HIV-1 infection, particularly its late phase, AIDS, is complicated by a variety of neurological disorders that contribute importantly to both morbidity and mortality. Prominent among these is a syndrome impairing cognitive and motor function, the AIDS dementia complex (ADC)[1-5], which is also referred to by several other terms, including HIV-associated cognitive-motor complex. The cognitive impairment of early ADC is characterized by disturbances in attention, concentration and processing speed, and is characteristically closely tied to concomitant slowing in motor speed; together these characteristics have led to classification of ADC among the subcortical dementias[2,7,8]. While the pathogenesis of ADC is still uncertain in detail, the most widely held hypothesis is that ADC relates to an effect of HIV-1, itself, on the central nervous system (CNS) rather than to a secondary opportunistic infection or other process. Most theories invoke ‚indirect‚ mechanisms of brain injury that are driven by HIV-1, since productive infection within the CNS is confined predominantly, and perhaps exclusively, to macrophages and their resident CNS counterpart, microglia[9-11].
Whatever the intermediary steps linking HIV-1 infection to brain injury, if brain infection by the AIDS virus is indeed the prime mover in ADC pathogenesis, antiretroviral therapy represents a rational approach to its prevention and treatment. Indeed, this approach is supported by a number of studies of zidovudine (ZDV) monotherapy[12-15]. However, there has been limited study of the effect of other antiviral treatments, and particularly of combination drug regimens, on this aspect of HIV-1 infection[16-19]. There are several reasons why this issue has not been studied extensively in recent years. One of these relates to the difficulty of performing clinical trials that target subjects with diagnosed ADC. Although this approach may have the great advantage of utilizing a relatively homogeneous study population, implementing such studies has been difficult because of ethical considerations involving treatment randomization and blinding, and the inability to assemble a sufficiently large group of ADC patients meeting stringent entry criteria, particularly in adults. These obstacles have markedly impeded the timely assessment of the impact of newer treatments on ADC and the neurological morbidity of HIV-1 infection. As a result, there have been only limited recent efforts at prospective clinical trials for ADC.
In order to evaluate the feasibility of assessing the neurological impact of new antiretroviral drugs and drug combinations at an earlier stage in drug development and testing, we incorporated neurological evaluations into a multi-center AIDS Clinical Trials Group (ACTG) trial protocol 193A, comparing four reverse transcriptase inhibitors in antiviral regimens of largely neurologically asymptomatic late-stage HIV-1-infected subjects. These evaluations were of two types: a more intensive, detailed evaluation, the macro-neurological evaluation which included a standardized bedside neurological history and examination along with a number of quantitative ‚neuropsychological‚ tests. This macro evaluation was performed at centers with specialized expertise on a limited subset of subjects. The second evaluation was an abbreviated micro-neurological evaluation consisting of a brief questionnaire, derived from the macro-neurological history, and a subset of four of the quantitative tests selected from the macro evaluation. The micro evaluation was used to assess the majority of enrolled subjects at all participating centers. A more detailed methodological treatise dealing with these two approaches and a comparison of their uses and results, which were similar, will be presented in a future analysis. At this time we report only the results of the primary outcome measure of the micro-neurological assessment; the combined score derived from the four quantitative tests. These quantitative neurological performance measures assess functions characteristically altered by ADC, particularly timed simple and complex motor performance, and can serve as surrogate markers for clinical outcome[14,16,22-24]. In the present study, these performance measures showed the superiority of two of the study arms with respect to neurological outcome commensurate with their impact on systemic disease.
Materials and methods
The parent trial, ACTG protocol 193A, was a multi-center, randomized, double-blind study designed to determine the relative clinical efficacy of four regimens of reverse transcriptase inhibitors in HIV-1-infected persons with advanced disease: (1) zidovudine (ZDV) 200 mg three times a day alternating monthly with didanosine (ddI) 200 mg twice a day (alternating monotherapy); (2) ZDV 200 mg three times a day plus zalcitabine (ddC) 0.75 mg three times a day (ZDV/ddC); (3) ZDV 200 mg three times a day plus ddI 200 mg twice a day, adjusted to 150 mg twice daily in subjects under 60 kg (ZDV/ddI); and (4) ZDV 200 mg three times a day plus ddI 200 mg three times a day (dose was adjusted as in the third regimen) plus nevirapine 200 mg twice a day, started at once daily and increased to twice daily after 4 weeks (triple therapy). Entry criteria included a CD4 T-lymphocyte count < 50×106 cells/l, and the primary endpoint was survival (time from enrollment to death). This trial has been reported in detail elsewhere.
A total of 1313 subjects enrolled in the parent study between January 1993, and June 1996. Patients were stratified according to the duration of prior nucleoside antiretroviral therapy (longer versus less than 18 months prior to study entry), AIDS defining diagnosis (‚simple‚ or ‚complex‚), and Karnofsky score (below versus above 80). Appropriate placebos were provided for all drugs.
Neurological sub-studies and assessments
The micro-neurological assessment consisted of a brief clinical questionnaire and four quantitative ‚neuropsychological‚ performance tests derived from the larger macro-neurological assessment. It was administered to the majority of 193A subjects at baseline, at 4 weeks after starting therapy and at 16-week intervals thereafter. The five-item questionnaire queried symptoms related to concentration and quickness of thinking, attention in reading and watching television, difficulty with memory, walking and hand coordination. Each response was scaled to a range of five levels: normal; mild, moderate, or severe impairment; and complete loss of use. The questionnaire was used for screening and for simple categorization of symptom severity but was not intended as a quantitative outcome instrument. The four components of the quantitative performance battery were: timed gait, finger tapping (dominant hand), grooved pegboard (dominant hand) and digit symbol[23,25-27]. These individual tests were selected on the basis of the simplicity of their administration in the outpatient clinic setting, reproducibility, relatively low ‚practice effect,‚ acceptability by subjects for repeated testing, and capacity to measure the characteristic abnormalities of ADC and particularly the changes in these abnormalities over time[22,23]. The raw score on each of the four performance tests was standardized by subtracting the age-specific mean score from a cohort of HIV-infected, neurologically asymptomatic subjects, whose clinical neurological examinations were judged to be normal (JJ Sidtis, RW Price, BJ Brew unpublished data), and dividing that by the control standard deviation for that test to derive a normalized (‚z‚) score. The signs of each test were adjusted so that better-than-mean performance had a positive sign and worse-than-mean performance a negative sign. The four individual test z-scores were averaged to derive the principal outcome variable, the combined mean ‚quantitative neurological performance z-score,‚ termed the QNPZ-4. This composite score was thus a normalized deviation from zero, which is considered the ‚norm‚. At baseline, a positive value indicates neurological performance above the mean of the control group expressed in units equal to the standard deviation of the control group, and a negative value reflects similar units below that mean. Likewise, a positive change in QNPZ-4 score over time indicates improved performance and a negative change, a performance decline. Data on the QNPZ-4 battery were available on 1031 subjects.
Quantitative assessment of HIV-1 RNA in plasma was performed by a commercially available bDNA assay (Quantplex HIV-1 RNA Assay, Chiron Corporation, Emeryville, California, USA) which had a cutoff of quantitation at 500 genome copies/ml. Plasma viral load measurements were performed at the University of Minnesota on preserved samples. Analyses of HIV-1 RNA correlates at baseline, and week 8 and 24 were performed on data from a subset of 224 subjects with at least baseline QNPZ-4 evaluations, CD4 T-lymphocyte counts and HIV-1 RNA measurements. CD4 T-lymphocyte counts were performed by flow cytometry at the local ACTG-certified sites laboratories.
Comparisons of numerical variables were based on parametric linear models and non-parametric tests. Categorical variables were compared via the Fisher‚s exact test, and where appropriate, via the χ2 test. There were two types of multivariate analyses
Assessment of treatment benefit on neurological performance
This was assessed by comparison of the QNPZ-4 differences from baseline in the four treatment arms by a repeated-measures model that accounted for the correlation among successive evaluations on the same subject. Evaluations were limited to data up to week 52, since by this point a large number of subjects had left the study, markedly limiting any analysis and interpretation of data based on subsequent weeks.
Assessment of risk factors on patient survival
Risk factors were assessed by the Cox proportional hazards model  stratified over the four treatment arms. In that model, factors that were determined at baseline were regarded as fixed (such as Karnofsky score, AIDS-defining events and prior antiretroviral therapy). Markers that were routinely measured during the course of the study were considered as time-updated (such as QNPZ4, CD4 T-lymphocyte counts and HIV-1 RNA measurements).
Statistical tests were carried out at the 5% level of significance unless otherwise noted.
Analyses were performed on available observations, as well as on data with missing values replaced by the last available observation (last observation carried forward - LOCF - approach). Results were consistent in both cases. Only available-data analyses are presented here.
The results of the parent study are presented elsewhere. This report focuses on neurological measures, chiefly the QNPZ-4, which were available for 1031 out of 1313 study subjects. There was a relatively high attrition from the study treatment. Only 16% of subjects that started treatment completed the protocol on assigned treatment, and 119 subjects (9%) died while receiving the assigned treatment.
Treatment arms were balanced with respect to patient baseline demographic characteristics (Table 1). Only a minority of patients suffered from clinically overt neurological disease as indicated by the micro-neurological questionnaire. A small number of subjects had moderate or more severe reductions in memory (4.6%), ability to think quickly (2.8%), concentrate (3.1%), use of their hands (1.2%), or walking (1.6%). Study subjects performed below the control group as implied by the negative standardized component quantitative test and combined QNPZ-4 scores (Table 2). QNPZ-4 scores were balanced among the four treatment arms.
Effect of antiviral treatment on neurological performance
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.
QNPZ-4 as a prognostic factor of patient survival
Analyses based on the neurological cohort (1031 patients)
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).
Analyses based on the virology sub-cohort (224 patients)
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.
ADC is among the most common of the major CNS complications of HIV-1[30,31]. A number of studies have supported the efficacy of antiretroviral therapy in treating ADC in adults[14-17]. However, most of these reports, and particularly the reports of controlled clinical trials have described the effects of ZDV administered as monotherapy[14,15]. Although emerging individual reports and case series suggest a prophylactic or therapeutic effect of combination antiretroviral therapy on ADC[18,19,32], there still remains a remarkable dearth of direct study of this issue. Although the specific drug regimens studied here are no longer representative of contemporary recommended therapies, , the results nonetheless support the general contention that combination therapy has a salutary effect on neurological outcomes, indeed that the neurological effects parallel those on systemic disease and survival. The results of this study also indicate that neurological status is an independent predictor of survival.
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. Cited Here...