Lopinavir

Background

Lopinavir is a HIV protease inhibitor always given in combination with low-dose ritonavir (which boosts lopinavir plasma levels by inhibiting CYP3A4 metabolism). Although previously a preferred first-line protease inhibitor, lopinavir/ritonavir is no longer recommended for treatment-naive adults due to higher pill burden, GI intolerance, and metabolic side effects compared to newer alternatives (e.g., boosted darunavir, dolutegravir-based regimens). It remains in use in some resource-limited settings as a second-line option and in select pediatric populations.

Lopinavir/ritonavir was studied for COVID-19 treatment early in the pandemic. Multiple large randomized trials (RECOVERY, WHO SOLIDARITY) have definitively shown no clinical benefit for hospitalized COVID-19 patients (see Comments section).

Administration

• Type: Antiviral (HIV protease inhibitor, boosted)
• Dosage Forms: 100 mg/25 mg, 200 mg/50 mg (tabs); oral solution 80 mg/20 mg per mL (400 mg/100 mg per 5 mL)
  • Oral solution contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v) — relevant for neonates, pregnancy, and patients on metronidazole or disulfiram
• Routes of Administration: PO
• Common Trade Names: Kaletra (lopinavir/ritonavir)
• Tablets can be taken with or without food; oral solution should be taken with food

Adult Dosing

• HIV treatment
  • 400 mg/100 mg PO BID
  • Once-daily dosing (800 mg/200 mg) may be used in treatment-naive patients not receiving efavirenz, nevirapine, nelfinavir, or amprenavir
  • Dose may need to be increased when used in combination with efavirenz or nevirapine (500 mg/125 mg PO BID or 533 mg/133 mg PO BID with solution)
• HIV post-exposure prophylaxis
  • 400 mg/100 mg PO BID (typically for 28 days as part of a 3-drug regimen)
  • Note: Lopinavir/ritonavir is no longer a preferred PEP regimen in most current guidelines; newer integrase inhibitor-based regimens (e.g., dolutegravir or raltegravir) are preferred when available

Pediatric Dosing

• HIV treatment
  • 14 days-12 months old: 16 mg/4 mg/kg PO BID (solution)
  • 13 months and older, <15 kg:
    • Treatment-naive: 12 mg/3 mg/kg PO BID (solution)
    • Treatment-experienced: 13 mg/3.25 mg/kg PO BID (solution)
  • 13 months and older, 15-45 kg: 11 mg/2.75 mg/kg PO BID (solution)
  • 13 months and older, >45 kg: 400 mg/100 mg PO BID
  • Children <18 years should NOT use once-daily dosing
• HIV post-exposure prophylaxis
  • 14 days-12 months old: 16 mg/4 mg/kg PO BID (solution)
  • 13 months and older, <15 kg: 12 mg/3 mg/kg PO BID (solution)
  • 13 months and older, 15-40 kg: 10 mg/2.5 mg/kg PO BID (solution)
  • 13 months and older, >40 kg: 400 mg/100 mg PO BID

Special Populations

Pregnancy

• Tablets may be used in pregnancy
• Oral solution is CONTRAINDICATED in pregnancy due to high alcohol (42.4%) and propylene glycol content — no safe level of alcohol exposure during pregnancy
• No adequate well-controlled studies; weigh risks/benefits; enrollment in the Antiretroviral Pregnancy Registry is encouraged

Lactation

• Women with HIV should NOT breastfeed (risk of HIV transmission to infant via breast milk regardless of viral load)

Renal Dosing

• No adjustment required

Hepatic Dosing

• Not studied; use with caution in hepatic impairment
• Lopinavir is primarily hepatically metabolized — plasma levels may be increased
• Contraindicated in severe hepatic impairment (for tablet formulation)

Contraindications

• Allergy to lopinavir or ritonavir
• Neonates <14 days postnatal age (or <42 weeks postmenstrual age) due to toxicity risk from alcohol and propylene glycol in the oral solution
• Congenital long QT syndrome
• Hypokalemia (uncorrected)
• Co-administration with drugs highly dependent on CYP3A4 for clearance where elevated levels may cause serious or life-threatening events (see Drug Interactions)

Drug Interactions

This is a critically important section for emergency physicians

• Lopinavir/ritonavir is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor — it significantly increases levels of many co-administered drugs
• Contraindicated combinations (risk of serious/life-threatening reactions):
  • Amiodarone, flecainide (cardiac arrhythmias)
  • Ergotamine, dihydroergotamine (ergotism/vasospasm)
  • Oral midazolam, triazolam (prolonged sedation) — IV midazolam may be used with caution and monitoring
  • Simvastatin, lovastatin (rhabdomyolysis)
  • Sildenafil when used for pulmonary arterial hypertension
  • Rifampin (substantially decreases lopinavir levels)
• Clinically significant interactions:
  • Warfarin — monitor INR closely
  • Methadone — decreased methadone levels; may precipitate withdrawal
  • Oral contraceptives — ethinyl estradiol levels decreased; use alternative/additional contraception
  • Fentanyl — increased fentanyl levels; risk of respiratory depression
  • Colchicine — dose reduction required; contraindicated in renal/hepatic impairment

Adverse Reactions

Serious

• QT prolongation/Torsade de pointes
• PR prolongation/AV block (2nd or 3rd degree reported)
• Pancreatitis (can be fatal; suspend therapy if suspected)
• Hepatotoxicity (elevated transaminases ± bilirubin; monitor LFTs)
• Hyperglycemia/new-onset diabetes mellitus
• Hypercholesterolemia/hypertriglyceridemia
• Immune reconstitution inflammatory syndrome
• Stevens-Johnson syndrome / toxic epidermal necrolysis
• Angioedema
• Hemolytic anemia
• Neonatal toxicity — life-threatening cardiac toxicity, lactic acidosis, renal failure, and CNS depression reported in premature neonates receiving the oral solution

Common

• Diarrhea (most common; up to 27% moderate-severe)
• Nausea/vomiting (up to 16%)
• Abdominal pain
• Dysgeusia
• Fatigue/asthenia
• Headache
• Rash
• AST, ALT, GGT, CK elevation
• Lipodystrophy (with prolonged use)

Pharmacology

• Half-life: 5-6 hours
• Metabolism: Hepatic, primarily via CYP3A4 (ritonavir inhibits CYP3A4, markedly boosting lopinavir levels)
• Excretion: Primarily fecal (~83%); renal (~11%)
• Protein binding: 98-99% (bound to albumin and alpha-1-acid glycoprotein)

Mechanism of Action

Lopinavir binds to the active site of HIV-1 protease, preventing cleavage of viral Gag-Pol polyprotein precursors into mature, functional proteins required for viral assembly. This results in production of immature, non-infectious viral particles. Ritonavir serves as a pharmacokinetic booster by inhibiting CYP3A4-mediated metabolism of lopinavir, increasing its plasma half-life and trough concentrations.

Comments

COVID-19: No Benefit Demonstrated

Lopinavir/ritonavir was investigated for COVID-19 based on in-vitro activity against SARS-CoV-2 and prior data from SARS-CoV-1. Multiple large randomized controlled trials have now conclusively shown no clinical benefit:

• RECOVERY trial (N=4,970): No significant difference in 28-day mortality (23% lopinavir/ritonavir vs 22% usual care; RR 1.03, 95% CI 0.91-1.17; p=0.60). No benefit in time to discharge or risk of progression to mechanical ventilation.
• WHO SOLIDARITY trial (>11,000 patients): No reduction in mortality, initiation of ventilation, or duration of hospitalization.
• Cao et al. (N=199, the initial Chinese RCT): No benefit in time to clinical improvement (HR 1.31, 95% CI 0.95-1.80).

Based on these results, WHO halted the lopinavir/ritonavir arms of the SOLIDARITY trial in 2020, and lopinavir/ritonavir is not recommended for COVID-19 treatment.

See Also

• HIV
• Ritonavir
• HIV post-exposure prophylaxis
• Antiretrovirals