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AIDS Dementia Complex

AIDS dementia complex (ADC) is one of the most common neurological complications of late HIV infection. It causes the loss of mental function, affecting the ability to function in a social or occupational setting. more...

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AIDS dementia complex (ADC) is characterized by cognitive dysfunction (trouble with concentration, memory and attention), declining motor performance (strength, dexterity, coordination) and behavioral changes. It occurs primarily in more advanced HIV infection when the CD4 cell counts are relatively low. Other terms for this condition are HIV-associated cognitive motor complex and HIV-associated dementia.

As many as 33% of adults and 50% of children with HIV experience AIDS dementia. Prior to the onset of HAART (Highly Active Anti-Retroviral Therapy), the incidences were much greater.

While the progression of dysfunction is variable, it is regarded as a serious complication and untreated can progress to a fatal outcome. Diagnosis is made by neurologists who carefully rule out alternative diagnoses. This routinely requires a careful neurological examination, brain scans (MRI or CT scan) and a lumbar puncture to evaluate the cerebrospinal fluid. No single test is available to confirm the diagnosis, but the constellation of history, laboratory findings, and examination reliably establish the diagnosis when performed by experienced clinicians. The amount of virus in the brain does not correlate well with the degree of dementia, suggesting that secondary mechanisms are also important in the manifestation of ADC.

AIDS Dementia Complex (ADC) is not a true opportunistic infection. It is one of the few conditions caused directly by the HIV virus. But it is not quite as simple as that because the central nervous system can be damaged by a number of other causes:

  • opportunistic infections - there are many
  • direct effects of HIV in the brain
  • toxic effects of drug treatments
  • malnutrition

Those with ADC have HIV-infected macrophages in the brain. That means HIV is actively infecting brain cells.

Symptoms of ADC include: Early - symptoms of AIDS Dementia can be confused with general manifestations of clinical depression. These include apathy, loss of interest in one's surroundings and the like. Later - symptoms involve cognitive and motor problems. Memory loss, as well as mobility problems, come into the picture.

Many researchers believe that HIV damages the vital brain cells, neurons, indirectly. According to one theory, HIV either infects or activates cells that nurture and maintain the brain, known as macrophages and microglia. These cells then produce toxins that can set off a series of reactions that instruct neurons to kill themselves. The infected macrophages and microglia also appear to produce additional factors chemokines and cytokines - that can affect neurons as well as other brain cells known as astrocytes. The affected astrocytes, which normally nurture and protect neurons, also may now end up harming neurons. Researchers hope that new drugs under investigation will interfere with the detrimental cycle and prevent neuron death.


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Treatment of early AIDS dementia in intravenous drugs users: high versus low dose Peptide T
From American Journal of Drug and Alcohol Abuse, 11/1/97 by Thomas R. Kosten


Peptide T, an analog of vasoactive intestinal peptide (VIP), was developed to counter the neurotropic effect of the HIV virus and possibly reverse AIDS dementia complex (ADC) (1-6). This octapeptide is an analog to the HIV envelope glycoprotein GP-120, which is thought to bind to the CD4 receptor. Initial clinical trials with Peptide T were encouraging. Improvement in neuropsychiatric and constitutional symptoms were observed in a phase I trial (7) done with six men who received 0.033 to 0.27 mg/kg intravenously every 8 hours for 30 days. In a subsequent 20-week open-label trial (8), significant improvement in cognitive functioning was noted in 14 men who received Peptide T intravenously for 12 weeks in doses ranging from 0.1 to 3.2 mg/kg per day. Subsequent work (9) suggested that lower doses of an intranasal form of the drug may be as, if not more, efficacious as higher doses.

This study was designed to extend the work done with this compound by examining the efficacy of two different doses of Peptide T in a sample of intravenous drug users using a nine-week, double-blind, placebo-controlled design. A cross-over design with both Peptide T doses was not undertaken because of concerns about carry-over effects between the two doses of Peptide T and the required length of hospitalization. Consequently, two groups of subjects were enrolled in this study at the two Peptide T doses. The effectiveness of the higher 15 mg daily intranasal dose was tested first, and in a preliminary within-subject analysis, these five subjects demonstrated improvement in cognitive functioning while receiving active medication (10). In this paper, we report the results of the full study which included a second group of four subjects who were treated in the same paradigm with a 10-fold lower dose. This lower dose was selected for the second phase of the study because preliminary data from an open-label trial done elsewhere (9) suggested that lower doses of Peptide T may be as efficacious.



Nine HIV seropositive intravenous drug users demonstrating moderate neuropsychological impairment completed the study after giving written informed consent. All subjects met DMS-III-R criteria for a diagnosis of opioid dependence, and all were maintained on an average of 53 mg of methadone daily (Range = 30 to 70 mg) while enrolled in the study. The two dosage groups were demographically similar. There were four men in each group and the average age in both groups was 42 years (Range = 39 to 46 years). Because AZT has also shown some efficacy in the treatment of ADC (11-15), all subjects were required to have been taking AZT for at least three months prior to their admission. All except one subject, whose dosage was 300 mg daily, continued to receive 100 mg of AZT five times daily during this trial. The substance abuse history for the two groups was also similar with a mean of 14 years of opioid abuse and 6 years of cocaine abuse. Potential subjects with neurological or psychiatric conditions that predated the onset of HIV-related disease were not allowed to participate. All subjects also demonstrated borderline to low average intelligence (Range = 75 to 96) on the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (16), and all demonstrated at least sixth grade reading ability on the Reading Recognition and Reading Comprehension subtests of the Peabody Individual Achievement Test (17).

Neuropsychological Assessment

To be eligible for admission to the study, all subjects had to meet criteria for moderate neuropsychological impairment. To do so each subject had to have two or more scores from a battery of five tests falling at least 1.5 standard deviations below the mean for the general adult population. The five screening measures included the Trail Making Test: Part B (18), the Auditory Verbal Learning Test (19), the Grooved Pegboard Test (20), the Stroop Color Word Test (21), and the Levin Revision of the Paced Auditory Serial Addition Test (22-24). The scores from these measures used to determine eligibility are noted in Table 1.

Statistical Analysis

To facilitate both comparison across measures and the computation of a single index of neuropsychological status, scores derived from each neuropsychological measure were converted to z-scores using the best available normative data for the general adult population. References indicating the sources of the normative data are cited above in the description of the test battery. A composite index representing neuropsychological status at baseline and the end of each drug trial was then computed for each subject by averaging z-scores representing degree of impairment in performance on each of the 16 outcome measures listed in Table 1. As is typically done, all scores were computed so that negative scores reflect greater impairment when compared with the norm for the general adult population.

A series of planned comparisons done within a repeated measures analysis of variance (ANOVA) was done to test for between-group differences in neuropsychological functioning. In these analyses, drug condition (baseline, placebo, and active) was the repeated factor and dosage (high vs. low) was the between-subjects factor. We also compared the two dosage groups during the active medication period both with and without adjustment for individual differences in the baseline scores. Finally, we tested for between-group differences during the active phase of the study using each of the 16 individual neurpsychological test scores as the dependent measure.


At baseline the number of tests indicating impairment of at least 1 standard deviation (SD) below the mean for the general population ranged from 5 to 14 out of 16 scores. At baseline on the composite of all 16 tests, the high-dose group had a mean impairment level of -0.74 SD (SEM = 0.13) and the low-dose group had somewhat greater impairment at -1.0 SD (SEM = 0.3). This difference did not prove statistically significant (t[7] = 0.8; N.S.).

On placebo the patients in the high-dose group improved to -0.25 SD (SEM = 0.12) and those in the low-dose group improved to -0.43 SD (SEM = 0.35). On Peptide T the patients in the high-dose group improved to -0.13 SD (SEM = 0.11) and those in the low-dose group improved to only -0.60 SD (SEM = 0.19). The dose effects at the three time points were not significant at baseline (F[1, 8] = 0.8; N.S.), or after placebo (F[1, 8] = 0.3; N.S.), but they were significant after Peptide T (F[1, 8] = 4.9; p < 0.05). To further examine this dosage difference after Peptide T, we performed an analysis of covariance adjusting for individual differences in baseline scores and found that the dosage difference remained significant (F[2, 8] = 5.7; p < 0.05). Furthermore, on the composite index four of five subjects on high-dose Peptide T, but only one of four subjects on low-dose Peptide T, improved more on Peptide T than placebo.

We had previously shown significant improvement with high-dose Peptide T using the initial five screening tests (10), but no significant improvement was shown with the low dose on the five tests (F[1, 3] = 0.2; N.S.). The 16 individual scores making up the composite were then compared between the two dosage groups after Peptide T. Three tests showed significantly better scores for the high dose group: Part A of the Trail Making Test (0.54 SD vs. -0.28 SD), the Digit Symbol test (-0.68 SD vs. -1.44 SD), and the score for the Grooved Pegboard trial done with the nondominant hand (0.1 SD above normal vs. -0.9 SD). No test showed a significantly better score for the low-dose group, and no differences were found by sequence, that is, whether placebo or Peptide T was given first.


In this placebo-controlled study comparing two dosages for Peptide T, we found that the higher intranasal dosage of 15 mg daily was significantly better than a 10-fold lower dose in reducing neuropsychological impairment in methadone-maintained patients with AIDS Dementia Complex (ADC). We had previously shown that the higher dose of Peptide T was significantly better than placebo in this population who were concurrently maintained on AZT (10). These results were consistent with previous trials among homosexuals with AIDS who were not maintained on AZT or methadone (7, 8, 9). We had undertaken this dosage comparison because previous studies in homosexuals who were not on methadone or AZT had good therapeutic success with dosages five to ten times lower than those in our initial study with methadone patients.

Several factors may have contributed to the poorer efficacy of this lower dosage among methadone patients including differences from homosexual patients and a marked level of improvement on placebo. In contrast to the studies in homosexuals using intravenous dosing, an intranasal route of administration was necessary in these studies due to poor venous access in former intravenous drug users. Intranasal dosing in these former substance abusers who also had used intranasal cocaine might lead to lower absorption due to erosion of the nasal mucosa. Thus, the high-dose group in our study may have been effectively getting a dose more closely approximating the low dose in the homosexual sample and our low-dose group may have gotten virtually no Peptide T. Blood levels of Peptide T are undetectable at these dosages, and levels need to be ascertained from cerebrospinal fluid, which was not available. Furthermore, the possible interactive effects of Peptide T with either methadone or AZT were not determined. Methadone may interfere with the activity of Peptide T by either inducing its metabolism and thereby lowering its effective dose or directly interfering with its anti-HIV effects (38).

All of our patients also showed substantial improvement from baseline whether they initially received placebo or Peptide T, making differences between placebo and Peptide T more difficult to detect with this small sample size. Some of the contributing factors to this improvement included improved nutrition, discontinuing all illicit drug use, and a more stable daily routine leading to better sleep and stabilization of concurrent medical conditions. In spite of this rather broad improvement associated with hospitalization, the two doses of Peptide T showed distinctly different effects compared to placebo. The high dose showed relative improvement in neuropsychiatric status compared to placebo, while the low dose did not. Furthermore, since these patients had already been stabilized on AZT, they may have derived some improvement in cognitive function from it. More Peptide T may be needed to counteract HIV viral effects in those brain cells that have not responded to AZT alone (11-15).

Finally, this study highlights some of the methodological problems associated with the execution of this type of clinical trial with HIV seropositive substance abusers. Cross-over designs that create benefits associated with the study of the same individuals under different conditions create the potential for carry-over effects and the need for extended hospital stays to ensure abstinence from drugs of abuse with the potential to alter neuropsychological performance as individuals cycle through states of intoxication and withdrawal. While between-subjects designs might be used for short hospital stays, they create a need for larger samples at greater cost to maintain the same level of statistical power. When working with this population, which has been largely excluded from clinical trials, there is also a need to isolate, as much as possible, neuropsychological impairment due to HIV disease from that due to acute and chronic effects of substance abuse, concurrent psychiatric disorders, neurological insult, and premordid learning, attentional, and intellectual disorders. The absence of repeatable neuropsychological batteries with thorough documentation of their psychometric properties in samples that adequately represent the general adult population also makes it difficult to document change that might be occurring in clinical trials where, even when there is a fairly consistent neuropsychiatric syndrome, different subjects will still demonstrate different patterns of impairment within any given battery of neuropsychological measures.

In summary, these preliminary data suggest that unlike studies in homosexual men with ADC, who were treated with intravenous Peptide T, relatively lower dosages of Peptide T given intranasally are unlikely to be effective in methadone-maintained patients with ADC who are also receiving AZT. Higher intranasal dosing of Peptide T may be needed to demonstrate meaningful improvement in neuropsychological functioning. Studies done in the future need to address some of the conceptual, methodological, and dosing issues highlighted by our experience with this pilot study.


Supported by National Institute on Drug Abuse Grants P50-DAO4060, R18-DA07190 and KO2-DAO112 (TRK).


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Thomas R. Kosten, M.D.(*)

(*) To whom correspondence should be addressed at VA Connecticut (Pyschiatry 116a), 950 Campbell Avenue, West Haven, CT 06516. Telephone: (203) 937-4914. Fax: (203) 937-4915/(203) 937-3886.

COPYRIGHT 1997 Taylor & Francis Ltd.
COPYRIGHT 2004 Gale Group

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