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Minocycline Does Not Improve HIV-Associated Neurocognitive Disorder
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Minocycline, an antibiotic with antinflammatory and neuroprotective properties, did not improve neurocognitive impairment in a placebo-controlled trial of 107 HIV-positive people [1]. US researchers speculated that the treatment period may have been too short or the dose used may not offer adequate central nervous system penetration--or that minocycline may just be an ineffective remedy for this problem.
HIV-associated neurocognitive disorder (HAND) continues to affect up to half of HIV-positive people in the current treatment era [2]. Because minocycline has both antiinflammatory and neuroprotective effects in in vitro models of HAND, ACTG A5235 investigators planned this double-blind, placebo-controlled trial.
The ACTG team enrolled 107 people with progressive cognitive impairment while taking a stable antiretroviral regimen, randomizing them to 100 mg of minocycline every 12 hours or matching placebo for 24 weeks. The investigators measured neurocognitive function with the 8-item neuropsychological z score (NPZ-8), which averages z scores from eight tests. The trial's primary outcome was change in composite NPZ-8 from baseline to week 24.
The 52 people randomized to minocycline and the 55 randomized to placebo did not differ substantially in age (average 51), education (average 14 years), gender (83% male), race (50% white, 42% black), history of injection drug use (23%), positive HCV status (23%), average CD4 count (543), proportion with a viral load below 30 copies in blood plasma (86%) or cerebrospinal fluid (93%), average CES depression score (7.21), or subjective neurocognitive decline (89%). Pretreatment NPZ-8 scores were also similar in the two groups.
Forty people randomized to minocycline and 43 randomized to placebo completed the 24-week double-blind phase of the trial.
In an intention-to-treat analysis adjusted for pretreatment neuropsychological test score and antiretroviral central nervous system penetration effectiveness score, NPZ-8 change did not differ significantly between the minocycline group and the placebo group (+0.12 and +0.17, P = 0.651). Changes in only one of the eight individual tests, a grooved-pegboard task, differed between groups, favoring the minocycline group (+0.46 versus +0.08, P = 0.017). At 24 weeks the minocycline group did not differ from the placebo group in functional measures or changes in CD4 count or viral load in plasma or cerebrospinal fluid.
One person taking minocycline reported thinking of suicide during the trial, and one person had tooth discoloration. Severe adverse events were more numerous in the placebo group and included general body pain in 2 and depression, fever, headache, cough, and vomiting in 1 each. Laboratory abnormalities could be detected in 25 placebo takers and 20 people taking minocycline. Ten people taking minocycline had mild to moderate hyperpigmentation, a recognized side effect of this antibiotic.
The ACTG researchers suggested several reasons why minocycline may not have improved cognitive function in this trial: (1) minocycline may be ineffective in treating HIV-associated neurocognitive disorders, (2) treatment was too brief, (3) the 100-mg dose is not high enough to penetrate the central nervous system adequately, (4) cognitive impairment in these people may be caused by factors not addressed by minocycline, such as comorbid conditions or medication side effects, or (5) minocycline-induced neuroprotection may be reflected only in cerebrospinal fluid markers or by neuroimaging. The investigators are evaluating neuroprotection markers in cerebrospinal fluid markers now.
References
1. Sacktor N, Miyahara S, Deng L, et al. Minocycline treatment for HAND: results from a multicenter trial. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 421. Poster online at http://www.retroconference.org/2011/PDFs/421.pdf.
2. McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann Neurol. 2010;67:699-714.
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