These analyses were based on 1031 subjects with at least baseline QNPZ-4 data. Treatment effects on neurological performance (as measured by changes in QNPZ-4 scores from baseline) were based on repeated measures models, in order to account for the correlation between successive QNPZ-4 measurements on each subject. Differences in neurological performance became progressively evident over time (treatment-by-week interaction P=0.004). This resulted from preservation of neurological performance in the combined triple therapy and ZDV/ddI arms in conjunction with progressive deterioration in the alternating monotherapy and ZDV/ddC regimens (ZDV/ddI plus triple therapy versus ZDV/ddC plus alternating monotherapy P<0.001; Fig. 1). Neither the comparison between triple therapy and combined ZDV/ddI treatment nor the comparison between ZDV/ddC and alternating monotherapy were statistically significant. The effects of several baseline factors including Karnofsky score, duration of prior antiretroviral therapy, AIDS-defining events, and baseline QNPZ-4 scores were assessed, but only baseline QNPZ-4 was significantly associated with on-study QNPZ-4 difference scores (P<0.001). Subjects scoring higher at baseline also had the largest decreases in QNPZ-4 scores (reductions in neurological performance) during the study.
Treatment effects on neurological performance closely paralleled those on survival as described by Henry et al.. In the parent study, triple therapy was shown to be superior in terms of survival, compared with alternating monotherapy and the combination of ZDV/ddC, although again the difference in survival between the triple therapy and combination ZDV/ddI was not significant.
Neurological performance, as measured by QNPZ-4, was strongly associated with patient survival even after adjusting for counts of CD4 lymphocytes (Table 3). This analysis was based on the whole neurological cohort (1031 subjects). AIDS-defining events (complex versus simple), lower baseline Karnofsky score (<80 versus >80), and lower CD4 count were also significant prognostic factors of mortality (P<0.001 in all cases). Even after accounting for these factors, QNPZ-4 decreases were statistically significant predictors of survival (P<0.001).
The prognostic effect of QNPZ-4, along with that of CD4 T-lymphocyte counts and baseline factors including Karnofsky score, duration of prior antiretroviral use, and AIDS defining events, was also examined in the subgroup of 224 subjects for whom at least baseline QNPZ-4, CD4 counts and HIV-1 plasma RNA concentrations were available. Analyses measured the impact on subsequent survival of baseline plasma HIV-1 RNA levels as well as changes from baseline to week 8 or week 24 (addressing short- and medium-term virologic responses respectively). Baseline viral load as well as increase in viral load from baseline to week 8 were significant predictors of patient outcome (P<0.001 and P<0.001 respectively). However, viral load change from baseline to week 24 was not (P=0.210). In the analysis of viral load changes to week 8 and 24, longer duration of prior antiretroviral therapy was associated with higher risk of death (P=0.010 and 0.021 respectively), possibly reflecting longer duration of symptomatic disease, or the development of resistance to antiretroviral therapy. Decreases in QNPZ-4 were associated with shorter survival, even after accounting for HIV plasma viral load and CD4 count fluctuations (Table 4). This means that among patients with similar CD4 cell counts, plasma HIV-1 viral load at baseline, and similar virologic response to antiretroviral therapy, those with preserved neurological performance were at lower risk of death compared to those with neurological deficits.
The four treatment arms investigated in this trial were not equally effective in influencing neurological outcome. Indeed, their relative impact on neurological performance largely paralleled their benefits on systemic disease. The triple therapy was superior in preserving neurological performance, compared with alternating monotherapy and combination ZDV/ddC, but no statistically significant improvement was discerned between the triple therapy and combination ZDV/ddI despite early trends favoring the triple therapy over the ZDV/ddI combination (Fig. 1). From these results, it is difficult to formulate definite conclusions regarding the relative efficacy of individual drugs in preventing or treating ADC. All regimens contained ZDV, a drug with relatively good CNS penetration  that has been the mainstay of ADC treatment in the monotherapy era. This neurological substudy showed that alternating monthly dosing of ZDV with ddI was less effective than simultaneous dosing of the two drugs in its neurological effect, just as it is in its systemic effect. Neither ddI nor ddC have been reported to penetrate well into the CNS. However, the addition of ddI to ZDV appeared to have a salutory effect on neurological outcome thus implying perhaps that drug penetration is only one possible factor in neurological treatment and that systemic efficacy may be even more important. Although nevirapine has favorable blood-brain-barrier penetration, this study did not provide clear evidence that this drug afforded additional neurological or systemic benefit despite consistently observed improvement over double therapy. Further assessment of nevirapine and other CNS-penetrating versus non-penetrating drugs (including the protease inhibitors) will require a more targeted study design.
There are a number of factors that might have contributed to attenuating the capacity of this study to detect treatment differences. There was differential dropout from the inferior treatments. The overall median time on treatment was 41.3 weeks. Subjects stayed on assigned treatment for a median of 37 weeks on alternating monotherapy, 38.9 weeks on ZDV/ddC, 43.6 weeks on ZDV/ddI, and 48 weeks on triple therapy. Because neurological deterioration was associated with increased mortality, the most neurologically impaired subjects may have selectively dropped out from the inferior treatment arms, while being retained at higher rates in the superior arms (either by preservation of neurological function, survival, or both). In addition, as many of the subjects were on the study treatment for only a limited period, the observed treatment effect was likely attenuated further. On the other hand, study subjects had variable prior experience with the treatment drugs, and hence would be expected to sustain a range of virological responses based upon development of antiviral drug resistance. Although this hypothesis was not directly tested, longer duration of antiretroviral therapy prior to study enrollment was an important prognostic factor of poor outcome. Most study patients were neurologically asymptomatic, or suffered only mild symptoms. Moreover, the range of change in neurological function likely to be observed was relatively small, at least in the aggregate. In one direction the possible range of changes in neurological status over time was limited to improvement in subclinical disease with a nearby ceiling effect. In the opposite direction, deterioration in function might result in selective dropout either when subjects were no longer able to continue on the protocol because of neurological impairment or when they actually died early as predicted by their neurological disease. Indeed, in this study the major drug treatment effect documented was in sustaining neurological function rather than in improving function, and hence the major effect was in preventing ADC rather than in its reversal. For these reasons, it is especially notable that we found treatment differences with respect to neurological preservation.
The study also demonstrates that neurological performance, as measured by the QNPZ-4 test battery, is a prognostic factor of patient survival. This finding confirms and extends in a prospective therapeutic trial setting previous observations that neurological impairment, from milder neurological dysfunction to overt ADC, is associated with high mortality[30,37-42]. Decline in neurological function is, therefore, either a marker for or more direct contributor to death. Development of ADC is a late complication of HIV-1 infection and may therefore indicate a late virological and immunological milestone in its course. Because of its association with direct brain infection, it signals advancing extra-lymphatic infection and important dysregulation of the immune system[11,43]. Advanced ADC may, in itself, be fatal as it leads to secondary infection, poor fluid and food intake and other sequelae. It also alters treatment compliance and persuades both patients and those assisting in their life decisions to limit further care.
The four components of the QNPZ-4 battery are simple to administer and evaluate, and together provide a balanced instrument for following neurological performance over time. Although not a substitute for clinical diagnosis, they are also of ancillary value in clinical assessment. Our analyses indicate that poor neurological performance, as measured by the combined QNPZ-4 score, provides a prognostic indicator for survival independent of both CD4 lymphocyte counts and plasma RNA concentrations. Although the magnitude of this effect was surprising, it provides an additional external ‚validation‚ of this type of quantitative neurological evaluation as a useful component of AIDS study. Wider implementation of this strategy would allow earlier assessment of new treatment regimens on neurological outcomes, and hence on an important aspect of HIV-1-related morbidity and mortality.
In conclusion, these observations emphasize the frequency of declining neurological performance in late HIV-1 infection, and suggest that systemically effective combination antiretroviral therapy can alter this natural history. Neurological impairment is not only a source of direct morbidity but also a predictor of survival independent of information provided by CD4 lymphocyte counts and plasma viral load. It is currently uncertain whether therapies specifically ‚tailored‚ to treat this neurological dysfunction are necessary, most notably by the inclusion of CNS-penetrating drugs, or whether simply treating systemic infection is effective in secondarily alleviating neurological outcomes. Although the current study might be invoked to support the latter, it was not structured to more specifically address this question. Moreover, there may be differences in treatment requirements for early versus late HIV-1 infection and for prevention (predominating in this study) versus therapy of established ADC. Because of the relative ease of incorporating the QNPZ-4 assessment into clinical trials, this methodology might be useful in addressing these important issues which otherwise will remain imprecisely answered by current approaches to assessing efficacy of combination drug regimens.
The authors are very grateful for the co-operation of all the participating investigator and study patients.
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Participating sites and investigators
M. Glicksman PhD, W. G. Powderly, MD, Washington University; S. Swindells, MD, G. Rudberg, RN, MS, University of Minnesota; C. Cooper, RN, H. Kessler, MD, Northwestern University; M. Borucki, MD, P. Galatas, RN, University of Texas Galveston; C. van der Horst, MD, C. Kapoor, MD, K. Robertson, PhD, W. Robertson, MS and the University of North Carolina GCRC; D. Simpson, MD, D. Dorfman, PhD, Mt. Sinai Medical Center; B. Sinclair, PhD, C. Olson, RN, University of Southern California; K. Marder, MD, M. Crawford, RN, Columbia Presbyterian Medical Center; T. Flynn, ANP, C. Wanke, MD, D. Craven, MD, Harvard University; J. Reid, RNC, MS, R. Holloway, MD, University of Rochester Medical Center; K. Fife, MD, PhD, K. Todd, RN, MSN, Indiana University Hospital; C. M. Marra, MD, A. C. Collier, MD, D. Cummings, ARNP, University of Washington, Seattle; K. L. Tyler, MD, B. A. Putnam, RN, ANP, University of Colorado Health Sciences Center; H.Hollander, MD; J. Walker, PhD; San Francisco General Hospital; I. Matozzo, RN, I. Frank, MD University of Pennsylvania; P. Kumar, MD, Georgetown University; M. Guerrero, MD, S. Kruger, MS, UCLA; M. Fischl, MD, E. Scerpella, MD, A. Rodriguez, MD, University of Miami; P. T. Frame, MD, S. Kohrs, RN, BSN, University of Cincinnati; M. Lederman, MD, Case Western Reserve University; G. Vazquez, MD, I. Lopez, MD, University of Puerto Rico; R. Delapenha, MD, Y. Butler, MD, Howard University; M. Saag, MD, K. E. Squires, MD, S. Deloach, RN, B. McCulloch, MSN, University of Alabama; E. Cooney, MD, C. Frank, RN, Yale University; M. J. Nealon, RN, L. Ponticello, RN, Memorial Sloan-Kettering Cancer Center; R. Soeiro, MD, Albert Einstein College of Medicine; F. Valentine, MD, M. Vogler, MD, New York University; K. Chirgwin, MD, SUNY Health Sciences Center, Brooklyn; S. Szebenyi, MD, Albany Medical College; M. Rinki, RN, BSN, D. Slamowitz, RN, BSN, Stanford University; D. Ogata-Arakaki, RN, M. Millard, RN, University of Hawaii; R. Ellis, M.D., R. Snyder, RN, University of California, San Diego; NHF Region III: M. E. Eyster, MD, C. Ehmann, MD, M. S. Hershey Medical Center; C. Kessler, MD, C. Quinlan, MD, George Washington University; NHF Region I: D. B Brettler, MD, P. Forand, RN, New England Hemophilia Center, Memorial Health Care; NHF Region II: S. Seremetis, MD, Mount Sinai Medical Center; M. Brady MD, J. Hunkler RN, Ohio State University; NHF Region IV: H. Saba, MD, B. Tannenbaum, RN, University of South Florida; NHF Region VI; K. Hoots, MD, University of Texas Health Sciences Center; NHF Region IX: T. D. Coates, MD, A. Sosa, MS, Children‚s Hospital of Los Angeles; M. A. South, MD, Meharry Medical College; A. Rubinstein, MD, J. Weiler-Einstein/Pediatric; NHF Region V: J. Gill, MD, P. Timmons, RN, MS, Blood Center of Southeastern Wisconsin; NHF Region VIII: S. Stabler, MD, S. Giambartolomei, RN, University of Colorado Health Sciences Center; P. Clax, MD, DAIDS; A. Kenton, BS, L. Underwood, RN, Social & Scientific Systems, AACTG Operations Center; C. Tierney, PhD, Statistical and Data Analysis Center.