Evidence of HIV DNA in cerebrospinal fluid (CSF) was linked to worse performance on neurocognitive testing in HIV patients on antiretroviral therapy (ART), a small study found.
Participants with detectable cell-associated HIV DNA in cerebrospinal fluid were linked with significantly worse neurocognitive outcomes, including global deficit score, reported Serena Spudich, MD, of Yale University in New Haven, Connecticut, and colleagues.
Moreover, more than half of examined patients had detectable cell-associated HIV DNA in their cerebrospinal fluid, the authors wrote in the Journal of Clinical Investigation.
While they noted that neurological complications of HIV are well-recognized, an accompanying editorial by David Clifford, MD, of Washington University in St. Louis, explained the problem more clearly.
“To date, we do not understand the cause or course of brain impairment associated with HIV. The frequent impairment in function in our patients is most often stable over time but in some patients appears to progress,” he wrote. “The possibility that HIV itself continues to trigger this dysfunction must be taken seriously, since it leaves open the possibility of progressive decline associated with the virus.”
Spudich and colleagues explained the purpose of their research as two-fold — not only is evaluating HIV in CSF important in the field of cure research, but in potentially filling in gaps in knowledge about HIV persistence and HIV-associated neurocognitive disorder (HAND), which they noted “remains a major cause of morbidity in the ART era.”
Sara Bares, MD, of the University of Nebraska Medical Center in Omaha, said that at her institution, they still see a fair amount of HAND, even though it has declined significantly, and that they also see “mild, almost subclinical impairment” even in patients who are virally suppressed.
“This may be the causes of the mild cognitive impairment we are seeing in patients, and we didn’t have a clear mechanism for what that was before,” Bares, who was not involved in the study, told MedPage Today. “This is one of the first studies to link detection of CA-DNA in CSF with worse neurocognitive outcomes. It’s an important study and it adds to the literature on HIV and neurocognitive function, and HIV persistence in CSF.”
Researchers examined blood and CSF samples from a group of 69 patients with HIV that Clifford described as representing “the best outcomes for optimal management.” They were a median age of 50, about 70% were white, and nearly all were men. More importantly, they were on ART for a median 8.6 year duration. All participants except two had plasma HIV RNA of <40 copies/mL at the time of CSF sampling, the authors said.
Of the 69 participants, 65 participants with at least 12 years of education took part in a 7-domain neuropsychological test battery to determine global deficit scores and total Z score.
For comparison, blood and CSF samples were taken from 19 HIV-negative patients, who were a median age of 49, and almost 70% were men.
Overall, HIV DNA was detected in CSF of 48% (95% CI 36%-60%) of participants, whereas only 9% (95% CI 3%-18%) had detectable cell-associated HIV RNA and 4% (95% CI 1%-12%) had detectable HIV RNA in 3-5 mL cell-free CSF fluid, the authors said.
They also found that detection of CSF HIV DNA was significantly linked to a lower median neurocognitive total Z score and global deficit score versus no detection. This association persisted after adjustment for a variety of factors, such as pre-ART CD4 count, current CD4 count, and age. The researchers noted that four of 35 participants with no detectable CSF HIV DNA were clinically impaired, while nine of 30 with detectable CSF HIV DNA were in the “clinically impaired range.”
Clifford characterized the presence of cell-associated HIV DNA in cerebrospinal fluid as “surprising,” given the overall combination ART compliance in this group.
“Ultimately, optimized brain function is the most prized achievement of HIV therapy, making the negative neurocognitive association with CSF CA-HIV DNA a reason for ongoing concern,” he wrote. “If excellent HIV therapy extends life but fails to protect brain function, the achievement of successful HIV therapy is a Pyrrhic, or hollow, victory.”
One limitation noted by Spudich and colleagues said that the significance of these findings “in relation to a persistent reservoir of replication competent HIV in the CNS compartment is unknown.” Not only that, but the proportion of cell-associated HIV DNA in CSF cells “which is intact or inducible” is also unknown.
“The latter is a fundamental unanswered question that has major implications for prevention and treatment of HIV-associated CNS disease as well as efforts for long-term HIV remission,” the authors wrote.
The study was supported by the National Institute of Allergy and Infectious Diseases and the National Institute of Mental Health of the NIH.
Clifford disclosed support from the NIH.