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Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy

Price, Richard W.a; Yiannoutsos, Constantin T.b; Clifford, David B.c; Zaborski, Lawrenceb; Tselis, Alexd; Sidtis, John J.e; Cohen, Brucef; Hall, Colin Dg; Erice, Alejoe; Henry, Keithe; for the AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team

Clinical: Original Papers

Objective: In a large multi-center clinical trial of combination reverse transcriptase inhibitors (RTIs), we assessed the impact of antiretroviral therapy on neurological function, the relationship between neurological and systemic benefit, and the prognostic value of neurological performance in late HIV-1 infection.

Design: Neurological evaluations incorporated in a randomized, multi-center trial of combination antiretroviral therapy.

Setting: Forty-two AIDS Clinical Trials Group sites and seven National Hemophilia Foundation sites

Patients: Adult HIV-infected patients (n=1313) with CD4 counts < 50×106 cells/l.

Interventions: Four combinations of reverse transcriptase inhibitors consisting of zidovudine (ZDV), alternating monthly with didanosine (ddI), or in combination with zalcitabine (ddC), ddI or ddI and nevirapine.

Main outcome measures: Mean change from baseline of a four-item quantitative neurological performance battery score, the QNPZ-4, administered to 1031 subjects.

Results: Triple therapy and ZDV/ddI combination preserved or improved neurological performance over time compared with the alternating ZDV/ddI and ZDV/ddC regimens (P<0.001), paralleling their impact on survival in the same trial as previously reported. QNPZ-4 scores were predictive of survival (P<0.001), after adjusting for CD4 counts and HIV-1 plasma RNA concentrations.

Conclusions: Combination antiretroviral therapy can have a salutary effect on preserving or improving neurological function. Superior systemic treatments may likewise better preserve neurological function. The significant association of poor neurological performance with mortality, independent of CD4 counts and HIV-1 RNA levels indicates that neurological dysfunction is an important cause or a strong marker of poor prognosis in late HIV-1 infection. This study demonstrates the value of adjunctive neurological measures in large therapeutic trials of late HIV-1 infection.

From the aUniversity of California, San Francisco, CA, the bHarvard School of Public Health, Boston, MA, the cWashington University, St. Louis, MO, dUniversity of Pennsylvania, Philadelphia, PA, the eUniversity of Minnesota, St Paul, MN, the fNorthwestern University, Chicago, IL, and the gUniversity of North Carolina, Chapel Hill, NC, USA. * See Appendix.

Sponsorship: Supported by the Adult AIDS Clinical Trials Group (AACTG) and the Statistical and Data Analysis Center (SDAC; AI 38855) funded by the National Institutes of Allergy and Infectious Diseases; the NARC (P01 NS3228) funded by the National Institutes of Neurological Diseases and Stroke (NINDS); and NINDS P01-NS25701. Reagents for the plasma HIV RNA assays were provided by grants from Bristol-Myers Squibb, Glaxo-Wellcome, Boehringer Ingelheim, and Chiron Corporation.

Correspondence to Constantin T. Yiannoutsos, PhD, CBAR, Harvard School of Public Health, 651 Huntington Avenue, FXB 609, Boston, MA 02115, USA.Tel: (617) 432-3266; fax: (617) 432-3163; e-mail:

Received: 26 January 1999; revised: 17 May 1999; accepted: 27 May 1999.

© 1999 Lippincott Williams & Wilkins, Inc.