382b
Suppression of HIV Replication in Plasma Requires Suppression of HIV Replication in Cerebrospinal Fluid
Christina Marra*1, S Sinha2, D Clifford3, S Evans2, S Letendre4, R Ellis4, F Aweeka5, G Schifitto6, R Coombs1, K Robertson7, and Adult AIDS Clinical Trials Group 736 Team
1Univ of Washington, Seattle, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Washington Univ of St Louis, MO; 4Univ of California, San Diego, US; 5Univ of California, San Francisco, US; 6Univ of Rochester, NY, US; and 7Univ of North Carolina at Chapel Hill, US
Background: HAART for HIV may
decrease cerebrospinal fluid (CSF) HIV RNA and improve neuropsychological
function. Consensus has not been reached regarding whether regimens that
include agents that penetrate the central nervous system (CNS) improve these
outcomes.
Methods: Adult AIDS Clinical
Trials Group (ACTG) study 736 was a multi-site longitudinal natural history
study conducted at 15 adult ACTG units in the United States. Subjects with
advanced HIV disease beginning a new HAART regimen or changing an existing
regimen because of virologic failure were eligible for participation. Subjects
underwent a structured medical and medication history and neurological
examination, venipuncture and lumbar puncture, and neuropsychological tests
before and at 24 and 52 weeks after beginning therapy. Zidovudine, abacavir,
stavudine, nevirapine, efavirenz, lamivudine, and indinavir were defined as
agents with good CNS penetration. Regimens that contained 2 or more of these
agents were considered to have good CNS penetration. Generalized estimating
equations with an autoregressive correlation structure were used to examine the
association between variables at each time point.
Results: Of the 101 subjects
enrolled in the study, 77 either met a study endpoint or completed the study.
The odds of undetectable CSF HIV RNA were 3.10-fold (95%CI 1.03 to 9.30)
greater in those who took an antiretroviral regimen with good CNS penetration
and 3.49-fold (95%CI 1.20 to 10.18) greater in subjects who were
antiretroviral-naive. For every 1-log decrease in concurrent plasma HIV RNA,
the odds of undetectable CSF HIV RNA increased 2.94-fold (95%CI 1.96 to 4.35).
Also, for every 1-log decrease in concurrent CSF HIV RNA, the odds of
undetectable plasma HIV RNA increased 25-fold (95%CI 12.50 to 100.00).
Conclusions: Our data support
the hypothesis that control of CSF virus, which is more likely when an
antiretroviral regimen has good CNS penetration, is integral to suppression of
plasma viremia. These findings further suggest that the efficacy of a regimen
in CSF, and not just in plasma, should be considered when designing optimal
antiretroviral therapy. A longitudinal study of CSF and plasma virologic
response to antiretroviral regimens with good compared to poor CNS penetration
is needed to confirm the results of our observational study.
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