBI/FTC/TAF), Cabenuva (CAB/RPV LA), Sunlenca (lenacapavir)

Adult Dosing

HIV Post-Exposure Prophylaxis (PEP) — The Key ED Indication

Initiate as soon as possible, ideally within 24 hours, and no later than 72 hours after exposure.

Duration: 28 days

Preferred regimens (adults and adolescents):

• Bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) — 1 tablet PO daily (preferred single-tablet regimen)
• Dolutegravir 50 mg PO daily PLUS tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) PLUS emtricitabine (FTC) or lamivudine (3TC)

Alternative regimen (when INSTIs unavailable or contraindicated):

• Darunavir/cobicistat (Prezcobix) 1 tab PO daily PLUS emtricitabine/tenofovir (Truvada or Descovy) 1 tab PO daily
• Raltegravir 400 mg PO BID PLUS emtricitabine/tenofovir (Truvada or Descovy) 1 tab PO daily

Do NOT delay the first dose for lab results — give in the ED and arrange follow-up

PEPline for expert consultation: 1-888-448-4911

HIV Treatment

• Dosing is regimen-specific; do not modify, hold, or restart a patient's ART regimen in the ED without specialist consultation
• If a patient cannot take oral medications (e.g., intubated, NPO for surgery), consult HIV specialist urgently — treatment interruption decisions must balance resistance risk

Pediatric Dosing

HIV PEP (Pediatric)

• Age ≥2 years and ≥25 kg: Biktarvy (BIC/FTC/TAF) — weight-based dosing available in pediatric tablets
• Age ≥4 weeks and ≥3 kg: Dolutegravir (weight-based) PLUS age-appropriate NRTI backbone (FTC/TAF or AZT/3TC for neonates)
• Neonates (<4 weeks): Consult pediatric ID specialist; regimens vary by age and weight
• PEPline: 1-888-448-4911 for pediatric dosing assistance

HIV Treatment (Pediatric)

• Dosing is weight-based and regimen-specific; managed by pediatric HIV specialists
• Do not modify regimens in the ED

Special Populations

Pregnancy

• ART should be continued throughout pregnancy to prevent vertical transmission
• Preferred agents in pregnancy: Dolutegravir-based regimens (previously avoided in first trimester due to neural tube defect concern; now recommended based on larger safety data)
• Avoid: Efavirenz (teratogenicity concern); oral solutions containing alcohol/propylene glycol
• For PEP in pregnancy: Preferred regimen is raltegravir + emtricitabine/tenofovir (Truvada); dolutegravir is also acceptable
• Consult OB/ID for management of HIV-positive pregnant patients in the ED

Lactation

• In the United States, women with HIV are advised not to breastfeed regardless of viral load (per US guidelines)
• WHO guidelines differ — in resource-limited settings, breastfeeding while on suppressive ART is recommended

Renal Dosing

• Tenofovir disoproxil fumarate (TDF): Requires dose adjustment with CrCl <50 mL/min; avoid if CrCl <30 mL/min
• Tenofovir alafenamide (TAF): No adjustment needed unless CrCl <15 mL/min and not on dialysis
• Dolutegravir, bictegravir, raltegravir: No renal adjustment needed
• Emtricitabine, lamivudine: Require dose adjustment with CrCl <50 mL/min
• Consult specific drug labeling or HIV pharmacist for complex renal impairment

Hepatic Dosing

• Most NRTIs: No adjustment (renally eliminated)
• Protease inhibitors (PIs): Hepatically metabolized; use with caution, contraindicated in severe impairment
• NNRTIs: Variable; efavirenz and rilpivirine should be avoided in severe hepatic impairment
• INSTIs: Generally no adjustment needed for mild-moderate impairment; limited data in severe impairment
• Abacavir: Contraindicated in moderate-severe hepatic impairment (hepatically metabolized)

Contraindications

• Allergy to specific drug/class
• Abacavir: Contraindicated if HLA-B*5701 positive (risk of fatal hypersensitivity reaction — do NOT restart after suspected reaction)
• Tenofovir DF (TDF): Avoid in significant renal impairment (CrCl <30 mL/min)
• Protease inhibitors: Multiple contraindicated co-medications due to CYP3A4 inhibition (see Drug Interactions)
• Dofetilide, flecainide, amiodarone: Contraindicated with boosted PIs

Drug Interactions (Critical for ED Practice)

ARV Class	Key Interaction Mechanism	ED-Critical Interactions
Boosted PIs (darunavir/r, atazanavir/r)	Potent CYP3A4 inhibitors	Contraindicated: oral midazolam, triazolam, ergotamines, simvastatin, lovastatin, amiodarone, flecainide. Caution: fentanyl (increased levels), methadone (decreased levels), warfarin, direct oral anticoagulants
Cobicistat (in Genvoya, Prezcobix)	CYP3A4 inhibitor (pharmacokinetic booster)	Same as boosted PIs above; also inhibits tubular creatinine secretion (raises creatinine without true GFR change)
INSTIs (dolutegravir, bictegravir, raltegravir)	Chelation with polyvalent cations	Separate from antacids, calcium, iron, magnesium by ≥2 hours (reduced absorption). Few other significant interactions — INSTIs are the safest class for drug interactions
NNRTIs (efavirenz, rilpivirine)	CYP3A4 inducers (efavirenz) or substrates	Efavirenz decreases methadone levels. Rilpivirine: avoid PPIs (reduced absorption); H2-blockers must be given 12 hours before or 4 hours after
NRTIs	Minimal CYP interactions	Tenofovir: avoid with nephrotoxic drugs. Zidovudine: additive hematologic toxicity with other myelosuppressive drugs

ED Pearl: If a patient on ART needs procedural sedation, IV midazolam may be used cautiously with boosted PIs (with dose reduction and monitoring), but oral midazolam is contraindicated. Propofol, ketamine, and etomidate have no significant ARV interactions and are safe choices.

Adverse Reactions

Serious (Class-Specific)

• Abacavir hypersensitivity reaction: Fever, rash, GI symptoms, respiratory symptoms within first 6 weeks. NEVER rechallenge — can be fatal. Prevented by HLA-B*5701 screening
• Lactic acidosis/hepatic steatosis: NRTIs (especially older agents: stavudine, didanosine; rare with current agents)
• Tenofovir DF (TDF) nephrotoxicity: Fanconi syndrome, acute kidney injury, decreased bone mineral density
• Immune reconstitution inflammatory syndrome (IRIS): Paradoxical worsening of preexisting infections (TB, MAC, CMV, PML, cryptococcus) after ART initiation; typically within first 4-8 weeks
• QT prolongation: Rilpivirine, PIs (especially with other QT-prolonging agents)
• Hepatotoxicity: NNRTIs (nevirapine > efavirenz), PIs; risk increased with hepatitis B/C co-infection
• Stevens-Johnson syndrome / TEN: NNRTIs (nevirapine, efavirenz), abacavir
• Hepatitis B flare: Discontinuation of tenofovir, emtricitabine, or lamivudine (which have dual HIV/HBV activity) may trigger severe HBV reactivation — another reason not to stop ART in the ED

Common

• GI effects: Nausea, diarrhea, abdominal pain (most common with PIs; common reason for PEP nonadherence)
• CNS effects: Insomnia, vivid dreams, dizziness, depression (efavirenz; also reported with dolutegravir and bictegravir)
• Weight gain: INSTIs (especially dolutegravir, bictegravir) and TAF-containing regimens
• Metabolic: Hyperlipidemia, insulin resistance (especially PIs)
• Rash: NNRTIs, abacavir
• Elevated creatinine (non-pathologic): Cobicistat and dolutegravir inhibit tubular creatinine secretion — creatinine rises ~0.1-0.15 mg/dL without true GFR change. Do NOT reflexively hold ART for this

Pharmacology

• Half-life: Varies widely by class; oral agents typically 5-20 hours; long-acting injectables (cabotegravir, lenacapavir) have effective half-lives of weeks to months
• Metabolism: NRTIs — primarily renal; NNRTIs and PIs — primarily hepatic (CYP450); INSTIs — hepatic (UGT1A1) with renal component
• Excretion: Class-dependent (see above)

Mechanism of Action

Each class targets a different step in the HIV replication cycle:

• NRTIs: Incorporated into growing viral DNA chain by reverse transcriptase, causing chain termination
• NNRTIs: Bind directly to reverse transcriptase at an allosteric site, altering enzyme conformation
• PIs: Block HIV protease from cleaving Gag-Pol polyprotein precursors into functional viral proteins
• INSTIs: Block integrase enzyme from inserting viral DNA into the host cell genome
• Entry/Fusion inhibitors: Block viral attachment (CCR5 antagonists), membrane fusion, or capsid assembly at various pre-integration steps

Comments

Key ED Pearls

• Never stop ART — even temporarily. Risk of viral rebound, HBV flare (if co-infected), resistance development. If oral route unavailable, consult HIV specialist urgently
• PEP is time-sensitive — give the first dose in the ED, do not wait for labs. Biktarvy (1 tab daily × 28 days) is the simplest preferred regimen
• IRIS is not treatment failure — it is a sign of immune recovery. Treat the underlying OI, continue ART. Consider steroids for severe IRIS after ID consultation
• Abacavir reaction = never rechallenge. Even if prior reaction was mild.
• Procedural sedation: Avoid oral midazolam with PIs/cobicistat. Propofol, ketamine, etomidate are safe alternatives
• PEP to PrEP transition: For patients with ongoing HIV risk, link PEP patients to PrEP after completing the 28-day course
• Expert consultation: PEPline — 1-888-448-4911 (National Clinician Consultation Center; available 7 days/week)

See Also

• HIV
• HIV post-exposure prophylaxis
• HIV Pre-exposure prophylaxis (PrEP)
• Immune reconstitution inflammatory syndrome
• Opportunistic infections in HIV