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TWO VARIABLES IDENTIFIED AS PREDICTORS OF MORTALITY IN ADVANCED HIV INFECTION

MIAMI BEACH—Researchers have identified two predictors of death in patients with advanced HIV infection, they reported here in April at the AAN Annual Meeting.

Jeffrey Sevigny, MD, Assistant Professor of Clinical Neurology at Columbia University Medical Center in New York City, told Neurology Today that in analyses designed to evaluate cognitive status and markers of immune activation as predictors of death, HIV patients with dementia or high levels of the pro-inflammatory chemokine monocyte chemoattractant protein (MCP-1) in blood and CSF are more likely to die than patients without dementia or elevations in these markers. Elevated plasma levels of MCP-1 were significantly associated with mortality (P = 0.002), whereas the association between elevated CSF levels and death approached significance (P = 0.06).

The study, involving 329 patients, was part of the NINDS-funded North East AIDS Dementia (NEAD) cohort study, a multicenter study led by Leon Epstein, MD, Professor of Pediatrics and Neurology at the Northwestern University Institute for Neuroscience in Chicago, with the original aim of determining predictors of dementia in patients who have a CD4 lymphocyte count of less than 300.

COGNITIVE DECLINE, COMMON COMPLICATION

This longitudinal study provides fresh evidence that, even with protease inhibitor treatment, HIV-caused neurological disease continues as a threat and is associated with critical outcomes, including death, said David Clifford, MD, principal investigator of the Neurologic AIDS Research Consortium and Professor of Neurology at Washington University in St. Louis. Dr. Clifford was not involved in Dr. Sevigny's study.

“Loss of cognitive ability is still a prominent and common complication of HIV infection even in well-treated subjects,” Dr. Clifford said.

MCP-1: MARKER FOR WORSE SURVIVAL

Dr. Sevigny, who headed this investigation, said that knowing that high levels of a particular biomarker – in this case, MCP-1 – predict worse survival may allow investigators to target the associated pathways in the brain with new therapeutics. “How MCP-1 contributes to neuronal injury and ultimately to death in this population is unclear,” Dr. Sevigny said. “But we know HIV enters the brain through monocytes, and when MCP-1 is produced locally in the brain, monocyte trafficking increases from the periphery into the brain.”

According to Dr. Clifford, although the pathophysiological mechanisms at work remain to be fully characterized, these results support the importance of products of the activated immune system, and the chemokine MCP-1 demonstrates the most impressive association with serious consequences of HIV disease.

An earlier NEAD cohort study found that elevated CSF MCP-1 levels were predictors of dementia, and others have associated elevated serum MCP-1 levels with non-HIV related diseases such as acute coronary syndrome. In animal models of HIV-associated dementia, Christine Zink, DVM, PhD, and Janice Clements, PhD, colleagues at Johns Hopkins University School of Medicine in Baltimore, reported that elevated levels of MCP-1 in the CSF predict the development of encephalitis (J Infect Dis 2001:184:1015–1021).

“Drugs that either reduce the production of MCP-1 or block its downstream actions could be developed to improve outcomes in several diseases, including those associated with HIV,” Dr. Sevigny said.

DEMENTIA IN HIV-AIDS

Dementia was also a significant predictor of death in the NEAD cohort, “possibly because people who are cognitively impaired do not adhere to medication regimens and therefore lose virological control,” Dr. Sevigny suggested.

The degree of dementia seen in patients of the current study was not particularly severe and would likely go unnoticed if not carefully screened. “If the higher risk of death in those with dementia is in part mediated by poor adherence,” he said, “then appropriate screening tests should become standard of care and rigorous adherence programs should be implemented in those identified with cognitive impairment.”

Most patients in the NEAD cohort were using highly active antiretroviral therapy (HAART), but, Dr. Sevigny added, adherence was not measured in the study.

Experts noted that the incidence of dementia has declined since the introduction of HAART. In the early 1980s, when HIV infection was largely untreated, two-thirds of patients with AIDS showed signs of clinical dementia. With one or two antiretroviral agents available, 20 percent of patients with AIDS showed signs of dementia, and with current HAART regimens, less than 10 percent of AIDS patients have it, mostly those who have higher viral loads.

“Ongoing work on optimal protection for our patients from the consequences of smoldering HIV infection remain critical challenges for neuroscience,” Dr. Clifford said.

ARTICLE IN BRIEF

  • ✓ HIV patients with dementia or high levels of the pro-inflammatory chemokine monocyte chemoattractant protein in blood and CSF are more likely to die than patients without dementia or elevations in these markers.