People who started antiretroviral therapy (ART) within four months of HIV infection had lower HIV DNA molecular diversity in cerebrospinal fluid (CSF) than did people who started ART more than 14 months after infection. But HIV DNA levels in CSF and neurocognitive function did not differ substantially between the early and late ART groups.
HIV enters the central nervous system (CNS) during early infection, potentially establishing a latent CNS reservoir and possibly contributing to CNS inflammation, brain damage and neurocognitive impairment. Independent replication of HIV in the CNS would complicate attempts at viral eradication. How early ART may affect these processes remains incompletely understood.
To address these issues, U.S. researchers compared HIV DNA and selected CNS markers and outcomes in nine adults who began ART within four months of their estimated date of HIV infection and seven adults who started ART more than 14 months after infection. They measured cognitive function by Global Deficit Score and used droplet digital PCR to quantify HIV DNA in peripheral blood mononuclear cells (PBMCs) and CSF cell pellets. In blood and CSF the researchers measured markers of inflammation (sCD163, IL-6, MCP-1, TNF-α) and neuronal damage (neurofilament light).
The nine early-ART participants did not differ significantly from the late-ART participants in median age (44 and 35 years), proportions of men (88.9% versus 100%), proportions of Caucasians (77.8% and 100%), nadir CD4 count (473 and 373 cells/mm3) or median lifetime exposure to ART (2.8 and 2.6 years). All participants had sustained viral suppression in peripheral blood through a median of 3.5 viral load measurements with a median of 168 days between visits.
HIV DNA diversity in CSF was lower with early ART than late ART, though the difference stopped short of statistical significance (0.9% versus 2.5%, P = .11). In a separate analysis using a mixed-effects model in which log-transformed time on ART from estimated date of infection predicted baseline diversity, HIV DNA diversity in CSF was significantly lower with early ART (P = .05). HIV DNA molecular diversity in PBMCs did not differ substantially between the two groups (2.1% and 2.5%, P = .26). HIV DNA levels in CSF were nonsignificantly higher in the early ART group (10,559.7 versus 1,554 copies/million cells, P = .34), while HIV DNA levels in blood were nonsignificantly lower in the early-ART group (14.1 versus 39.1 million cells, P = .62).
Concentrations of two inflammation markers were significantly lower in the CSF of the early-ART group compared with the late-ART group: IL-6 (0.9 versus 1.2 pg/mL, P = .03) and TNF-α (0.2 versus 0.3 pg/mL, P = .02). Levels of those two markers did not differ between the two groups in blood. Concentrations of other markers of inflammation or neuronal damage did not differ significantly between the two groups. Nor did the groups differ significantly in Global Deficit Score.
Despite lower HIV DNA diversity and CSF inflammation in the early ART group, early treatment did not prevent HIV from establishing compartmentalized HIV DNA populations in CSF. This analysis relied on deep sequencing of eight paired CSF and PBMC samples. Six of these eight (75%) had HIV DNA compartmentalized in CSF, including two of three early-ART patients (67%). One of the early-ART patients started antiretrovirals during primary infection. Two participants with longitudinal sampling had sustained HIV DNA compartmentalization in CSF at all sampling points.
The researchers conclude that early ART is associated with lower molecular HIV DNA diversity in CSF and that lower diversity was not associated with age, peak viral load or levels of CD4 cells or CD8 cells. CSF concentrations of two inflammation markers -- IL-6 and TNF-α -- were significantly lower with early ART than late ART. But early therapy did not prevent HIV DNA compartmentalization in CSF. The authors believe the HIV DNA compartment "needs to be considered for the design of future eradication strategies and might contribute to the neuropathogenesis of HIV."