What antiretroviral therapy (ART) regimen has maximum central nervous system (CNS) penetration?

Antiretroviral Therapy with Maximum CNS Penetration

For HIV patients requiring maximum CNS penetration, efavirenz-based regimens demonstrate the highest CNS exposure (85% unbound CSF penetration), though integrase strand transfer inhibitor (InSTI)-based regimens remain the preferred first-line therapy due to superior efficacy and tolerability, with CNS penetration considerations reserved for specific clinical scenarios such as HIV-associated neurocognitive disorders. 1

Understanding CNS Penetration Measurement

The assessment of CNS penetration is complex and often misunderstood:

• True CNS penetration requires measuring unbound drug concentrations in CSF relative to plasma, not just total drug ratios 1
• Efavirenz was historically classified as having poor CNS penetration (0.87% CSF:plasma ratio), but when unbound concentrations were measured, it demonstrated excellent penetration at 85% 1
• Single time-point CSF:plasma ratios can misclassify CNS penetration ability; area under the curve measurements of unbound drug provide more accurate assessment 1

Drugs with Documented High CNS Penetration

NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)

• Efavirenz: CSF/plasma ratio of 0.681 (0.555-0.819) with all CSF concentrations above IC50 2
• Nevirapine: CSF/plasma ratio of 1.203 with CSF concentrations above IC50 2
• Zidovudine: CSF/plasma ratio of 0.718 (0.711-1.227) with 83% of CSF concentrations above IC50 2

NRTIs with Moderate CNS Penetration

• Lamivudine: CSF/plasma ratio of 0.464 (0.331-0.607) with all CSF concentrations above IC50 2
• Abacavir: CSF/plasma ratio of 1.344 (0.670-2.450), though 50% of CSF concentrations were below IC50 2

Drugs with Poor CNS Penetration

• Tenofovir: CSF/plasma ratio of only 0.021 (0.020-0.024) with 100% of CSF concentrations below IC50 2
• Emtricitabine: CSF/plasma ratio of 0.365 (0.343-0.435) with 100% of CSF concentrations below IC50 2

Critical Evidence on CNS Penetration and Clinical Outcomes

A major caveat exists regarding high CNS-penetrating regimens:

• High CNS Penetration Effectiveness (CPE) score regimens (>9) were associated with increased risk of HIV dementia with a hazard ratio of 1.74 (95% CI: 1.15-2.65) compared to low CPE regimens 3
• High CPE regimens did not reduce risk of other neuroAIDS conditions including toxoplasmosis, cryptococcal meningitis, or progressive multifocal leukoencephalopathy 3
• Emerging evidence suggests high CNS concentrations of some antiretrovirals may be neurotoxic and paradoxically associated with development of HIV-associated neurocognitive disorder (HAND) 1

Contemporary InSTI-Based Regimens and CNS Penetration

Bictegravir/Emtricitabine/Tenofovir Alafenamide

• Unbound bictegravir CSF concentrations: 4.4 (1.6-9.6) ng/mL with CSF fraction of 34% (15%-82%) 4
• Low overall CSF exposure observed for all three components of this regimen 4
• Should be used with caution as first-line treatment for patients with HIV-related CNS impairment, particularly those under 51 years of age 4
• Age over 51 years was associated with higher CSF concentrations 4

Dolutegravir

• Recommended as first-line therapy with high barrier to resistance and excellent systemic efficacy 5
• Specific CNS penetration data for dolutegravir is limited in the provided evidence
• Part of recommended regimens but CNS penetration characteristics not as well-characterized as older agents 6

Clinical Algorithm for Regimen Selection

For Most HIV Patients (Without CNS Disease)

1. Initiate InSTI-based regimen: Bictegravir or dolutegravir plus two NRTIs (tenofovir alafenamide/emtricitabine or tenofovir disoproxil fumarate/emtricitabine) 5, 6
2. These regimens prioritize systemic viral suppression, high barrier to resistance, and tolerability over CNS penetration 5, 6

For Patients with HIV-Associated Neurocognitive Disorders

1. Consider efavirenz-based regimens if maximum CNS penetration is the priority, though recognize increased CNS adverse effects (rash, neuropsychiatric symptoms) 5
2. Alternative: Nevirapine or zidovudine-containing regimens demonstrate good CNS penetration 2
3. Monitor closely for paradoxical worsening, as high CPE regimens may increase dementia risk 3

Important Contraindications

• Avoid tenofovir-based backbones if CNS penetration is the primary concern, as both tenofovir and emtricitabine have poor CNS penetration 2
• Efavirenz should be avoided in pregnancy during first 8 weeks and in patients with psychiatric conditions 5

Common Pitfalls to Avoid

• Do not assume newer agents have better CNS penetration: Bictegravir/emtricitabine/tenofovir alafenamide has low CNS exposure despite being a preferred first-line regimen 4
• Do not rely on total drug CSF:plasma ratios: These can dramatically underestimate (efavirenz) or overestimate true CNS penetration 1
• Do not automatically choose high CPE regimens for all CNS disease: The association with increased HIV dementia risk suggests potential neurotoxicity 3
• Do not use abacavir without HLA-B*5701 testing: Life-threatening hypersensitivity reactions can occur 5
• Do not use lamivudine or emtricitabine alone for HBV coinfection: High risk of HBV resistance; must combine with tenofovir 5