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Cerebrospinal fluid concentrations of tenofovir and emtricitabine in the setting of HIV‐1 protease inhibitor‐based regimens

In the combination antiretroviral therapy (cART) era, prevalence of HIV-associated neurocognitive disorders (HAND) remains high: 36.2-44.8% 1, contributing to morbidity 1 and mortality 2. Suboptimal control of HIV in the central nervous system (CNS) likely plays a role in this phenomenon, as supported by elevated neopterin and detectable HIV-1 RNA in cerebrospinal fluid (CSF) of patients on long term cART 3. Studies have shown that limited CNS penetration by antiretroviral (ARV) drugs is associated with HAND 4,5. 
 
Multiple factors impact CNS drug penetration, including molecular size, lipophilicity, plasma protein binding, and affinity for efflux pump transporters 6. For example, the ATP-binding cassette (ABC) superfamily of efflux transporters, including p-glycoprotein and multidrug-resistance associated proteins (MRPs), are expressed at blood-brain and blood-CSF barriers and can limit drug disposition7. Because many ARVs are substrates and/or inhibitors of ABC transporters, complex drug-drug interactions can occur. Specifically, protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV) are common in cART regimens when given with ritonavir (RTV) plus a backbone of tenofovir disoproxil fumarate (TDF), the tenofovir (TFV) pro-drug, and emtricitabine (FTC) 8. Both ATV and DRV inhibit p-glycoprotein and MRP-1 9-11 ; these transporters are found at blood-brain and blood-CSF barriers and are important for TFV 12 and FTC transport 13. 
 
We compared CSF TFV and FTC concentrations between patients receiving two different RTV-boosted PI regimens: ATV vs DRV. We also examined associations between CSF drug concentrations and CSF HIV-1 RNA detection.