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Brain-Breaching Antiretroviral Score Not Tied to Neuropsych Function in Canada
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
A better antiretroviral central nervous system penetration effectiveness (CPE) score did not predict better overall neuropsychological performance in a 529-person Ontario study, although there were significant correlations with some specific tests and neuropsychological domains [1]. The findings add to mixed results of studies assessing the value of CPE scores in ranking antiretroviral regimens for their ability to penetrate the brain and thus prevent or remedy neurocognitive impairment.
US researchers proposed the CPE score in 2006 [2] and updated it in 2010 [3]. Both of those studies linked CPE scores to HIV RNA levels in cerebrospinal fluid. But attempts to correlate CPE scores with better or worse neuropsychological performance or central nervous system disease have yielded inconsistent results [4-6].
The new study involved 529 people in the Ontario HIV Treatment Network who underwent neuropsychological testing [1]. The four tests (digit symbol, grooved pegboard, spatial span, and Hopkins verbal learning) assess working memory, complex psychomotor efficiency, dexterity, and verbal learning/memory. These tests evaluate people in three broad domains--motor efficiency, spatial working memory, and memory. The investigators hypothesized that people taking antiretroviral combinations with higher CPE rankings would perform better overall on measures of neuropsychological functioning.
Most study participants (83%) were men, and most (61%) were white. Age averaged 48.6 years, education 13.8 years, and time with HIV infection 13.1 years. Two thirds of the study group (67.5%) had a lowest-ever (nadir) CD4 count below 200, and 46% had a recent CD4 count under 500. About 90% of these people had an undetectable viral load in blood. Only 12% reported depressive symptoms, and only 13% reported substance use in the past 6 months.
The Ontario team calculated both the 2006 CPE score [2] and the 2010 score [3] for these cohort members. The 2010 CPE score ranks three antiretrovirals as the best CNS penetrators with a score of 4, none of them in the first antiretroviral rank in developed countries (zidovudine, nevirapine, and indinavir/ritonavir), followed by 10 antiretrovirals with a score of 3 (abacavir, emtricitabine, delavirdine, efavirenz, darunavir/ritonavir, fosamprenavir/ritonavir, unboosted indinavir, lopinavir/ritonavir, maraviroc, and raltegravir), six with a score of 2 (lamivudine, stavudine, etravirine, unboosted atazanavir, atazanavir/ritonavir, fosamprenavir/ritonavir), and eight with a low score of 1 (tenofovir, didanosine, zalcitabine, nelfinavir, ritonavir, saquinavir/ritonavir, tipranavir/ritonavir, and enfuvirtide).
With 2006 scoring, 53% of patients had low CNS penetration (score at or below 1.5) and 47% had high penetration (score above 1.5). With the 2010 system, 40% had a low score (at or below 7) and 60% had a higher score (above 7).
Neither the 2006 CPE score nor the 2010 CPE score correlated with a global deficit score at or above 0.5, the cutoff used in this study. Statistical analysis adjusted for age, race, gender, education, HCV diagnosis, current CD4 count, nadir CD4 count, high versus low CPE, duration of HIV infection, drug use in the last 6 months, and depressive symptoms disclosed no significant associations between either the 2006 score or the 2010 score and a global impairment rating, global deficit score above 0.5, or global deficit score above 1.0.
The study did identify correlations between the 2006 CPE score and (1) better spatial span results and (2) better results in the working memory domain, and between the 2006 CPE and (1) worse results in the digit symbol test and (2) worse results in the motor efficiency domain. But the 2010 CPE score did not correlate with these or any other individual neuropsychological test results or domains.
The Ontario investigators suggested that continuing studies on CPE score and neurocognitive function should explore the timing and length of antiretroviral therapy and confounding conditions (such as HCV infection), while addressing methodological issues. Scott Letendre (University of California, San Diego), who has spearheaded efforts to develop and test the CPE score, proposed that cross-sectional studies such as this one may suffer from confounding because clinicians are increasingly aware of the CPE concept and may be prescribing high-score antiretrovirals for people with neurocognitive problems. from Jules: another confounder is some patients have irreversible brain damage so HAART with a high CPE score may not help them, so if these patients are included in the analysis that makes it much more difficult to find a benefit.
References
1. Rourke SB, Carvalhal A, Zipursky AR, et al. Examining the impact of CNS penetration effectiveness of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living with HIV: findings from the Ontario HIV Treatment Network (OHTN) cohort study. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract MOAB0104.
2. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65:65-70.
3. Letendre S, FitzSimons C, Ellis R, et al, and the CHARTER Group. Correlates of CSF viral loads in 1221 volunteers of the CHARTER cohort. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 172.
4. Garvey L, Winston A, Walsh J, et al; UK Collaborative HIV Cohort (CHIC) study. Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease. Neurology. 2011;76:693-700.
5. Smurzynski M, Wu K, Letendre S, et al. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS. 2011;25:357-365.
6. Tozzi V, Balestra P, Salvatori MF, et al. Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive disorders. J Acquir Immune Defic Syndr. 2009;52:56-63.
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