Background:  HIV can be detected in the brain early in the course of HIV disease. Some studies show greater decreases in cerebrospinal fluid (CSF) HIV RNA and improvement in neurocognitive function in patients treated with ART with better central nervous system (CNS) penetration. ACTG 736 was an observational study to determine whether subjects with greater decline in CSF HIV RNA after beginning HAART also had greater improvement in neurocognitive function, and whether predicted CNS penetration influenced these changes.

Methods:  Eligibility criteria included starting a new HAART regimen;CD4⁺ T cells <200/mL with plasma HIV-1 RNA >2000 copies/mL or plasma HIV-1 RNA >50,000 copies/mL and any CD4⁺ T cell count. Subjects underwent standardized medical and neurologic history and examination, venipuncture, lumbar puncture, and neuropsychological tests before starting HAART, and 24 and 52 weeks later. Neuropsychological test results were expressed as Z scores (NPZ4). The predicted CNS penetration of each ART was assigned a score of 0 for no penetration; 0.5, weak penetration; or 1, good penetration based on published data. The CNS penetration of a HAART regimen was calculated as the sum of the scores of each agent.

Results:  Characteristics of 101 subjects at entry were:  39 years of age; 83% male, 52% white; 49 ART-naïve; CD4 108; CSF HIV RNA 3.17 log; plasma HIV RNA 4.88 log; NPZ4 –0.38. CSF and plasma HIV RNA decreases at week 24 were greater in ART-naïve (p = 0.05 and p <0.01); this association remained significant at week 52 for plasma HIV RNA (p <0.01) and less so for CSF (p = 0.07). Naïve subjects had a 3- to 5-fold greater likelihood of having a sustained virological response, and of becoming undetectable in CSF and plasma than treatment-experienced subjects (p <0.05). CSF HIV RNA decreased more in subjects whose ART regimen had better CNS penetration (p <0.01). NPZ4 showed no significant improvement over time and there was no association between changes in NPZ4 and changes in CSF HIV RNA. NPZ4 was significantly better in subjects with higher CD4 (p <0.01).

Conclusions:  In this cohort of subjects with advanced HIV infection, beginning or changing a potent ART regimen led to decline in CSF HIV RNA at week 24 and 52. In general, better virologic responses were seen in ART-naïve subjects. Greater decline in CSF HIV RNA was seen in subjects who took drug regimens that had better CNS penetration. Inclusion of CNS-penetrating ART may lead to better virologic control within the CNS.