For a treatment‑naïve adult HIV‑1 patient without pregnancy, severe hepatic impairment, or significant psychiatric history, what is the recommended efavirenz dose, administration instructions, and monitoring plan?

Efavirenz Dosing and Administration for Treatment-Naïve HIV-1 Adults

For treatment-naïve adults without contraindications, efavirenz 600 mg once daily at bedtime is the standard dose, taken on an empty stomach, though it is no longer a preferred first-line agent and should only be used when integrase inhibitor-based regimens cannot be prescribed. 1

Current Role in HIV Treatment

• Efavirenz has been superseded by integrase strand transfer inhibitor (InSTI)-based regimens as the preferred first-line therapy due to superior efficacy, tolerability, and resistance profiles of drugs like bictegravir and dolutegravir. 2
• Efavirenz is now primarily reserved for specific clinical scenarios, particularly tuberculosis co-infection where rifampin-based TB treatment is required, as efavirenz has fewer drug-drug interactions with rifamycins compared to most INSTIs and protease inhibitors. 3, 2
• When tuberculosis co-infection is present and rifampin is being used, increase efavirenz to 800 mg once daily for patients weighing ≥50 kg. 1

Standard Dosing Protocol

• Dose: 600 mg once daily 1, 3
• Timing: At bedtime to minimize neuropsychiatric side effects 1, 3
• Food: On an empty stomach to optimize absorption 1
• Formulation: Single 600 mg tablet simplifies adherence 1

Combination Therapy Requirements

• Never use efavirenz as monotherapy or add as a single agent to a failing regimen due to rapid resistance development from its low genetic barrier. 1
• Efavirenz must be combined with two nucleoside reverse transcriptase inhibitors (NRTIs), typically tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) or lamivudine (3TC). 2, 4
• The historical regimen of efavirenz + TDF + FTC/3TC demonstrated 70% virologic suppression in treatment-naïve patients but has been replaced by more effective options. 5

Mandatory Pre-Treatment Assessment

• Do not delay ART initiation while awaiting laboratory results; start treatment immediately after diagnosis if the patient is ready. 2
• Required baseline testing (obtain but do not wait for results):
  • HIV-1 RNA viral load 2
  • CD4 cell count 2
  • Genotypic resistance testing (reverse transcriptase, protease, integrase) 2
  • Hepatitis B surface antigen and hepatitis C antibody 2
  • Serum creatinine/eGFR 2
  • Pregnancy test for individuals of childbearing potential 2
  • Baseline lipid panel (total cholesterol and triglycerides) 1
  • Liver function tests, especially if underlying hepatic disease 1

Critical Monitoring Plan

Virologic Monitoring

• Week 4-6: First HIV-1 RNA measurement to assess initial response 2, 6
• Every 4-6 weeks: Continue testing until viral load <50 copies/mL (target achievement by week 24) 2
• First year: Every 3 months once suppressed 2
• After 1-2 years of sustained suppression: Every 6 months 2

CD4 Monitoring

• Every 3-6 months during the first year 2
• Every 6 months after the first year until CD4 >250 cells/µL for ≥1 year 2
• Discontinue CD4 monitoring once sustained viral suppression and CD4 recovery achieved 2

Safety Monitoring

• Weeks 1-4: Monitor closely for rash (occurs in first 1-2 weeks, usually resolves within 4 weeks) 1, 3
• Weeks 1-4: Assess for neuropsychiatric symptoms (typically begin 1-2 days after initiation, resolve in 2-4 weeks in most patients, but may persist up to 2 years in some) 1, 4
• Ongoing: Liver function tests, particularly in patients with hepatitis B/C co-infection or pre-existing liver disease 1
• Ongoing: Lipid panel monitoring (efavirenz elevates total cholesterol and triglycerides) 1

Absolute Contraindications

• Pregnancy, especially first trimester: Efavirenz causes neural tube defects and other fetal harm; avoid in women of childbearing potential unless effective contraception is ensured. 1, 3, 2
• Previously demonstrated hypersensitivity including Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions 1
• Coadministration with elbasvir/grazoprevir 1
• Severe psychiatric history: Efavirenz causes serious psychiatric symptoms including severe depression and suicidal ideation; immediate medical evaluation required if these develop. 1, 3

Relative Contraindications and Cautions

• High baseline viral load (>100,000 copies/mL) or low CD4 (<200 cells/µL): Efavirenz-based regimens are less effective than INSTI-based regimens in these populations; strongly prefer bictegravir or dolutegravir. 2
• History of seizures: Use with caution as efavirenz may lower seizure threshold 1
• QTc prolongation risk: Consider alternatives in patients taking medications with known Torsade de Pointes risk or those at higher baseline risk 1
• Hepatic impairment: Not recommended in severe hepatic impairment; monitor closely if mild-moderate disease 1

Common Adverse Effects and Management

Neuropsychiatric Symptoms (Most Common)

• Dizziness, abnormal dreams, impaired concentration, insomnia occur in >50% of patients 1, 4
• Symptoms typically begin 1-2 days after initiation and resolve within 2-4 weeks, though may persist longer 1, 4
• Bedtime dosing significantly improves tolerability 1, 3
• Neuropsychiatric symptoms are not predictive of subsequent serious psychiatric adverse events 1

Rash

• Occurs in first 1-2 weeks, usually resolves within 4 weeks 1, 3
• Discontinue immediately if severe rash develops or if accompanied by blistering, desquamation, mucosal involvement, or fever 1

Hepatotoxicity

• Monitor liver enzymes, particularly in patients with hepatitis B/C co-infection 1
• Cases of hepatic failure have occurred, including in patients without pre-existing liver disease 1

Critical Drug Interactions

• Contraindicated with: Astemizole, cisapride, midazolam, triazolam, ergot derivatives, St. John's Wort (risk of serious cardiac arrhythmias, prolonged sedation, respiratory depression) 3
• Rifampin co-administration: Increase efavirenz to 800 mg daily for patients ≥50 kg 1
• Oral contraceptives: Efavirenz may reduce effectiveness; use additional or alternative contraceptive methods 3
• Other antiretrovirals: Do not combine with ATRIPLA (which already contains efavirenz) unless dose adjustment needed for rifampin 1

Common Pitfalls to Avoid

• Using efavirenz as first-line therapy when INSTIs are available: This is outdated practice; bictegravir- or dolutegravir-based regimens have superior efficacy and tolerability. 2
• Prescribing to pregnant women or those planning pregnancy: Teratogenicity risk is well-established; dolutegravir is now preferred during pregnancy. 3, 2, 1
• Failing to dose at bedtime: Daytime dosing significantly worsens neuropsychiatric tolerability. 1
• Not counseling about transient CNS symptoms: Patients who discontinue prematurely due to expected, self-limited side effects lose treatment benefit. 1, 4
• Ignoring psychiatric history: Efavirenz can precipitate severe depression and suicidality; screen carefully before prescribing. 1
• Inadequate contraception counseling: Women of childbearing potential must use reliable contraception throughout treatment. 1