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CROI 2013: Researchers Look at Neurological Complications among People with HIV

Data from a small, yet well-designed trial to evaluate whether particular antiretroviral therapy (ART) regimens penetrate the central nervous system (CNS) and enhance neurocognitive performance were among several interesting findings regarding neurological complications among people with HIV presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) this month in Atlanta. Another study looked at similarities between Alzheimer's disease and neurocognitive impairment in people with HIV.

ART CNS Penetration

Ronald Ellis from the University of California at San Diego was the principal author of the antiretroviral penetration study. Different antiretroviral may have more impact on virus levels in the brain, as they are able to penetrate the protective blood-brain barrier. It has been hypothesized that particular drugs may reach higher levels lead to better virological suppression in the cerebral-spinal fluid (CSF), thus reducing CNS inflammation and synapto-dendritic dysfunction and potentially improving neurocognitive function.

The study featured an extensive evaluation prior to randomization that included selection of new ART regimens, collection of disease histories, current HIV RNA and CD4 cell count levels, neurocognitive performance, and drug resistance testing. A multidisciplinary antiretroviral planning committee reviewed candidates' information and provided a list of suitable regimens, based on viral susceptibility, to primary care physicians. Specific regimens were also characterized as CNS-targeted or non-CNS targeted, based on their specific CNS penetration ability.

A total of 59 participants were randomized to receive either a CNS penetrating or non-CNS penetrating regimen. Participants had to be on either stable ART or no ART for 8 weeks prior to starting the trial and tests showing impaired neurocognitive performance. Major neurocognitive co-morbidities or active substance use or dependence were not allowed.

The primary endpoint was change in neurocognitive performance based on difference in global deficit score (GDS) from week 0 to 16 (adjusting for initial performance). Secondary endpoints included secondary neurocognitive outcomes, HIV viral load, CD4 cell count, and regimen safety and tolerability. The researchers used an intent-to-treat analysis as well as a secondary as-treated sensitivity analysis.

Results

• After 16 weeks on the selected regimen, CNS-targeted therapy yielded only modest improvement in neurocognitive function among patients diagnosed with HIV-associated neurocognitive disorders.
• CNS-targeted ART yielded a slight but non-significant benefit in neuropsychological performance compared with non-CNS-targeted ART.
• The difference in standardized effect size between the arms was 0.09, or
• < 0.4 which is considered a small difference.
• Essentially, there was not a significant difference between the 2 treatment arms, yet among people who were ART-naive the difference was greater.
• The group on CNS-targeted therapy had lower rates of viral suppression in both plasma and CSF.
• This may be related to lower CD4 cell nadir (lowest-ever level) and higher prevalence of hepatitis C coinfection in the CNS-targeted group.
• Researchers found no difference in safety, tolerability, or drop-out rates between the 2 arms.

The trial had originally intended to enroll 120 patients to provide higher statistical power, but ended up stopping early due to slow patient accrual and low likelihood of detecting differences between the arms.

Alzheimer's-like Neurocognitive Disease

Turning to another neurological topic, a study by Lucette Cysique from St. Vincent’s Hospital in Sydneyand colleagues in Australia and the UK found that slightly more than 10% of older Australian patients with well-controlled HIV had CSF marker profiles consistent with those of Alzheimer's disease -- 10 times higher than in the general population of the same age.

There has not been a clear understanding of Alzheimer’s risk in people with HIV because it is not a simple condition to assess. Essentially, researchers are looking at 2 manifestations -- older age plus APOE genotypes and HIV disease.

In this analysis the investigators wanted to begin defining an Alzheimer’s risk profile. The study looked at 44 HIV positive people with undetectable plasma and CSF viral load, as well as 2 control groups of 5 HIV negative people with Alzheimer's disease and 3 older HIV negative control subjects. The researchers analyzed CSF biomarkers at baseline in order to evaluate risk for Alzheimer’s, using established published cut-offs with optimal sensitivity and specificity.

Results

• Among the HIV positive patients, 11.4% (5/44) had a CSF Alzheimer’s profile (4.5% had profile 1, 7.1% had profile 2, and 6.8% had profile 3; 1 case met the criteria for all 3 cut-offs).
• When comparing HIV positive patients with and without Alzheimer’s disease CSF profiles, there was no age difference, but those Alzheimer's profiles had a lower nadir CD4 cell count (117 vs 181 cells/mm³), longer duration of HIV infection (23 vs 19 years), and greater neurocognitive impairment (mean T score 39 vs 49).
• 30% of the HIV positive group carried at least 1 copy of the APOE ε4 allele, irrespective of CSF-Alzheimer's profiles.
• Past immune compromise and longer HIV duration influenced CSF-Alzheimer’s profiles, while age and carriage of APOE ε4 allele did not.
• 5 factors predicted having an Alzheimer’s profile: APOE genotype ε4/ε4, lower current neurocognitive performance, history of HIV-associated dementia, lower nadir CD4 count, and longer HIV duration, but the latter 2 factors were not statistically significant.

According to this study, some people with chronic HIVdisease appear to be at higher risk for having an Alzheimer’s-like profile based on their CSF biomarkers. The risk prevalence is more than 10 times higher than the Alzheimer’s prevalence in the general population of the same age. The researchers noted, however, that it still is not clear whether the prognostic profiles they used in the trial have prognostic implications for people with HIV.

References

R Ellis, F Vaida, S Letendre, et al. A randomized, controlled trial of a central nervous system–targeted ART strategy for HIV associated neurocognitive disorders. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 20.

L Cysique, J Lamoury, T Hewitt, et al. Prevalence of CSF Alzheimer's disease-like profile in chronic middle-aged HIV+ individuals. 20th Conference on Retroviruses and Opportunistic Infections. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 442.

Other Source

S Letendre, R Ellis, B Best B, et al. Penetration and effectiveness of antiretroviral therapy in the central nervous system. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 8(2):169-183. 2009.