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Cognitive Problems in Stable HIV Patients May Indicate Virus in CSF

Samson, Kurt

doi: 10.1097/01.NT.0000516108.47129.e1
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Researchers found a significant association between diffuse white matter signal abnormalities and CSF/plasma viral load discordance and/or viral escape in patients with asymptomatic HIV type 1 with neurocognitive disorders.

Neurocognitive disorders in asymptomatic HIV-type 1 (HIV-1) patients on antiretroviral therapy may be due to the virus escaping into the cerebrospinal fluid (CSF) and replicating as it travels to the brain, even in patients with normal CD4 levels, researchers reported in the March 13 online edition of Clinical Infectious Diseases.

Investigators at University College London in the United Kingdom conducted a review of magnetic resonance imaging (MRI) findings in HIV patients who had undergone lumbar puncture and found a significant association between diffuse white matter signal abnormalities (DWMSA) and CSF/plasma viral load discordance and/or viral escape.

The relationship was especially strong in patients who were undergoing antiretroviral therapy (ART), noted lead author Ravindra K. Gupta, MD, MPH, PhD, professor of infectious diseases in the division of infection and immunity at University College London.

Although HIV-1 escape and replication in the CSF have been documented in the past, this is the first time that DWMSA has been reported to be significantly associated with CSF discordance and escape, according to the single-institution retrospective analysis.

Dr. Gupta's laboratory, which also studies the biology of macrophages and microglia in relation to HIV infection, has an extensive HIV drug resistance program, including in vitro studies on HIV protease inhibitors and epidemiology of drug resistance.

The team found that 15 percent of HIV-1 patients had CSF/plasma viral load discordance, similar to rates reported in other studies, and 6 percent had CNS escape. In patients receiving ART, 8 percent had CSF discordance. Most subjects with evidence of viral escape were treatment-experienced.

CSF/plasma discordance refers to a state where there are higher levels of HIV in CSF than in plasma. The clinical significance of discordance is unknown, however.

A subgroup of subjects with CSF escape had normal (>350 cells/μL) CD4 counts at the time of lumbar puncture (LP), an observation consistent with findings from an earlier case series. The analysis was based on 163 lumbar punctures in 143 patients.

The 15 percent prevalence of CSF discordance is similar to that reported in other studies, but unlike some prior studies, the researchers found no association between antiretroviral therapy (ART) clinical penetrance effectiveness CNS scores.

However, Dr. Gupta said this finding “should be viewed with caution” because therapy was not randomized and might have confounded this data.

“Although ART is highly effective, some individuals continue to experience morbidity related to HIV, especially if they were infected more than 20 years ago and if they have been treated with multiple drug regimens,” he told Neurology Today.

“DWMSAs in HIV-infected individuals with neurological problems should raise suspicion of possible CSF discordance/escape. In the context of HIV, neurological symptoms in ART treated patients should prompt investigation for HIV even if their viral load is undetectable.”

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The single-institution retrospective analysis was based on LP data from 146 HIV-infected patients, 80 percent of whom were receiving ART. A total of 163 diagnostic LPs were evaluated, and clinical and neuroimaging variables associated with CSF discordance/escape were identified using multivariate logistic regression.

MRI findings were interpreted by a specialist neuroradiologist — blinded with regard to discordance or viral escape — at the time of each patient's presentation.

The researchers defined CSF discordance as a CNS viral load of 0.5 log10 copies, HIV-1 RNA greater than plasma viral load, and escape as of HIV viral load >50 copies/mL in CSF in patients with suppressed plasma viral load <50 copies/mL.

In patients with signs of HIV escape, 60 percent complained of subacute neurological problems, 20 percent had acute complaints, and 20 percent had chronic neurological impairment. Acute neurology problems were defined as any new presentation including headaches, confusion, sensory and motor symptoms, and symptoms within one month of onset. Chronic symptoms of neurocognitive impairment included global cognitive impairment, memory impairment, attention difficulties, and cognitive impairment with neuropathy. Subacute complaints included any other neurological presentation.

The median CD4 count was 430 (IQR, 190-620) cells/μL. Twenty-four (14.7 percent) LPs in 22 patients showed CSF discordance, of which 10 (6.1 percent) represented CSF escape. All patients with CSF escape had been diagnosed more than seven years earlier, and 6 out of 6 subjects had evidence of drug resistance in their plasma. The 15 percent prevalence of CSF discordance is similar to rates reported by other investigators.

Although 30 percent of the subjects had acceptably low levels of HIV in their plasma, 15 percent of the LPs indicated CSF/plasma viral load discordance, including 8 percent of those from RT patients. Viral escape was observed in 6 percent of LPs from ART patients.

Baseline data showed definite DWMSAs in 10 percent and subtle abnormalities in 68.1 of samples. In the analysis, definite results were found in 7 percent and subtle abnormalities in 29 percent.

“MRI can be used in patients complaining of neurological symptoms and if abnormal CSF examination might reveal viral escape. Hopefully the findings might expedite the use of MRI in HIV infected patients with neurological symptoms even before referral to a neurologist,” Dr. Gupta said.

The next step is to conduct a prospective, controlled analysis of patients initiating ART to investigate positive and negative predictive value of MRI screening, with an asymptomatic control group.

The study had limitations, mostly due to its cross-sectional design, the researchers noted. They also did not assess compliance with ART or when therapy began.

Longitudinal studies with serial MRI findings compared to peripheral and CSF viral load will be needed to further evaluate the findings, and the investigators advocate formation of collaborative research cohorts to better detect risk factors for viral escape in CSF under specific clinical presentations, which was proposed at a meeting of the Global HIV-1 CSF Escape Consortium in June 2016.

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“The brain can be a sanctuary site for HIV, and the study suggests that patients with systemic load suppression may not have suppression in the brain,” noted Ned Sacktor, MD, professor of neurology at the Johns Hopkins University School of Medicine in Baltimore, who was not involved with the study.

“When HIV has spread to the brain, we can change the treatment regimen to add drugs that cross the blood-brain barrier more effectively to control the infection, but it is unclear whether this will help or not. If we only consider viral load in the plasma, however, we might not know.”

Also, in addition to helping detect viral escape, MRI can point to different possible causes that can then be investigated and treated, he added.

“Even so, it is unclear whether an elevated viral load in the brain's CSF will have an impact on treatment, although physicians may change ART to an antiretroviral agent with greater CNS penetrance,” he said.

David B. Clifford, MD, FAAN, professor of neurology and medicine and the Seay Professor of Clinical Neuropharmacology at Washington University in St. Louis, said the findings are not surprising, but the subject is not well-defined in the medical literature.

“I think the paper reinforces and reaffirms the need to evaluate CNS viral load in HIV patients with neurocognitive complaints regardless of their systemic status — it's a good lesson,” he told Neurology Today.

“Too many physicians rely exclusively on plasma viral load in their HIV patients and, if it is acceptably low, assume complaints are due to other causes. While viral escape is not common, it is present in some patients and this issue needs to be better recognized.”

Unfortunately, many physicians and patients are reluctant when it comes to lumbar punctures, Dr. Clifford noted.

“It really is not part of routine care, but I would advocate for LP being performed more often, especially when there are cognitive issues. As a neurologist who sees these patients, I think the findings demonstrate that a subset of patients may be more vulnerable and have elevated levels of virus in their brain. Evidence of signal abnormalities on MRI makes this much more likely but LP is also needed.”

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•. Kugathasan R, Collier DA, Haddow LJ, et al Diffuse white matter signal abnormalities on magnetic resonance imaging are associated with human immunodeficiency virus type 1 viral escape in the central nervous system among patients with neurological symptoms Clin Infect Dis 2017: Epub 2017 Mar 13.
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      •. Nightingale S, Michael BD, Fisher M, et al CSF/plasma HIV-1 RNA discordance even at low levels is associated with up-regulation of host inflammatory mediators in CSF Cytokine 2016;83:139–146.
        © 2017 American Academy of Neurology